ࡱ> ;=*+,-./0123456789:}I \ o  o q` 20 x 109/LIIBlago krvarenje/po koja petehija, modrica ili blago krvarenje iz nosaBroj trombocita d" 20 x 109/LIIIZna ajno krvarenje, gastrointestinalno krvarenje, jaka hematurija, krvarenje iz nosa koje zahtijeva transfuziju crvenih krvnih zrnacaBroj trombocita d" 20 x 109/L i/ili zna ajno sni~enje hemoglobina (d" 100 g/L)IVKrvarenje u organe ili krvarenje koje ugro~ava ~ivot, krvarenje u CNS (Prema: Minchinton R, Blanchette V, Imbach P, Akatsuka JI, Nugent D. International Study on EARLY CHRONIC ITP in Children and Adolescents. ITP Staging.1995; Appendix 3.) Brojne internacionalne studije ispituju parametre relevantne za prognozu AITP. Takvim parametrima bi se moglo odrediti hoe li bolesnik razviti ranu kroni nu AITP i mo~e li lije enje kortikosteroidima ili intravenoznim imunoglobulinima (IVIG) poboljaati prognozu bolesti u djece s ranom kroni nom AITP (3). Trombociti su neophodni za normalno zgruaavanje krvi, tako da osobe koje imaju jako sni~eni broj trombocita mogu lako prokrvariti, a ponekad ta krvarenja mogu biti ozbiljna i po ~ivot opasna. Kada dijete prvi put dolazi na pregled, lije nik ne mo~e predvidjeti hoe li njegova bolest biti kroni na, jer se dijagnoza rane kroni ne AITP mo~e postaviti tek ako je bolest prisutna du~e od 6 mjeseci. Ameri ko udru~enje za hematologiju (engl. American Society of Hematology - ASH) je donijelo panel prakti nih smjernica i preporuka za dijagnozu i lije enje AITP u djece i odraslih (4). U djece je preporu eno da se dijagnoza AITP postavi na osnovu anamneze, fizikalnog pregleda, kompletne krvne slike i analize razmaza periferne krvi, koji e isklju iti ostale uzroke trombocitopenije. Analiza koatane sr~i (KS) se preporu a ako dijete ima perzistentnu trombocitopeniju, koja traje viae od 6-12 mjeseci ili kod one djece koja ne odgovaraju na terapiju IVIG-om. Nije potrebno hospitalizirati i lije iti djecu koja imaju broj trombocita u perifernoj krvi > 30 x 109/L, a nemaju simptome bolesti. Njima nije potrebno davati IVIG, kortikosteroide, niti anti-Rh(D) kao rutinsko lije enje. Djeca koja imaju broj trombocita < 20 x 109/L i zna ajna krvarenja iz sluznica, kao i djeca koja imaju broj trombocita < 10 x 109/L uz manju purpura, trebala bi biti lije ena kortikosteroidima ili IVIG-om. Djecu s teakim krvarenjem, koje im ugro~ava ~ivot, treba lije iti visokim dozama kortikosteroida, IVIG-om i transfuzijama trombocita. Ako se planira splenektomija, dijete treba preoperativno pripremiti IVIG-om (4). U odraslih osoba, prema preporuci ASH-a, dijagnoza AITP se mo~e postaviti takoer na osnovu anamneze, fizikalnog pregleda, kompletne krvne slike i analize razmaza periferne krvi, koji e isklju iti ostale uzroke trombocitopenije. Analiza KS se preporu a kod bolesnika starijih od 60 godina i onih kod kojih se predvia splenektomija. Ne hospitaliziraju se bolesnici iji je broj trombocita u perifernoj krvi > 20 x 109/L ako nemaju simptome bolesti ili imaju blagu purpuru. Oni iji je broj trombocita u perifernoj krvi > 50 x 109/L ne zahtijevaju rutinsko lije enje IVIG-om ili kortikosteroidima. Lije enje je indicirano u bolesnika s brojem trombocita u perifernoj krvi < 20 x 109/L i < 50 x 109/L ako imaju zna ajna krvarenja iz sluznica ili imaju rizi ne imbenike krvarenja kao ato su poviaen krvni tlak i pepti ki ulkus. Hospitalizacija se preporu a bolesnicima s brojem trombocita < 20 x 109/L i zna ajnim krvarenjima. Odrasli bolesnici s krvarenjem opasnim po ~ivot lije e se visokim dozama parenteralnih kortikosteroida, IVIG-om i transfuzijama trombocita (4). Razli iti patogenetski mehanizmi mogu biti odgovorni za nastanak akutnog ili kroni nog oblika ove bolesti. Jedan od moguih etioloakih imbenika je poremeaj ravnote~e citokina, koji je zamijeen u tih bolesnika (5-7). Danas se joa uvijek malo zna o ulozi citokina u autoimunoj patogenezi ove bolesti. Citokini su polipeptidi koji djeluju naj eae lokalno i vrlo su va~ni imbenici obrambenog sustava (8). Njihova aktivnost je izra~ena i u ekstremno niskim koncentracijama. U razli itim patoloakim stanjima citokini mogu imati sistemski u inak i tada se mogu otkriti u serumu bolesnika (8). Upalni citokini, kao ato su imbenik tumorske nekroze ( (engl. tumor necrosis factor ( - TNF-(), interferon-( (IFN-(), interferon-( (IFN-(), interferon-( (IFN-(), va~ni su u patogenezi autoimunih bolesti, reumatskih i ostalih bolesti vezivnog tkiva, kao i autoimunih endokrinih bolesti (9,10). Citokini imaju va~nu ulogu i u usmjeravanju imunoloake reakcije limfocita Th1 (engl.T helper  Th) i Th2 (11,12). Neravnote~a izmeu proinflamatornih Th1 i antiinflamatornih Th2 citokina pogoduje nastanku autoimunih bolesti (13). U bolesnika s kroni nom AITP primarno su naene poveane vrijednosti IL-2, IFN- i IL-10, ato se odra~ava na Th0- i Th1-stani nu aktivaciju (5). Razli iti antigeni, posebice virusi, mogu izazvati neravnote~u citokina. Grupa herpes virusa, primjerice citomegalovirus (CMV), Epstein-Barrov virus (EBV) (14-18), humani herpesvirus-6 (HHV-6) (19,20), adenovirus i parvovirus B19 su naj eai uzro nici infekcije u djece, a mogu oatetiti njihov imunosni sustav i izazvati odreeni oblik autoimune bolesti, izmeu ostalog i AITP. Tako je za HHV-6 pokazano da ima imunomodulatornu aktivnost poti ui lu enje TNF-( i IFN-( (20). Hipoteza od koje polazi ovo istra~ivanje jest da i u akutnoj AITP poremeaj citokinske ravnote~e igra va~nu ulogu u patogenetskom mehanizmu nastanka bolesti, te da se vjerojatno razlikuje u djece i odraslih ljudi. Svrha ovog doktorskog rada je, izmeu ostalog, procjena va~nosti i uloge citokina u patogenezi AITP i to posebno za one citokine za koje se zna da sudjeluju u regulaciji i kontroli limfopoetskog i mijelopoetskog sustava. 1.2. Trombociti Trombociti ili krvne plo ice su stanice bez jezgre, a nastaju iz citoplazme pupanjem membrane citoplazme svojih prete a megakariocita, koji su primarno smjeateni u KS, gdje ih ima 0,5% svih stanica. Oni nastaju iz primitivnih megakariocitnih kolonija (engl. burst forming units for megakaryocites - BFU-MK) i jedinica koje stvaraju kolonije za megakariocite u koatanoj sr~i (engl. colony forming units for megakaryocites - CFU-MK). Kolonije ovih stanica proliferiraju u megakariocite (slika 1).  SHAPE \* MERGEFORMAT  Slika 1. Zreli megakariocit Diferencijacija u zrele megakariocite odvija se pod djelovanjem razli itih citokina, uklju ujui trombopoetin, primarni fizioloaki regulator stvaranja trombocita, koji djeluje sinergisti ki s ostalim citokinima ubrzavajui sazrijevanje citoplazme megakariocita. Stvara se kontinuirano u jetri, slezeni i u stromalnim stanicama KS (21). Megakariocitopoezu joa stimuliraju i eritropoetin (EPO), IL-1, IL-3, IL-6, IL-11 i imbenik stimulacije granulocita i makrofaga (engl. granulocit-macrophage colony stimulating factor - GM-CSF) (22,23). Najnezrelija stanica trombocitne loze je magakarioblast, koja sazrijeva u promegakariocit i kona no u megakariocit. Jezgra megakarioblasta je lobulirana i sinhrono se dijeli bez dijeljenja citoplazme. Citoplazma sadr~i specifi ne trombocitne granule i demarkacijski sustav membrane (24). Kod AITP u KS mo~emo nai poveani broj megakariocita. Iz svakog megakariocita nastane oko 4000 trombocita. Ciklus nastanka traje deset dana. Nakon otpuatanja iz KS mladi trombociti se zadr~avaju u slezeni 36 sati prije ulaska u cirkulaciju gdje primarno sudjeluju u hemostazi (25). Slezena je spremiate trombocita i u njoj je pohranjena 1/3 ukupnih trombocita. Trombociti se uniatavaju u KS, jetri i slezeni. Du~ina ~ivota trombocita u perifernoj krvi je 9-11 dana, a normalan broj je, bez obzira na dob, 150-450 x 109/L. Diskoidnog su oblika, veli ine prosje no 1-2 mikrometra, dok je prosje ni stani ni volumen 5.8 fL. Mlai trombociti su vei, a veli ina im se smanjuje sa staroau. Membrana trombocita sadr~i glikoproteine, koji su nu~ni za po etak adhezije, agregacije i stvaranja trombocitnog epa tijekom hemostaze. Trombociti sadr~e guste granule i alfa granule. Guste granule sadr~e nucleotide ADP, ATP, kalcij, serotonin i pirofosfat, dok alfa granule sadr~e fibrinogen, vWF, trombocitni factor 4 (TF4), fibronektin, beta-tromboglobulin, imbenik rasta trombocitnog podrijetla (engl. platelet-derived growth factor - PDGF) i trombospadin. Nakon adhezije fosfolipidi na povraini trombocita uspostavljaju interakciju i aktivaciju koagulacijskih faktora u kaskadi koagulacije (24). Najva~nija funkcija vWF-a je odr~avanje adhezivnih interakcija trombocita u brzoj struji krvi. Trombociti imaju dva receptora za vWF glikoprotein Ib i integrin GP IIb-IIIa kompleks (26). Oslobaanje vWF-a iz endotelnih stanica nastaje pod utjecajem adrenalina i dezmopresina kod napora i stresa ime se znatno poveava njegova koncentracija u cirkulaciji (24). 1.3. Imunosni sustav Imunosni sustav u organizmu ovjeka je odgovoran za otpornost prema infekcijama i bolesti, a posebno za prepoznavanje vanjskih stranih i ovjekovih vlastitih antigena. Ovaj sustav dijelimo na priroeni i ste eni od kojih svaki ima svoju funkciju i ulogu. Filogenetski primitivniji priroeni imunosni sustav predstavlja inicijalnu obranu protiv razli itih patogenih organizama, olakaava djelovanje specifi ne imunosti, a vezan je uz fagocitne stanice (neutrofile, monocite i makrofage), one koje izlu uju upalne medijatore (bazofili, mast stanice i eozinofili) i prirodno ubila ke stanice (engl. natural killer cells - NK). U molekularne komponente priroenog imuniteta ubrajamo komplement, proteine akutne faze i citokine kao ato su interferoni. Ste eni imuni odgovor je organiziran pomou dvije vrste specijaliziranih stanica limfocita T i B, koji su antigen specifi ni i nakon stimulacije povrainskih receptora antigenom po inju proliferirati (27). Svaki od ovih limfocita posjeduje strukturalno jedinstvene receptore, iji je repertoar u cijeloj populaciji limfocita vrlo airok i ekstremno razli it. Sve to poveava mogunost susreta antigena sa receptorom i na taj na in podr~ava aktivaciju i proliferaciju stanica. Specijalizirane stanice, koje nazivamo antigenpredo nim stanicama, predo uju antigen limfocitima i surauju s njima u odgovoru na stimulaciju antigenom. Da bi imunosni sustav mogao biti u inkovit, neophodna je klonalna ekspanzija limfocita kao odgovor na infekciju. Danas je jasno da je limfoidno tkivo, kao ato su limfni vorovi i slezena vrlo va~no mjesto gdje nastaje primarni imuni odgovor. Limfni vorovi sakupljaju antigene iz tkiva iz kojih dreniraju limfu i jako utje u na limfocite T i B iz krvi kroz specijalizirane venule koje sadr~e mnogo endotela (28). Imunost i autoimunost su vezane uz monocitno-makrofagni sustav, koji je lokaliziran u va~nim strukturama organizma kao ato su koatana sr~, timus, slezena, limfni vorovi, krvne i limfne ~ile, sluznica dianog, probavnog i mokranog sustava. Danas su poznata dva tipa specifi ne imunosti: Humoralna imunost vezana uz limfocite B (engl. bone marrow derived lymphocytes - limfociti proizaali iz koatane sr~i) Celularna imunost vezana uz limfocite T (engl. thymus derived lymphocytes - limfociti proizaali iz timusa) Jedna od vrlo va~nih karakteristika imunosnog sustava jest da razlikuje vlastito od stranog. U posljednjih dvadeset godina mnogo je novih saznanja o biologiji, funkcijama imunosnog sustava, molekularnoj genetici i funkciji limfocita. Do sada je dato 10 Nobelovih nagrada za medicinsku fiziologiju, podru je imunologija, ato govori da je u svijetu prepoznata va~nost ove grane medicine koja zadire od trudnoe, cijepljenja pa do malignih bolesti. Jednim od veih napredaka na polju imunologije smatra se rad Zinkernagel i Doherty o specifi nosti stani ne imune obrane (29). 1.3.1. Limfociti Limfociti su stanice koje prepoznaju antigen i nakon prepoznavanja imunoloaki reagiraju. Kao i sve stanice imunosnog sustava potje u iz krvotvorne mati ne stanice. Negdje 1960. godine saznajemo da limfocite mo~emo podijeliti u dvije populacije na osnovu njihova podrijetla i funkcije. Tijekom 1970. godine razvoj monoklonalnih protutijela je omoguio diferenciranje subpopulacija limfocita T, B i NK stanica. Da bismo mogli raspoznati o kojim se stanicama radi poma~e nam diferencijacijska skupina antigena (engl. cluster of differentiation - CD), sustav koji definira molekule na povraini stanice. Stanice ozna avamo velikim slovima CD i brojem kojim je odreena stanica. Broj stanice se piae odmah uz slova, npr. CD8. Monoklonalnim protutijelima otkrivamo T stani ne antigene pomoni kih limfocita ili supresorsko-citotoksi nu populaciju. Limfocita T ima oko dvostruko viae nego limfocita B. Limfociti T imaju karakteristi ne T-stani ne receptore (engl. T cell receptors - TCRs) koji mogu prepoznati antigen prezentiran putem velikog sustava tkivne snoaljivosti (engl. major histocompatibility complex - MHC) na povraini stanica koje su u stanju predo iti antigen. U posljednjih 10 godina uvedena je bazi na terminologija u opisivanju subpopulacija limfocita T. Prepoznati su CD4 (pomoni ki) limfociti T koji lu e citokine i CD8 (citotoksi ko/supresorski) limfociti T. Stanice imunosnog sustava moraju se meusobno prepoznati da bi mogle meusobno komunicirati. Ovo prepoznavanje se odvija pomou polimorfnih stani nih povrainskih antigena koje kontroliraju geni glavnog sustava tkivne snoaljivosti (engl. human leukocyte antigen - HLA), koji se nalaze na kratkom kraku kromosoma 6. Klasa I antigena HLA-A, B i C se nalazi na povraini svih stanica s jezgrom i va~na je za prepoznavanje virusom inficiranih stanica od strane limfocita T8. Klase II antigena HLA-DR, DQ i DP rasporeene su na makrofazima, limfocitima B, Langerhansovim stanicama u ko~i i dendriti nim stanicama (engl. dendritic cells - DC) u razli itim organima. Pomou molekula klase II makrofazi prezentiraju antigen limfocitima T4 poti ui imunost koja je vezana uz limfocite T8, a poti ui i limfocite B da stvaraju imunoglobuline (30,31). Supresija imunog odgovora na vlastite antigene je regulirana pomou limfocita T8. Razlikujui tue od vlastitog, pomou brojnih polimorfnih HLA antigena, imunosni sustav mo~e prepoznati strane antigene i reagirati na njih. Na taj na in omoguava zaatitu organizma od virusne ili mikrobne invazije, kao i odreenih malignih bolesti koje se prezentiraju kao novi antigeni. Iz prethodno nezrelih limfoidnih stanica, limfociti B sazrijevaju u KS, a limfociti T u timusu. Procese sazrijevanja ovih stanice kontroliraju brojni citokini. Dvije populacije limfocita pomoni ki i citotoksi ko/supresorski limfociti T imaju razli itu funkciju, ali i jedni i drugi prepoznaju samo peptidne antigene, koji su vezani uz sustav MHC. Limfociti T4 i njihovi citokini su glavni regulatori imunoloake reakcije. Limfociti T4 specijalizirani su u prepoznavanju intracelularnih patogena ili njihovih produkata, aktivaciji makrofaga, ostalih limfocita T i NK stanica. Mogu uniatiti ciljne stanice kao ato su inficirani monociti i makrofazi, pomou Fas-Fas liganda (FasL). 1986. godine Mosman je predlo~io da se limfociti T4 kategoriziraju prema citokinima koje proizvode (32). Limfociti T4 mogu se podijeliti u 4 va~na tipa stanice, a podjela je bazirana na funkcionalnim karakteristikama limfocita: Tip 1 (engl. T helper 1 - Th1) limfociti T4 koji izlu uju IL-1, -2, -3, IFN-, TNF- i GM-CSF, ali ne IL-4, -5 ili -6. Va~ne su im funkcije reakcija kasne preosjetljivosti, aktivacija makrofaga i reakcije stani ne citotoksi nosti. Limfociti Th1 su proinflamatornog fenotipa. Tip 2 (engl. T helper 2 - Th2) limfociti T4 koji lu e IL-3, -4, -5, -6, -9, -10 i GM-CSF, ali ne IL-2 ili IFN-. Surauju s limfocitima B, stimuliraju sekreciju IgE, aktiviraju bazofile i mastocite i inhibiraju makrofage. Limfociti Th2 su antiinflamatornog fenotipa. Tip 0 (engl. T helper 0  Th0) limfociti T4, koji se ne polariziraju u Th1 ili Th2 fenotip i mogu lu iti proinflamatorne (IFN-) i antiinflamatorne citokine IL-4. Nastaju iz nezrelih limfocita T4. Th0 subpopulacija izlu uje IL-2, IL-4, IL-5, IFN-( i IL-10. Veina klonova neimuniziranih i imuniziranih ljudi je Th0. Ove stanice surauju s limfocitima B. Tip 3 (engl. T helper 3  Th3) limfociti T4 su jedinstvene stanice, koje se ne polariziraju u Th1 ili Th2 fenotip i prvenstveno izlu uju transformirajui imbenik rasta 1 (engl. transforming grow factor 1 - TGF 1), koji je povezan s CD4+CD25+ regulatornom funkcijom limfocita T (Tr). Djeluju supresivno za Th1/Th2 i ostale imune stanice (33). Van der Graaff smatra da neravnote~a izmeu proinflamatornih limfocita Th1 i antiinflamatornih Th2 ima za posljedicu stvaranje IFN- i IL-4 ato mo~e biti od va~nosti u nastanku autoimunih bolesti (34). Limfociti T8 prepoznaju antigen predstavljen putem sustava MHC i uniatavaju inficirane stanice sprije avajui tako umno~avanje virusa. Aktivirani limfociti T8 lu e IFN-, koji zajedno s IFN- i IFN- koje stvaraju inficirane stanice, uspostavljaju stanje rezistencije stanice na virusnu infekciju. Eliminiraju virusom zara~ene stanice, koje same sebe ozna e kao metu istim limfocitima T8 eksponirajui na povraini peptide nastale iz stani nih viralnih proteina. Nastaje kompleks viralni peptid - MHC, nakon ega se aktiviraju proteoliti ki enzimi posrednici u apoptozi ciljnih stanica iz kojih se oslobaa virus, koji postaje dostupan protutijelima. Limfociti T8 takoer stvaraju brojne citokine uklju ujui TNF-( i IFN-(. Imaju sposobnost liziranja ciljnih stanica, citotoksi ni su za aloantigene, te imaju pomoni ki i supresorski u inak na stvaranje protutijela od strane limfocita B. Poti u nastanak kasne upalne reakcije i reakciju transplantata protiv primatelja (engl. graft versus host disease  GvHD). Limfociti T4 prepoznaju antigen predstavljen pomou MHC klase II molekule, a oni Th1 i Th2 populacije mogu postati citotoksi ni nakon ato prepoznaju peptide, koje prezentira MHC klasa II molekule. Limfociti Th se diferenciraju u nekoliko faza. Prekursori Th (Thp) koji izlu uju IL 2 se nalaze meu neaktiviranim limfocitima T4. Razli iti steroidni hormoni moduliraju odgovor limfocita T. DHEA ili njegovi nepoznati metaboliti poti u Th1 skupinu poveavajui stvaranje Th1 citokina kao ato su IL-2, IFN-. Poja ava izlu ivanje IL-2 iz stanica periferne krvi u ovjeka (35-37). NK stanice odreenih fenotipskih karakteristika, izra~avaju CD4 obilje~je i T stani ne receptore vrlo uskog repertoara djelovanja. Ove stanice prepoznaju antigen putem neklasi ne MHC molekule CD1 i mogu imati imunoregulatornu ulogu jer lu e IL-4 i IFN-. Oateena aktivnost NK stanica obi no je udru~ena s teakom humanom herpes infekcijom ulju ujui i EBV infekciju. 1.3.2. Programirana stani na smrt Imunosni sustav je jedini kod kojeg nastaje zna ajno umno~avanje stanica kao imuni odgovor na infekciju ili kontakt sa stranim antigenom. Aktivirane citotoksi ne stanice zajedno s toksi nim medijatorima i sna~nim citokinima moraju biti kontrolirane, jer bi ina e mogle jako atetiti samom organizmu. Da bi se mogle odstraniti suviane stanice potrebno je da one same sebe uniate, a to je mogue pokretanjem procesa apoptoze, to jest programiranog samouniatenja stanice. Najva~nija molekula koja regulira smrt aktiviranih limfocita je Fas (CD95), a nalazi se na povraini limfocita T i B (38). Limfociti T i B umiru apoptozom. Nakon kontakta s antigenom Fas ekspresija na povraini stanice raste, kaskadno se aktiviraju stani ne proteaze ato dovodi do apoptoze. Ekspresiju Fas liganda, koja se pojavljuje nakon aktivacije zrelih limfocita T4 i T8, regulira imunosni sustav. Programirano samouniatenje stanice mo~e biti stimulirano oateenjem DNK, pomou TNF- ili nedostatkom IL-3 (39,40). Za vrijeme apoptoze stanice jezgra se kondenzira, DNA se degradira u mnogo komadia i na kraju stanica kolabira u multiple fragmente koje fagociti odstrane. Defektna apoptoza limfocita mo~e dovesti do razli itih autoimunih bolesti. Shenoj sa suradnicima je dokazao u 25% bolesnika s autoimunom hematoloakom citopenijom defekt u stani noj smrti limfocita vezan uz oateenu Fas ekspresiju, koja se mo~e oporaviti pomou rekombinantnog IL-2. Zaklju io je da oateena Fas ekspresija sa ili bez defektnog odgovora na IL-2 mo~e biti uzrokom hematoloakih autoimunosti (41). 1.3.3. Citokini Citokini su polipeptidi ili glikopeptidi molekularne mase od 6-70 kDa, a djeluju preko specifi nih receptora u samoj stanici i na stani noj membrani. Mogu biti pozitivni i negativni regulatori imunog odgovora. Oni su glasnici koji, pored hormona i neurotransmitera, spadaju u vrlo va~ne imbenike u komunikaciji izmeu ljudskih stanica. Citokini predaju informaciju ciljnoj stanici, koja ispoljava odgovarajui receptor. Nastaje aktivacija gena s posljedi nim fenotipskim ili funkcionalnim promjenama ciljne stanice. Sintezu i otpuatanje citokina mogu zaustaviti inhibitori modulirajui bioloaku aktivnost citokina ili inhibirajui sposobnost odgovora ciljne stanice. Aktivnost citokina ovisi o njihovoj koncentraciji u mikrookoliau i ja ini ekspresije specifi nih receptora na povraini ciljne stanice. U ljudskom organizmu svaka ~iva stanica s jezgrom stvara citokine. Vrsta citokina i koli ina sekrecije ovisi o tipu i stadiju diferencijacije stanice te aktivacijskom stadiju iste. Stvaranje ovih polipeptida potaknuto je antigen specifi nom aktivacijom limfocita T4. Interakcija citokina s receptorima za citokine rezultira aktiviranjem kaskade signala u stanici. Aktiviraju se faktori transkripcije, ulaze u jezgru gdje poti u aktivaciju razli itih gena. Rije  citokini je izvedena iz dvije rije i gr kog podrijetla -  cytos , ato zna i stanica, i  kine , iz rije i  kinein , ato zna i micati se. Ovaj naziv je uveden da bi se mogla razlikovati grupa imunomodulatornih molekula od hematopoetskih imbenika stani nog rasta. U citokine spada grupa: interleukina tumorskih imbenika rasta interferona Ovakva podjela odgovara bioloakim i strukturalnim razlikama, ali i sli nostima ovih medijatora. Izraz interleukin je prihvaen za grupu medijatora odgovornih za meusobno komuniciranje leukocita. Danas poznajemo 29 vrsta interleukina, koji se nazivaju od IL-1 do IL-29. Efektorske funkcije ovih proteina su aktivacija i diferencijacija stanice, kemotaksija i proliferacija airokog spektra stanica. Citokini su efektorske molekule ste ene imunosti, koje izlu uju limfociti T (limfokini), dok efektorske citokine uroene imunosti izlu uju mononuklearni fagociti (monokini). Posjeduju brojne bioloake aktivnosti i aktivni su u malim pico-femtomolarnim koncentracijama. Ponaaaju se sli no hormonima - kao sna~ne molekule koje se oslobaaju iz stanica, transportiraju se u druge dijelove organizma i djeluju na funkcije drugih stanica ato dovodi do brojnih bioloakih u inaka (42). Danas poznajemo preko 30 razli itih citokina. Mnogi od njih su imbenici rasta stanica, neki su hematopoetski faktori rasta, dok neki imaju antiviralnu aktivnost i nazivamo ih interferonima. Reguliraju rast i diferencijaciju stanica imunosnog sustava, a isto tako opseg i du~inu upalnog odgovora. Meusobno su povezani u citokinsku regulacijsku mre~u. Oni modificiraju bioloaki odgovor, a stimuliraju proliferaciju i diferencijaciju limfocita T i B i makrofaga. Humani imuni odgovor na infekciju reguliran je ravnote~om izmeu Th1 citokina (IL-2, IFN-) i Th2 citokina (IL-4, IL-5, IL-10). IL-4 i IL-10. Mogu olakaati stvaranje protutijela, ali i suprimirati stani ni imuni odgovor. Napredovanje infekcije je dodatni negativni u inak ovih imunoregulatornih citokina (43). Razlikujemo proinflamatorne i antiinflamatorne citokine. Upalni citokini uklju ujui TNF-(, IL-1 i IL-6, aktiviraju koagulaciju i inhibiraju fibrinolizu ato mo~e rezultirati difuznim oateenjem endotela kapilara, s posljedi nom disfunkcijom brojnih organa i smru (44). Danas znamo da postoji interakcija izmeu hemostaze, upalnih reakcija i imunosnog sustava, a isto tako znamo da imunokompetentne stanice i endotel krvnih ~ila meusobno utje u jedno na drugo. Stvaranje i aktivnosti citokina endotelnih stanica su interes brojnih istra~ivanja danas (45). Poveano izlu ivanje citokina nije udru~eno samo s infekcijama nego i s autoimunim i neurodegenerativnim bolestima. 1.3.3.1. Proinflamatorni citokini 1.3.3.1.1. Interleukin 1 Interleukin 1 (IL-1) je naziv za dva razli ita proteina, IL-1 i IL-1, za koje se smatra da su prvi u grupi upalnih i regulatornih citokina i prepoznaju isti stani ni receptor (46). Ghezzi je ustanovio da IFN- regulira stvaranje IL-1 (47). Tilg je ispitivao utjecaj IFN- i IFN- na antagonist IL-1 receptora (IL-1Ra), koji je inhibitor IL-1 i zaklju io da interferoni stimuliraju IL-1Ra i na taj na in mogu doprinijeti antiviralnom, antiinflamatornom i antiproliferativnom u inku interferona (48). Ne izlu uju ga stanice zdravih individua. IL-1 igraju va~nu ulogu u poja avanju ili smanjivanju upalne reakcije. Smatra se da je ovaj citokin proinflamatoran. IL-1 igra va~nu ulogu u funkciji imunosnog sustava, jer utje e na makrofage/monocite, limfocite T i B, NK stanice i limfocitima aktivirane stanice ubojice (engl. lymphocyte-activated killer cells - LAK). Inducira sintezu TNF i IL-6 i ima fundamentalnu ulogu u antitumorskoj aktivnosti makrofaga (49). Aktivira limfocite T to rezultira stvaranjem IL-2 (50). IL-1 izlu uju makrofazi, fibroblasti, endotelne stanice, keratinociti, DC, astrociti, limfociti B i aktivirani limfociti T, stanice glatkih miaia i stanice mikroglije (51). Stimulira tumor specifi ne limfocite T8 i aktivira diferencijaciju limfoidnih stanica. Sna~no inducira matrix-metalloproteinaze, koje degradiraju kolagen ato mo~e izazvati uniatavanje vezivnog tkiva npr. u zglobovima kod RA (52,53). Ima va~nu imunoregulacijsku funkciju, poti e sintezu IL-2 od limfocita T i poma~e ekspresiju IL-2 receptora na aktiviranim limfocitima T. Uz druge interleukine aktivira limfocite B da proliferiraju, sazrijevaju i poja avaju sintezu imunoglobulina (54). Uloga IL-1 u reumatologiji najprije je dokazana u RA, gdje je upalno promijenjena sinovijalna membrana infiltrirana monocitima i makrofazima, koji su glavni izvori IL-1. Glukokortikoidi zna ajno smanjuju IL-1 mRNA nivoe inhibirajui u inke IL-1 djelujui na taj na in antiinflamatorno i imunosupresivno (55). 1.3.3.1.2. Interleukin 2 Prvi put opisan je 1976. godine. IL-2 igra sredianju ulogu u imunom odgovoru u ovjeka (56-58). To je pleiotropni citokin kojeg primarno stvaraju mitogenom ili antigenom aktivirani limfociti T. Primarno ga sintetiziraju i lu e limfociti T4 (Th0, Th1). Stimulira proliferaciju timocita, proliferaciju i diferencijaciju limfocita B, inducira rast i citotoksi nost NK stanica, njihovu citoliti ku aktivnost i stvaranje citokina. Zna ajan je za aktivaciju, proliferaciju i diferencijaciju limfocita T. Stimulira generaciju limfocita T8 (59). Inducira funkciju limfocita T4. Inducira IFN- i TNF-. Gen za IL-2 se nalazi na humanom kromosomu 4q (60). Bioloaki u inak ostvaruje preko IL-2 receptora (IL-2R) (61). Stalno prisustvo IL-2 je nu~no za klonalnu ekspanziju aktiviranih limfocita T i sprije avanje njihove apoptoze. ak ako nastane blok proliferacije limfocita T IL-2 joa uvijek sprije ava smrt stanice (62,63). Poveane vrijednosti su naene kod razli itih autoimunih bolesti, a hipersekrecija endogenog IL-2 mo~e voditi u autoagresiju na viae na ina, primjerice inducirajui ostale citokine, kao IFN- i IL-10 (64). Rekombinantni IL-2 koristi se u terapiji bolesnika s HIV infekcijom, jer zna ajno podi~e vrijednosti limfocita T4. Abdel-Raheem i suradnici opisuju nastanak Evansova sindroma u bolesnika koji je lije en sa IL-2 (65). Protutijela na IL-2 ili IL-2R mogu biti korisna u lije enju autoimunih bolesti. 1.3.3.1.3. Interleukin 6 Spada u upalne citokine i lu i se tijekom upalnih stanja. Regulira imunosni i hematopoetski sustav i uzrokuje reakciju akutne faze upale. Stvaraju ga ne samo imune stanice nego i mnoge neimune stanice i organi (66,67). IL-6 poti e sazrijevanje megakariocita (68). Stimulira hepatocite, skrauje G0 fazu hematopoetskih progenitora, podsti e stvaranje imunoglobulina od aktiviranih limfocita B, poja ava stvaranje limfocita T, regulira ekspresiju IL-2R. Sve ove aktivnosti kontrolira jedan te isti gen, koji se nalazi na kratkom kraku kromosoma 7 i sadr~i 5 exona i 4 introna (69,70). Svoje bioloake u inke ostvaruje putem membranskih receptora za IL-6, koji se nalaze na mnogim stanicama uklju ujui megakariocite (71). Potiskuje lu enje TNF- i IL-1, aktivira i stimulira hipotalami ko-pituitarnu adrenalnu osovinu djelujui na kortikotropin-otpuatajui hormon i poma~e kontroli upalne reakcije (72). Glukokortikoidi inhibiraju transkripciju IL-6 interakcijom ligandom aktiviranim glukokortikoidnim receptorom Re1A subjedinicom transkripcijskog faktora NF-kappaB. Transkripciju IL-6 suprimiraju i estrogeni (73-75). IL-6 poti e finalno sazrijevanje limfocita B u stanice koje stvaraju protutijela ato govori o njegovom sudjelovanju u upalnim procesima nakon imunog odgovora organizma (76). Za vrijeme upale izlu uju se upalni citokini kao ato su TNF-(, IL-1 i IL-6. IL-6 tada potiskuje lu enje TNF-( i IL-1 aktivirajui stvaranje reaktanata aktivne faze iz jetre i stimulira osovinu hipotalamus-hipofiza-nadbubre~na ~lijezda i na taj na in poma~e kontroli upalne reakcije. U tom smislu IL-6 je proinflamatorni i antiinflamatorni citokin. Va~an je u stimulaciji rane faze hematopoeze. Djelovanje ovog citokina ima brojne bioloake posljedice i razli ito djelovanje na mehanizam hemostaze tako da mo~e povisiti broj trombocita u normalnih i trombocitopeni nih ~ivotinja, a isto tako i u ljudi (77-80). Djeluje na sazrijevanje megakariocita poveavajui broj i veli inu stanice i na sintezu trombocitnih proteina. U ljudi koncentracija serumskog IL-6 poveana je u reaktivnoj trombocitozi kod RA ili kod sekundarne trombocitoze uzrokovane anemijom zbog nedostatka ~eljeza. Sve ovo ukazuje na to da citokini mogu biti odgovorni za patoloaku megakariocitopoezu. IL-6 poveava veli inu trombocita i poja ava njihovu funkciju (81, 82). Kako IL-6 poveava stvaranje trombocita mogue je da promjene u funkcionalnosti trombocita nastaju zato ato u cirkulaciju ulaze novi potentniji trombociti, prije nego ato bi to bio rezultat utjecaja IL-6 na trombocite (83,84). Lije enje kortikosteroidima snizuje vrijednosti IL-6 u serumu (85,86). Brojni autori su ispitivali moguu korist dugotrajne aplikacije IL-6 u indukciji trombocitopoeze. Tako je Ryffel sa suradnicima dokazao da se broj megakariocita u koatanoj sr~i ne poveava djelovanjem IL-6, ali stupanj ploidije raste ato mo~e sugerirati da je u inak IL-6 ograni en na zrele megakariocite in vivo. Povisuje vrijednosti fibrinogena u plazmi (87). IL-6 ima sposobnost openito poticanja limfocita B posebno sekreciju IgG. Takoer podr~ava rast limfocita B inficiranih s EBV (88). 1.3.3.1.4. imbenik tumorske nekroze ( To je moan citokin kojeg stvaraju makrofazi, fibroblasti, monociti, limfociti T i B i u inak mu je razli it na fizioloaki i imunosni sustav. Spada u citokine koji nastaju iz makrofaga. Najbolje je prou ena njegova sposobnost izazivanja upalne reakcije. Osim ato stimulira stvaranje ostalih citokina (IL-1, IL-6, IL-8, GM-CSF) posreduje u kaskadi citokina, koja uzrokuje upalu i destrukciju zglobova u RA preko receptora koji su lokalizirani na makrofazima ili u stanicama u sinovijalnoj membrani (89). Isto kao i IL-1, TNF-( je u stanju inducirati hipoferemiju tako da povea unos ~eljeza u makrofage i monocite ato spada u dio akutne faze imunog odgovora vezanog uz citokine. Alvarez-Hernandez je dokazao da rekombinantni TNF uzrokuje zna ajni pad serumskog ~eljeza nakon 6 sati istovremeno ne uzrokujui promjene u totalnom kapacitetu prijenosa ~eljeza (90). Aktivnost mu je proinflamatorna i antitumorska. Uz mnoge u inke opisana je i njegova sposobnost da potakne smrt stanice. Regulira proliferaciju i diferencijaciju imunih stanica. Ovaj peptid je uklju en u procese vezane uz septi ki aok, autoimune bolesti i GvHD. Indirektno regulira upalnu reakciju tako da stimulira otpuatanje kortikotropina iz hipofize stimulirajui na taj na in koru nadbubre~ne ~lijezde da otpuata kortizol, koji inhibira upalu. Nakon blokiranja TNF-( protutijelima zna ajno se smanjuje stvaranje IL-1, IL-6, IL-3 i GM-CSF. Blokiranje ovog citokina mo~e imati presudnu ulogu u koncentraciji ostalih citokina u sinovijalnoj tekuini (91). Blokiranjem TNF-( monoklonskim protutijelima (engl. monoclonal antibody - mAb) mo~emo zaustaviti aktivnost bolesti tip II kolagen induciranog artritisa u miaa (92). 1.3.3.2. Antiinflamatorni citokini Dok neki citokini podr~avaju upalni proces drugi ga slabe. Dva do sada najbolje ispitane protuupalna citokina su IL-4 i IL-10. Oni zajedni ki inhibiraju stvaranje upalnih citokina (93,94). 1.3.3.2.1. Interleukin 4 IL-4 ili B stimulirajui faktor je pleiotropni citokin kojeg primarno stvaraju aktivirani limfociti T, limfociti T4 (Th2), bazofilne i mast-stanice, monociti i makrofazi, neutrofili, limfociti B i stromalne stanice koatane sr~i (95, 96). IL-4 podr~ava humoralni imuni odgovor regulirajui diferencijaciju prekursora subpopulacije limfocita T4 u tip 2 (Th2), koji odreuje humoralnu imunost i modulira stvaranje protutijela. Sudjeluje u diferencijaciji i rastu limfocita B, kao i sazrijevanju DC iz makrofaga uz pomo GM-CSF-a. In vitro inhibira aktivaciju limfocita Th1 i smanjuje stvaranje IL-1 i TNF-( i oateenje hrskavice. Takoer inhibira stvaranje IL-6 i IL-8 (94,97). Mo~e potaknuti nastanak autoimunih bolesti kao ato je sustavni lupus eritematodes (SLE). Ovaj citokin prevenira autoimunu bolest sli nu SLE tako da smanjuje pojavu IgG3 nefritogenih autoprotutijela (98). Naeno je da je IL-4 zna ajno poviaen kod EBV infekcije u djece u koje je izvraena transplantacija jetre i u koje je lan anom reakcijom polimeraze (engl. polymerase chain reaction  PCR) dokazana prisutnost ovog virusa ato govori o va~noj ulozi ovog citokina u infekciji EBV-om (99). Poveava rast limfocita B i stvaranje imunoglobulina, modulira mijeloidni rast, poja ava migraciju eozinofila i upalnu reakciju, modulira IL-2 stimulirane LAK stanice. IL-4 ima inhibitorni profil sli an IL-10, ali za razliku od njega djeluje kod te~ih oblika RA. Oba citokina smanjuju fagocitnu aktivnost humanih neutrofila kao odgovor na u inke proinflamatornih citokina (100). Pored gore navedenih aktivnosti poznato je da IL-4 poti e stvaranje IgE, a genetske studije povezuju patogenezu astme s genom za IL- 4 (101). Gen za IL-4 nalazi se na kromosomu 5q, vrlo blizu iznad gena za IL-3, IL-5, IL-13 i GM-CSF (95,96). Sonoda sa suradnicima je ispitivao djelovanje IL-4 na proliferaciju megakariocita u stani noj kulturi i zaklju io da ovaj interleukin mo~e potiskivati humanu megakariocitopoezu in vitro, dok je Snoeck dokazao da inhibira kolonije za makrofage (102,103). 1.3.3.2.2. Interleukin 10 IL-10 je pleiotropni citokin koji ima imunosupresivni ili imunostimulativni u inak na razli ite tipove stanica. Humani IL-10 mo~e inhibirati antigenom stimuliranu sintezu citokina ovisnu o monocitima i makrofagima, koja se odvija u mononuklearenim stanicama periferne krvi i NK stanicama. Poznato je da IL-10 mo~e smanjiti ekspresiju MHC II na makrofazima (104,105). Smatra se da IL-10 mo~e inhibirati nastanak i funkciju kostimulatora na membrani makrofaga, koji je potreban za aktivnost limfocita T i NK stanica (106). IL-10 je citokin kojeg najviae lu e humani limfociti T4 (Th 0 i Th 2) i monociti i makrofazi, stanice koje prezentiraju antigen. Poznato je da ga lu e i limfociti B, kao i mast stanice. Vjeruje se da ima va~nu funkciju potiskivanja imunog odgovora i mo~e biti uklju en u odr~avanje tolerancije imunosnog sustava. Blokira aktivaciju sinteze citokina putem limfocita Th1, aktiviranih monocita i NK stanica. Najva~nije funkcije su koaktivacija limfocita T i B, indukcija klase MHC II, pre~ivljavanje limfocita B i lu enje Ig: IgG1, IgG3, IgA. Mo~e stimulirati limfocite B na stvaranje imunoglobulina. Inhibira stvaranje nekoliko citokina, uklju ujui IL-1, TNF-(, IL-6 i IL-8 (105,107,108). Inhibira proliferaciju limfocita T in vitro. Poveane vrijednosti su naene u veeg broja bolesnika s AITP. Ima sna~an imunostimulatorni u inak na limfocite B i inducira sintezu IgA u CD40 aktiviranim stanicama (109). Stimulira proliferaciju limfocita B u slezeni i tonzilama (110,111). Nedostatak stani nog imuniteta esto je udru~en s jakim humoralnim imunim odgovorom, a dijelom je uzrokovan inhibicijom Th1 funkcije putem Th-2 citokina IL-10. IL-10 je jak inhibitor Th1 efektornih funkcija in vivo. Ova osobina mo~e biti korisna u kontroli nekih autoimunih bolesti vezanih uz Th1 upalni odgovor (112). IL-10 inhibira gubitak stani nog volumena, kondenzaciju kromatina i DNA fragmentaciju, sve ono ato karakterizira smrt stanice apoptozom (113). U svojim studijama Corinti i Fukao su dokazali da IL-10 prevenira spontano sazrijevanje DC in vitro (114,115). IL-10 mo~e utjecati na homeostazu ~eljeza inducirajui sintezu IFN- ili TNF-. Davanje IL-10 poveava nivo feritina u serumu i utje e na nastanak anemije kroni ne bolesti. IL-10 neposredno modulira sintezu feritina poja avajui ulaz feritina u monocite. 1.3.3.3. Interferoni Interferoni nastaju kao odgovor na virus, dvostruku RNA, antigene i mitogene. U ovjeka postoje tri izoforme interferona, a to su: alfa, beta i gama (116). Ovi proteini brane organizam od virusa, poveavaju otpornost stanica na virusnu infekciju i djeluju kao citokini. Imaju airoki spektar djelovanja: va~an antimikrobni, imunomodulatorni, antiproliferativni uz poticanje diferencijacije stanica, kao i poticanje apoptoze (117). Prepoznatljivi su po svojoj sposobnosti da inhibiraju replikaciju virusa unutar stanica. Poznati su inhibitori proliferacije hematopoetskih stanica. Raefsky i suradnici su ispitivali u inak rekombinantnog IFN- i IFN- na stvaranje hematopoetskih kolonija koatane sr~i. Dokazali su da su oba rekombinantna interferona sna~ni supresori mijeloidnih kolonija nastalih iz CFU-C i da djeluju sinergisti ki. IFN- inhibira eritroidne progenitore i ukupne kolonije CFU-E u koatanoj sr~i (118). Neki od interferona (IFN- i IFN-) mogu se sintetizirati u stanicama kao neposredna posljedica stani ne infekcije virusom zaati ujui stanicu od infekcije novim virusom. Drugu grupu interferona (IFN- i IFN-) stvaraju limfociti kao odgovor na stimulaciju antigenima. Ovi interferoni imaju produ~eno antiviralno djelovanje i sudjeluju u eliminaciji virusa iz limfocita. Razlikujemo interferone tipa I i II. U tip I interferon spadaju IFN-, IFN-, IFN-, IFN-o, IFN-. Ve~u se na stani ne receptore za interferone. Razlikujema dva tipa stani nih interferonskih receptora: Receptori tip I koji prepoznaju IFN- i IFN-, ali ne prepoznaju IFN- Receptori tip II koji prepoznaju IFN-, ali ne i IFN- i IFN-. Interferonski sustav ima svoju vlastitu funkcionalnu organizaciju. Za stvaranje interferona potreban je induktor koji je naj eae virus, a proizvoa  je humana stanica. Stanice koje stvaraju interferon (engl. interferon-producing cells  IPC) spadaju u malu populaciju leukocita koji lu e velike koli ine interferona tipa I (IFN- i IFN-) kao odgovor na virusnu infeciju (119,120). Interferoni moduliraju imunosni sustav indukcijom MHC i HLA sustava. Ovisno o tipu stanice koja ga proizvodi interferone dijelimo na IFN- kojeg stvaraju leukociti, IFN- kojeg stvaraju fibroblasti, IFN- kojeg stvaraju imunokompetentne stanice. IFN- i IFN- (Interferoni tipa I) su dosta srodni, a stvaraju ih leukociti i fibroblasti kao odgovor na virus ili dvostruku RNA. Suprotno tome IFN- (interferon tipa II) je vrlo malo sli an ostalim interferonima, a stvaraju ga najprije limfociti T kao odgovor na mitogene ili izlaganje antigenu. Utje u na regulaciju stani ne funkcije kao ato je fagocitoza, ali i poveavaju citotoksi nost limfocita T (IFN-), kao i aktivnost makrofaga i NK-stanica (121). 1.3.3.3.1. Interferon-( IFN-( je jedan od prvih citokina koji nastaje kao odgovor na virusnu infekciju. Ima va~na antiviralna i imunoregulatorna svojstva i uspjeano se upotrebljava u lije enju razli itih oboljenja. Poznate su 23 razli ite varijante i 12 funkcionalnih IFN-( podtipova koji djeluju preko jednog receptora, koji se naziva IFN-R (122). Aktivira citotoksi nost NK stanica i pospjeauje lizu stanica inficiranih virusom. Poja ava stani ni imuni odgovor regulirajui ekspresiju IL-12 receptora i na taj na in poti e nastanak limfocita Th1. Razlikujemo 23 razli ita IFN-( gena, koji se nalaze na kromosomu 9 i kodiraju najmanje 15 funkcionalnih proteina (123). IFN-( poti e ekspresiju MHC I. Za vrijeme infekciozne mononukleoze vrijednosti cirulirajueg IFN-( su sni~ene (124). Na taj na in EBV inhibirano stvaranje IFN-( sprije ava dekstrukciju imunosnog sustava. Ovaj interferon zna ajno poja ava IL-10, a blago IL-2 i IL-12. 1.3.3.3.2. Interferon-( IFN- je citokin molekularne mase oko 25000 daltona. Stvaraju ga aktivirani limfociti T i limfociti T4 kao odgovor na IL-12 i IL-18 i NK stanice, te monociti i makrofazi. Igra vrlo va~nu ulogu u obrani domaina ispoljavajui svoju aktivnost na airokom dijapazonu stanica, regulirajui aktivnost imunih stanica. Njegova bioloaka aktivnost ovisi o ekspresiji njegovog receptora (125). To je polipeptidni lanac s 1666 aminokiselina i ima samo jedan funkcionalni gen, koji se nalazi na kromosomu 12. Ima vrlo va~nu ulogu u kontroli bakterijskih, virusnih i parazitnih infekcija. Stani ni odgovor na IFN- odreuje receptor (IFN-R) koji aktivira signal prema stani noj jezgri i kona no regulira ekspresiju gena. IFN-( signal ovisi o broju povrainskih receptora koji ga provode (126). To je najva~niji proinflamatorni citokin odgovoran za aktivaciju i reguliranje fagocitne funkcije mononuklearnih stanica. Regulira stvaranje nekoliko imunomodulacijskih i proinflamatornih citokina kao ato su IL-12 i TNF-(. Sni~ene vrijednosti nalazimo kod RA, SLE, limfoma, kongenitalne rubeole ili citomegalije, malarije, herpes simpleks infekcije, AIDS-a, leishmanije i TBC. Receptor IFN-(R1 odreuje 30-kb gen, koji se nalazi na dugom kraku kromosoma 6. Taj isti receptor nalazimo na povraini skoro svih stanica. Do sada je opisano nekoliko mutacija vezanih uz ove komponente, a bolesnici koji imaju ove mutacije podlo~ni su infekcijama mikobakterija (127). Neposredno potiskuje eritropoezu, a visoke koncentracije EPO ne mogu poniatiti njegov inhibitorni u inak. IL-1 i TNF- inhibiraju stvaranje eritroidnih kolonija indirektno tako da stimuliraju otpuatanje IFN- (128,129). Funkcionalna interakcija IFN- s molekulama cjelokupne interleukinske i citokinske mre~e danas je interes brojnih znanstvenih istra~ivanja. Koliko je meusobno povezana interleukinska mre~a pokazao je Hsu sa suradnicima, kada je dokazao da antiinflamatorni citokini IL-4 i IL-10 inhibiraju IL-2 induciranu sintezu IFN- (130). 1.3.3.4. Interleukin 3 IL-3 je citokin koji primarno nastaje iz aktiviranih limfocita T. Stvaraju ga i limfociti T8. Gen za IL-3 nalazi se na humanom kromosomu 5 samo 9 kilobaza daleko od GM-CSF gena. Ovaj pleiotropni imbenik mo~e stimulirati proliferaciju i diferencijaciju pluripotentnih krvotvornih mati nih stanica, kao i razli itih hematopoetskih progenitora. Djelujui sinergisti ki s ostalim ranim hematopoetskim imbenicima rasta (IL-1, IL-6, SCF, G-CSF), poti e proliferaciju multipotentnih progenitora samo u ranom stadiju njihovog razvoja (131). GM-CSF, IL-5, M-CSF i EPO su potrebni za kona nu diferencijaciju ovih s IL-3 induciranih progenitora (132-134). Svoju bioloaku aktivnost provodi putem receptora na povraini stanice. U inci humanog i miajeg rekombinantnog IL-3 na hematopoezu in vivo prou eni su u raznim ~ivotinjskim modelima, koji su pokazali da IL-3 mo~e poja ati hematopoezu in vivo. IL-3 ima autokrini u inak na megakariocitopoezu djelujui zna ajno na megakariocite da otpuataju imbenik rasta deriviranog iz trombocita (engl.platelet-derived growth factor - PDGF) i TGF 1. Ovi imbenici poja avaju proliferaciju fibroblasta u KS (135). Hirayama sa suradnicima je dokazao da IL-3 pokazuje negativnu reakciju na ranu B-limfopoezu (136). Poveane vrijednosti IL-3 naene su u nekih bolesnika sa GvHD. 1.4. Virusi Dvije treine djece s AITP imaju u anamnezi neku od zaraznih bolesti nekoliko dana ili nekoliko tjedana prije pojave trombocitopenije. Smatra se da je poja ano uniatavanje trombocita putem monocitno-makrofagnog sustava djelomi no odgovorno za trombocitopeniju koja nastaje za vrijeme viremi ne faze ili danima i tjednima nakon virusne infekcije. Molekularna mimikrija izmeu viralnih antigena i proteina domaina odgovorna je za nastanak brojnih autoimunih bolesti, pa tako i za poja ano uklanjanje trombocita kod virusom uzrokovanih AITP (137). Viae je teorija koje pokuaavaju objasniti povezanost virusne infekcije i AITP: pojava trombocitnih reaktivnih protutijela u djece s EBV infekcijom, teorija imunih kompleksa i najbolje dokumentirana teorija molekularne mimikrije (138). Neki od virusa stvaraju svoje vlastite citokine i moduliraju aktivnost citokina u ovjeka. Identificirano je viae od 50 razli itih virusnih gena modulatora imunog odgovora. 1.4.1. Citomegalovirus CMV spada u grupu herpes virusa, koje karakterizira dvostruka DNA. Infekcija citomegalovirusom definirana je kao CMV viremija ili izolacija CMV iz tjelesnih tekuina ili mjesta u tijelu u asimptomatskog bolesnika, dok CMV bolest definiramo kao CMV viremiju ili izolaciju CMV iz tjelesnih tekuina ili prisustvo CMV u histoloakim uzorcima inficiranog tkiva u bolesnika s izra~enim simptomima bolesti. U bolesnika koji imaju latentnu CMV infekciju postoji rizik reaktivacije bolesti naro ito kod imunodeficijentnih stanja (139). Ste ena CMV infekcija je naj eai uzrok EBV-negativne mononukleoze (140). Klini ka slika sli i EBV infekciji s temperaturom, slaboau, umorom i ponekad grloboljom. Javlja se hepatosplenomegalija, limfadenopatija i virusom transformirani limfociti u perifernoj krvi do 15%. Mo~e se nai srednja neutropenija i trombocitopenija. Dijagnoza se postavlja na osnovu zna ajnog porasta CMV IgM u serumu. Primarna infekcija rezultira do~ivotnim prisustvom virusa u domainu, a reaktivacija je esta u imunokompromitiranih osoba. Epidemioloake studije ukazuju da se prenosi krvnim derivatima, koatanom sr~i ili solidnim organima (141-143). Ispitivanjem transplantiranih organa naeno je da su primarno mjesto zadr~avanja HCMV leukociti (144). Brojne studije periferne krvi bolesnika s HCMV boleau ili kod inficiranih ali asimptomatskih bolesnika identificirali su monocite kao predominantno inficirane stanice (145-147). Dokazano je da se virus neograni eno umno~ava u tkivnim makrofazima (148,149). 1.4.2. Ebstein-Barrov virus Ovaj virus su otkrili Epstein, Achong i Barr prije 36 godina u stanicama Burkitovog limfoma pomou elektronskog mikroskopa (150). Kasnije je dokazano da je isti virus uzro nik infekciozne mononukleoze. Spada u porodicu herpes virusa, a inficira oko 90% ljudi perzistirajui u organizmu cijeli ~ivot. Nakon infekcije ulazi u epitelijalne stanice orofarinksa, dok se limfociti B inficiraju gotovo istovremeno. U osoba koje su EBV seropozitivne i onih koje imaju akutnu EBV-om induciranu infekcioznu mononukleozu limfociti B zara~eni EBV-om imaju sposobnost neograni enog rasta. Nakon rekonvalescencije EBV se nalazi u perifernoj krvi u latentno inficiranim limfocitima B. NK stanice i limfociti T nakon reaktivacije latentne infekcije prepoznaju stanice inficirane virusom i uniatavaju ih. Naene su poviaene vrijednosti IL-4, IL-5, IL10 i IFN- kao imuni odgovor na EBV infekciju u djece kod koje je transplantirana jetra i kod koje je dokazana EBV infekcija (151). EBV perzistira u epitelnim stanicama orofarinksa i limfocitima B. Limfociti B se inficiraju nakon kontakta sa epitelijalnim stanicama orofarinksa. Neki autori navode da bi limfociti B u orofarinksu mogli biti primarno mjesto infekcije (152). Neka istra~ivanja ukazuju da u zdravih individua jedan od pedeset limfocita B na milijun u cirkulaciji je inficiran EBV-om i broj latentno inficiranih stanica ostaje stabilan godinama (153,154). Da bi mogao inficirati limfocite B EBV-u poma~e MHC klasa II molekule kao kofaktor (155). Ovaj virus je razvio viae strategija da bi mogao izigrati imunosni sustav kao ato su latentna infekcija sa ograni enom ekspresijom gena, ometanje citokina i limfocita T8. U vrijeme akutne EBV infekcije in vivo svi geni, koji su vezani uz transformaciju virusa ispoljavaju se na limfocitima B i mogu slu~iti imunosnom sustavu kao meta za uniatavanje limfocita B (156). Mo~e se prenijeti slinom, transfuzijama krvi ili transplantacijom KS. Inkubacijski period infekciozne mononukleoze traje od 3 do 7 tjedana. Klasi ni klini ki sindrom mononukleoze je definiran kao trijas temperatura, faringitis i adenopatija. U laboratorijskim nalazima vidljiva je apsolutna limfocitoza s viae od 10% virusom transformiranih stanica. Seroloaki dokaz EBV infekcije su IgM protutijela na EBV kapsidni antigen (anti-VCA) koja se pojavljuju brzo nakon infekcije i mogu perzistirati tjednima ili mjesecima i dokazuju primarnu infekciju. IgG anti-VCA pojavljuju se u akutnoj fazi i u fazi oporavka, njihov titar raste u po etku, nakon ega dolazi do pada. Protutijela na virusni rani antigen (engl. early antigen  EA) (anti-EA) javljaju se kod veine primarnih infekcija s najveim titrom do 1:640, a s vremenom nestaju (157). Drugi mehanizam kojim EBV pokuaava prevariti imunosni sustav je ometanje citokinske mre~e. EBV sadr~ava genski produkt BCRF1 koji ima viae od 80% aminokiselina istih kao humani IL-10 (158). Kao i humani IL-10, EBV IL-10 inhibira sintezu IFN- pomou limfocita B i NK stanica, dok IFN-( mo~e inhibirati rast EBV-om transformiranih limfocita B. Oba citokina takoer inhibiraju sintezu IL-1, IL-12 i TNF od strane makrofaga i proliferaciju limfocita T ovisnu o makrofazima (159). Interakcijom sa specifi nim stani nim receptorima brojni virusni glikoproteini stimuliraju stanice direktno da lu e citokine. Prvi val citokina koji se stvaraju za vrijeme EBV infekcije su IL-1, IL-6, IL-8, IL-18, TNF-, IFN-/, IFN-, IL-1 receptor antagonist i GM-CSF (160). Virus ometa imunosni sustav tako da suprimira T stani ne prepoznavajue molekule i molekule za adheziju na povraini stanice i na taj na in zaatiuje inficirane stanice od limfocita T8 (161). Virusni proteini mogu oatetiti sposobnost imunosnog sustava da eliminira virus inhibirajui proliferaciju limfocita T. EBV i humani IL-10 stimuliraju rast i diferencijaciju limfocita B i posti u njihovu EBV-om induciranu transformaciju. Ovaj virus je otkriven u slini viae godina nakon primarne infekcije, a autori pretpostavljaju da je orofarinks rezervoar odakle se limfociti B inficiraju u viae navrata, odlaze u periferiju gdje mogu biti uniateni pomou limfocita T (162). 1.4.3. Humani herpes virus-6 HHV-6 je humani T-limfotropni virus otkriven 1986. godine u kulturama mononuklearnih stanica periferne krvi u 6 bolesnika s limfoproliferativnom boleau. (163). Seropozitivno je 60-80% djece i odraslih. Infekcija se obi no dogaa u ranom djetinjstvu pod slikom egzantema subitum. Filogenetski je najbli~i CMV, 66% sekvence DNA CMV i HHV-6 je homologan (164). Opisane su dvije razli ite varijante HHV-6, HHV-6A i HHV-6B, koje su u 94-96% sekvence nukleotida identi ne. Obje varijante su izolirane u imunokompromitiranih bolesnika. U organizmu perzistira cijeli ~ivot kao inaparentna infekcija i kad bolesnik postane imunodeficijentan mo~e se reaktivirati. U imunokompetentnih osoba u kasnijoj dobi mo~e izazvati sindrom mononukleoze ili neke od autoimunih i malignih bolesti. Limfociti T4 su najva~nije mjesto replikacije HHV-6 virusa, a mo~e se replicirati u limfocitima T8, NK stanicama, makrofazima, stanicama glije, astrocitima i plunim fibroblastima (165-168). Udru~en je s brojnim neuroloakim oboljenjima kao ato su encefalitis, konvulzije i multipla skleroza (169). Reaktivacijom mo~e poja ati patogenost drugih virusa, njihovu reaktivaciju ili pogoraati postojeu autoimunu bolest. Danas se istra~uje njegov utjecaj putem molekularne mimikrije kao i utjecaj na regulaciju citokinske mre~e. Ovaj virus je najprije limfotropan za limfocite T i suprimirajui njihovu funkciju smanjuje sintezu IL-2 i stani nu proliferaciju. Smatra se da ovaj imunotropni virus mo~e direktno inficirati ili interferirati s viae va~nih komponenti imunosnog sustava. Najnovije spoznaje vezane uz kvantitativni PCR e pomoi da se otkrije priroda ove infekcije u djece i u imunokompromitiranih bolesnika (170,171). Gosselin smatra da herpes virusi, uklju ujui i HHV-6, mogu selektivno regulirati sintezu citokina i na taj na in ometati imunosni sustav (172). Razli iti autori, kao ato su Yoshikawa i Ma, povezuju HHV-6 s hematoloakim bolestima, primarno s trombocitopenijom. Yoshikawa smatra da direktna virusna inhibicija stvaranja trombocita ili induciranje citokina virusom inficiranih stanica mo~e biti mehanizam nastanka trombocitopenije inducirane HHV-6 infekcijom (173,174). 1.4.4. Adenovirusi Adenovirusi su pronaeni u prakti ki svakom organskom sustavu u ovjeka. Adenovirusna bolest je endemi na u svako godianje doba, zahvaa sve dobne skupine a naj eae akolsku djecu. Bez simptoma je 50% inficiranih bolesnika. Adenovirusi se mogu replicirati i izazivati bolesti oka, dianog, probavnog i mokranog sustava. Mnoge adenovirusne infekcije prolaze subklini ki i virus mo~e perzistirati u domainu mjesecima. Humani adenovirus ima promjer 70-90 nm, nema ovojnicu, ima kapsidu koja sadr~i 252 kapsomere, a sastoji se od 13% dvostruke DNA i 87% proteina. Adenovirusi se dobro umno~avaju u jezgrama stanica epitelnog podrijetla. Citopatogeni su za humane stani ne kulture najprije bubrega, a zatim i epitelijalnih stanica. Kada je stanica inficirana adenovirusom mogu se vidjeti nuklearne inkluzije koje sadr~e DNA. Inficiraju regionalne limfne vorove. Adenovirusni antigen poti e sekreciju IFN- iz perifernih mononuklearnih stanica 12 sati nakon inkubacije. Va~an je stani ni odgovor limfocita T4 na infekciju adenovirusom (175). Sigurna metoda kojom mo~emo dokazati da se radi upravo o adenovirusnoj infekciji je izolacija virusa iz zahvaenih organa ili njihovih sekreta ili ako je oboljenje vezano uz prethodnu epidemioloaku situaciju izazvanu adenovirusom. Iako je izolacija virusa zlatni standard u dijagnozi adenovirusne infekcije, da bismo ovom metodom dokazali virus potrebno je nekoliko dana ili tjedana. PCR-om brzo i sigurno mo~emo dokazati DNA svih 47 tipova humanog adenovirusa (176). 1.4.5. Parvovirus B19 Parvovirus B19 je jedini poznati parvovirus patogen za ovjeka, kojeg su otkrili Cossart i suradnici 1974. godine (177). Da je ovaj virus uzro nik erythema infectiosum otkriveno je 1983. godine (178). U djece mo~e uzrokovati polyarthralgia-arthritis sindrom, a u odraslih aplasti ne krize i fetalnu smrt. Infekciozni eritem je naj eaa manifestacija infekcije (179). Nocton i Reid povezuju parvovirus s artritisom u djece (180,181). Foreman i Lefrere naglaaavaju povezanost ovog virusa s idiopatskom trombocitopeni nom purpurom (182,183). To je vrlo mali DNA virus (18-24 nm u promjeru), bez ovojnice, s visokom termalnom stabilnoau. Species je specifi an, mo~e rasti u humanim stanicama KS. Jako je patogen za humane eritroidne stanice. Stani ni receptor za parvovirus B19 je antigen P, koji se nalazi na zrelim eritrocitima, eritroidnim progenitorima, megakariocitima, endotelnim stanicama, placenti, fetalnoj jetri i srcu. Umno~avanje virusa uzrokuje smrt stanice blokirajui stvaranje crvenih krvnih zrnaca. Humani parvovirus B19 je jedini lan porodice Erythrovirusa. Nalazimo ga svugdje u svijetu, a infekcija mo~e biti tipa epidemije ili sporadi na. Anderson navodi da pozitivan IgG ima 2% do 15% djece u dobi od 1 do 5 godina, a 15% do 60% djeca u dobi od 5-19 godina ~ivota (184). Mo~e se prenijeti i parenteralnim putem, transfuzijom krvi, koncentratima faktora F VIII ili F IX i vertikalno od majke na fetus. Parvovirus B19 infekcija u zdravih osoba dovodi do rane viremi ne faze, stvaranja IgM, a zatim i IgG protutijela, uklanjanja virusa i stvaranja trajnog imuniteta. Simptomi infekcije variraju od bolesti bez simptoma do karakteristi nog eritema, anemije i artritisa sli nog RA, uz smanjen broj retikulocita, limfocita, neutrofila i trombocita. Aplasti na anemija je prolazna u zdrave djece, dok u imunokompromitirane mo~e biti kroni na. IgM protutijela mogu se nai i osam mjeseci nakon infekcije (185). Trombocitopenija udru~ena s parvovirus B19 infekcijom mo~e nastati prije ili poslije pojave osipa. Virus mo~e sprije iti nastanak megakariocita i inducirati stvaranje anti-DNA i antilimfocitnih protutijela, poremetiti imunosni sustav i provocirati nastanak razli itih imunoloakih oboljenja, pa tako i ITP. Tipi na imuna trombocitopenija opisana je kratko nakon pojave erythema infectiosum (186). Pomou PCR-a se mo~e dokazati virus u organizmu dugo vremena nakon preboljele akutne infekcije (187). 2. C I LJ E V I I S T R A } I V A NJ A Trombocitopenija je naj eae posljedica imunog mehanizma. U srazu antigen-antitijelo na trombocitnoj membrani, trombociti zna ajno krae ~ive zbog destrukcije /fagocitoze/ od strane mononuklearno-makrofagnog sustava, prvenstveno u slezeni. Za o ekivati je da pri tom srazu i meureakciji antigen-antitijelo, te postupku fagocitoze sudjeluju ili se oslobaaju citokini. Stoga je svrha ovog rada procijeniti dijagnosti ku i prognosti ku vrijednost citokina u djece i odraslih s trombocitopenijom. Specifi ni ciljevi rada su: Odrediti serumsku koncentraciju citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u djece i odraslih s trombocitopenijom i razlike u odnosu na kontrolnu skupinu. Odrediti razlike serumskih koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( izmeu djece i odraslih s trombocitopenijom pri dijagnozi. Utvrditi povezanost serumskih koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( s apsolutnim brojem limfocita, postotkom cirkulirajuih limfocita T, B, T4, T8 i NK stanica u djece i odraslih s trombocitopenijom pri dijagnozi. Utvrditi povezanost serumskih koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( s prisustvom serumskih IgM i IgG protutijela na CMV, EBV, HHV-6, adenovirus i parvovirus B19 u djece i odraslih s trombocitopenijom pri dijagnozi. Utvrditi povezanost serumskih koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u djece i odraslih s te~inom trombocitopenije, njenim trajanjem i terapijskim odgovorom. Utvrditi povezanost promjena i odrediti prognosti ke vrijednosti serumskih citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u odnosu na prelazak bolesti u kroni ni oblik u djece i odraslih s akutnom AITP. 3. I S P I T A N I C I, M A T E R I J A L I M E T O D E 3.1. Ispitanici U prospektivno ispitivanje su uklju ena sva djeca u dobi do 15 godina (n = 48) koja su zaprimljena na Klinici za dje je bolesti Klini ke bolnice u Splitu s potvrenom dijagnozom akutne AITP u periodu od 01.01.1999. do 30.05.2003. Usporedno su u istra~ivanje uklju eni i stariji od 15 godina s akutnom AITP zaprimljeni na Klinici za dje je bolesti i odrasli bolesnici zaprimljeni na Klinici za unutarnje bolesti Klini ke bolnice u Splitu i Zavodu za hematologiju, Klinike za unutarnje bolesti, Klini kog bolni kog centra Rebro u Zagrebu u periodu od 01.01.1999. do 30.05.2003. (n = 19). Tablica 2. Ispitanici s AITP  Djeca (N = 48) Ispitivana skupina Djeca (N = 26) Kontrolna skupina Odrasli (N = 19) Ispitivana skupina Odrasli (N = 24) Kontrolna skupina Dob (godine) Raspon 5 (0 14) 6 (1 12) 23 (15 87) 35 (15 - 50) Spol M/}*  31/17 (65%/35%) 15/11 (58%/42%) 9/10 (47%/53%) 6/18 (25%/75%)* M/} = Muaki/}enski Kontrolnu skupinu sa injavala su zdrava djeca (n = 26), te zdravi odrasli (n = 24) iste dobne skupine i spola, bez znakova trombocitopenije, koji su dolazili dobrovoljno na poziv, a u posljednjih 6 mjeseci nisu imali klini kih znakova upale ili sli nih bolesti. Studija je odobrena od Eti ke komisije Klini ke bolnice u Splitu, kao i Eti kog komiteta Medicinskog fakulteta Sveu iliata u Zagrebu. Roditelji djece i adolescenata s AITP i odrasli bolesnici su dobili pismenu informaciju o istra~iva koj studiji u okviru obrasca pristanka za sudjelovanje u istoj. 3.2. Materijal Koncentracije citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( i protutijela IgM i IgG na CMV, EBV, HHV-6, adenovirus i parvovirus B19 odreena su iz seruma, a apsolutni broj limfocita, cirkulirajui limfociti T, B, T4, T8 i NK stanice iz pune krvi ispitanika. Prisustvo megakariocita odreeno je citoloakom analizom KS nakon aspiracijske punkcije pri dijagnozi. 3.3. Metode 3.3.1. Kriteriji dijagnoze Kriterij dijagnoze AITP bio je broj trombocita u perifernoj krvi < 80 x 109/L, prisustvo megakariocita u KS, bez nekog drugog klini ki jasnog stanja koje mo~e uzrokovati trombocitopeniju. Kriterij dijagnoze kroni ne AITP bio je broj trombocita u perifernoj krvi manji od 150 x 109/L aest mjeseci od dijagnoze AITP. Te~ina trombocitopenije - Temeljem broja trombocita bolesnici su svrstani u 4 skupine: - izrazito teaka trombocitopenija: trombociti < 10.0 x 109/L - teaka trombocitopenija: trombociti od 10.1  30.0 x 109/L - umjereno teaka trombocitopenija: trombociti od 30.1  50.0 x 109/L - umjerena trombocitopenija: trombociti od 50.1  80.0 x 109/L Lije enje AITP U slu aju izrazite AITP (broj trombocita u perifernoj krvi < 20 x 109/L) s klini kim znakovima krvarenja ili ako je broj trombocita u perifernoj krvi bio < 10 x 109/L odrasli su lije eni metilprednisolonom 80-100 mg/m2 s ili bez azatioprina, a djeca s ili bez IVIG-a (Octagam, Octafarma, Be , Austrija ili Endobulin, Baxter, Be , Austrija) 1g/kg dva dana za redom. Odreivanje citokina Odreene su serumske vrijednosti IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( specifi nim protutijelima u testu ELISA (engl. enzyme linked immunosorbent assay) (188). Tablica 3. Normalne koncentracije serumskih citokina Citokin pg/mlKontrolna skupinanMean + SD Min-Maks IL-1Djeca262,4 + 1,420,1 - 4,9Odrasli242,7 + 1,081 - 5,8IL-2Djeca2629,4 + 3,6718 - 43,2Odrasli2426,1 + 2,5817 31IL-3Djeca2648,5 + 9,5340,2 - 74,2Odrasli2470,5 + 29,9031,2 150IL-4Djeca268,5 + 0,317,9 - 8,9Odrasli2410,4 + 2,127,3 - 14,9IL-6Djeca264,5 + 0,983,2 - 7,1Odrasli247,4 + 1,583,12 - 9,54IL-10Djeca2618,2 + 2,9916,2 - 28,8Odrasli2418 + 2,914,7 - 29,8TNF-Djeca2622,9 + 3,2819  33Odrasli2420,6 + 3,3217 - 29,4IFN-Djeca2647,3 + 2,2244,1  51,2Odrasli2454,4 + 10,736 - 68,3IFN-Djeca2643,6 + 26,659,87  89Odrasli2427,7 + 21,474  89 Koriateni su slijedei kitovi proizvoa a R&D Systems, Minneapolis, USA: RD-DLA 50 IL 1 alpha human ELISA; RD-D2050 IL 2 human ELISA; RD-D3000 IL 3 human ELISA; RD-D4050 IL 4 human ELISA; RD-D6050 IL 6 human ELISA; RD-D1000 IL 10 human ELISA; RD-DTA 50 TNF alpha human ELISA; RD-DIF 50 IFN gama human ELISA; RD-41110-1 IFN alpha human ELISA. Koncentracije ispitivanih citokina u zdravih kontrolnih skupina prikazuje tablica 3. Odreivanje virusa Odreena su serumska IgM i IgG protutijela na CMV, EBV, EBV virusni kapsidni antigen (anti-VCA), rani antigen (anti-EA), EBV nuklearni antigen (anti-EBNA samo IgG), HHV-6, adenovirus i parvovirus B19. Upotrijebljeni su standardni postupci: test imunoflorescencije, ELISA i Western-blot esej (189,190). Odreivanje cirkulirajuih limfocita Apsolutni broj limfocita (CD45+), postotak cirkulirajuih limfocita T (CD3+/CD45+) i B (CD19+/CD45+), pomoni kih limfocita T4 (CD3+, CD4+/CD45+), citotoksi no/supresorskih limfocita T8 (CD3+, CD8+/CD45+) i NK stanica (CD16+, CD56+/CD45+) odreeni su pomou proto nog razvrstava a stanica FACSCalibur, Becton Dickinson Immunocytometry Systems, San Jose, California, USA (#E3906), Software: MultiSET V1.1.2 ili SimulSET v 3.1. (191). Referentne vrijednosti apsolutnog broja limfocita su 4000  13500/L, a postotka cirkulirajuih limfocita T 55% - 84%, B 6% - 25%, T4 31% - 60%, T8 13% - 41%, a NK stanica 5% - 27%. Plan ispitivanja Nakon ato je postavljena dijagnoza AITP (odreivanjem broja trombocita i citoloakim pregledom KS) odreene su serumske koncentracije citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-(, serumska protutijela na viruse CMV, EBV, HHV-6, adenovirus i parvovirus B19, apsolutni broj limfocita, postotak cirkulirajuih limfocita T, B, T4, T8 i NK stanica. Bolesnici s trombocitima < 20 x 109/L lije eni su samo metilprednisolonom ili kombinacijom metilprednisolona s azatioprinom i/ili IVIG-om. Osam tjedana i 6 mjeseci od dijagnoze odreen je broj trombocita u perifernoj krvi i serumske koncentracije citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( (slika 2). KS Citokini Citokini Citokini Pretrage Protutijela na viruse Limfociti Trombociti Trombociti Trombociti  Tjedni / 1____________________/8__________________/24  _____________lije enje/opservacija__________ Slika 2. Plan ispitivanja Prikaz rezultata i statisti ka obrada Pri statisti koj analizi podataka upotrijebljeni su specijalizirani ra unalni programi za statisti ke analize Statistica 6.0 za Windows software i Statisti ki paket za socijalne znanosti (engl. Statistical Package for Social Sciences software, SPSS) verzija 11.0. za Windows software (SPSS od SSCP Inc., Chicago, IL, USA). Parametrijskim t-testom za nezavisne uzorke s logaritamski transformiranim varijablama usporeene su serumske koncentracije citokina. Rezultati su prikazani kao srednja vrijednost + SD, minimum, maksimum, t i p vrijednost. U analizi podataka, prilikom usporedbe dviju nezavisnih varijabli upotrijebljna je analiza varijance s jednim promjenjivim faktorom (ANOVA), a od neparametrijskih metoda klasi ni 2 test, Fisherov exact test, Kruskal-Wallisova analiza varijance za usporedbu varijabli izmeu viae skupina, Mann-Whitneyev test za usporedbu dviju skupina, Friedmanova analiza varijance za usporedbu varijabli mjerenih na istim pacijentima u viae navrata (pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci) i Wilcoxonov test (engl. Wilcoxon Matched pairs test) za usporedbu jedne varijable mjerene u dva navrata na istim ispitanicima (192,193). Dobiveni rezultati izra~eni su kao aritmeti ke sredine i standardne devijacije (X + SD), medijan, minimalna i maksimalna vrijednosti ispitivanih varijabli. Koriatena je grani na razina zna ajnosti 5% (p < 0,05) i 1% (p < 0,01) (194). Da bi se mogla analizirati povezanost promjena i prognosti kih vrijednosti razine serumskih citokina u odnosu na prelazak bolesti u kroni ni oblik upotrijebljen je model viaestruke regresije kako bi se dobio optimalni broj regresorskih varijabli (prediktora), koje utje u na regresand varijablu. Odreen je koeficijent determinacije i protuma enost modela, a F-testom testirana je njegova zna ajnost (195). Pri tome je u djece s AITP upotrijebljena jednad~ba viaestruke regresije: w =107508 + 1462 x X1  7462 x X2  8361 x X3 + 3655 x X4 + 0,899 x X5, a u odraslih s AITP jednad~ba viaestruke regresije: w = 43766 - 7194 x X1 6326 x X2 + 0,103 x X3 + 2793 x X4. 4. REZULTATI 4.1. Broj trombocita u perifernoj krvi bolesnika s trombocitopenijom pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u djece i odraslih s AITP Broj trombocita pri dijagnozi bolesti u svih ispitanika bio je sni~en kako u skupini djece tako i u odraslih bolesnika (tablica 4). Djeca su imala prosje an broj trombocita pri dijagnozi 18,6 x 109 /L (minimum 0; maksimum 79 x 109/L; medijan 8 x 109/L), a odrasli 36,8 x 10 9/L (minimum 1 x 109/L; maksimum 74 x 109/L; medijan 42 x 109/L). Iz tablice 4 vidljivo je da je u veine bolesnika doalo do normalizacije broja trombocita nakon 8 tjedana odnosno nakon 6 mjeseci observacije ili lije enja, te je u svega 34,5% djece i 37,5% odraslih nakon 6 mjeseci naena trombocitopenija. Statisti ki je zna ajno porastao broj trombocita nakon 6 mjeseci u djece (2 = 40,82; p < 0,001) i odraslih (2 = 10,3; p < 0,006). Tablica 4. Prikaz broja trombocita pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u perifernoj krvi djece i odraslih s AITP i ukupno nTrombocitiMean +SD x 109 /LMedijan x 109 /LRaspon x 109 /L45Pri Dg18,56 + 21,228,00,0 - 79,0Djeca348 tjedan160,70 + 110,77163,58,0 - 463,0296 mjeseci191,76 + 110,12190,013,0 - 393,019Pri Dg36,84 + 24,8942,01,0 - 74,0Odrasli128 tjedan127,91 + 103,8785,041,0 - 346,086 mjeseci179,87 + 90,56177,549,0 - 351,064Pri Dg23,25 + 23,1711,00,0 - 79,0Ukupno468 tjedan152,15 + 108,85126,08,0 - 463,0276 mjeseci189,19 + 105,13190,013,0 - 393,0 Broj trombocita u perifernoj krvi djece i odraslih s AITP pri dijagnozi statisti ki se zna ajno razlikovao Mann-Whitney testom (z = 2,8; p = 0,05) i Studentovim t-testom za nezavisne uzorke (t = - 2,99; p = 0,004). U djece je bio zna ajno manji. U svih bolesnika pri dijagnozi djece i odraslih broj trombocita u perifernoj krvi bio je ispod 80 x 109/L. Analizirajui parametrijskim t-testom broj trombocita u perifernoj krvi u odnosu na spol u djece s AITP nije dokazana zna ajnost razlike u broju trombocita pri dijagnozi (t = - 0,62; p = 0,54), broju trombocita nakon 8 tjedana (t = 0,09; p = 0,928) i broju trombocita nakon 6 mjeseci (t = 0,87; p = 0,391). U preko 50% djece trombocitopenija je bila izrazito teka do teka, dok je u ostalih zadovoljavala kriterije umjereno teke do umjerene trombocitopenije. U 26% odraslih trombocitopenija je bila izrazito teka do teka, dok je u ostalih 74% zadovoljavala kriterije umjereno teke do umjerene trombocitopenije (tablica 5). Tablica 5. U estalost te~ine trombocitopenije u djece i odraslih Broj trombocita  DJECA N(%) ODRASLI N(%) P< 10 x 109/L26(58%)5(26%)0,01110.1  30.0 x 109/L8(18%)3(16%)0,42430.1  50.0 x 109/L8(18%)4(21%)0,390> 50.0 x 109/L3(6%)7(37%)0,001Ukupno45(100%)19(100%) U odraslih s AITP broj trombocita pri dijagnozi se statisti ki zna ajno razlikovao po spolu, tako da je u ~ena bio zna ajno ni~i (t = 2,56; p = 0,020), za razliku od broja trombocita nakon 8 tjedana (t = 1,24; p = 0,244) i broja trombocita nakon 6 mjeseci (t = 0,47; p = 0,658), gdje nije bilo statisti ki zna ajne razlike po spolu. Bolesnici su podijeljeni na one s akutnom AITP, u kojih je broj trombocita u perifernoj krvi 6 mjeseci od dijagnoze bio vei ili jednak 150 x 109/L, i na bolesnike s kroni nom AITP, u kojih je broj trombocita u perifernoj krvi nakon 6 mjeseci od dijagnoze bio manji od 150 x 109/L. Viae je bilo muake djece (70%) nego ~enske (30%) s kroni nom AITP. Nije bilo statisti ki zna ajne razlike u broju trombocita u perifernoj krvi izmeu muake i ~enske djece s kroni nom AITP (t = 0,35; p = 0,736). Srednje vrijednosti trombocita u muake djece su bile 73,4 + 48,18 x 109/L (minimum 25 x 109/L, maksimum 149 x 109/L), a u ~enske 61,0 + 60,65 x 109/L (minimum 25 x 109/L, maksimum 149 x 109/L). Analizom varijance s jednim promjenjivim faktorom nije dokazana statisti ki zna ajna razlika broja trombocita u perifernoj krvi u svih bolesnika s akutnom (n = 24) i kroni nom AITP (n = 13) pri dijagnozi (n = 37) (F = 0,26; p = 0,615). U bolesnika s akutnom AITP srednja vrijednost broja trombocita pri dijagnozi bila je 19,6 + 25,98 x 109/L (minimum 0; maksimum 79 x 109/L), a u bolesnika s kroni nom AITP bila je 23,85 + 20,19 x 109/L (minimum 6 x 109/L; maksimum 66 x 109/L). ) Broj trombocita u perifernoj krvi nakon 8 tjedana (n = 36), pokazivao je statisti ki zna ajnu razliku izmeu bolesnika s akutnom i kroni nom AITP (F = 6,89; p = 0,013). U bolesnika s akutnom AITP srednja vrijednost broja trombocita nakon 8 tjedana bila je 198,8 + 116,81 x 109/L (minimum 41 x 109/L; maksimum 463 x 109/L), a u bolesnika s kroni nom AITP bila je 104,2 + 59,59 x 109/L (minimum 15 x 109/L; maksimum 205 x 109/L). U troje bolesnika s kroni nom AITP broj trombocita nakon 8 tjedana je bio vei od 150 x 109/L i u njih je u razdoblju do 6 mjeseci uslijedio pad trombocita ispod 150 x 109/L. U bolesnika s akutnom AITP srednja vrijednost broja trombocita nakon 6 mjeseci (250,1 + 70,71 x 109/L (minimum 151 x 109/L; maksimum 393 x 109/L) je bila statisti ki zna ajno vea (F = 62,97; p < 0,001) nego u u bolesnika s kroni nom AITP je bila 76,2 + 47,56 x 109/L (minimum 13 x 109/L; maksimum 146 x 109/L). 4.2. Koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u serumu djece s trombocitopenijom pri dijagnozi Usporeujui serumske koncentracije odabranih citokina izmeu zdrave djece i djece s AITP pri dijagnozi uo ena je zna ajnost razlike u serumskim koncentracijama IL-2, IL-4 i TNF- (tablica 6). U djece s trombocitopenijom naene su grani no vee koncentracije citokina IL-4 (t = - 1,91; p = 0,062; slika 3., tablica 6), i statisti ki zna ajno manje koncentracije citokina IL-2 (slika 4, tablica 6; t = 2,37; p = 0,021) i TNF- (slika, tablica 6; t = 2,71; p = 0,009). Koncentracija ostalih citokina bila je unutar referentnih vrijednosti.  Slika 3. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, standardne pogreke (SE) i SD IL-4 u zdrave i djece s AITP pri dijagnozi  Slika 4. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-2 u zdrave i djece s AITP pri dijagnozi  Slika 5. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD TNF-( u zdrave i djece s AITP pri dijagnozi Tablica 6. Prikaz razlika serumskih kocentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u zdrave i djece s AITP pri dijagnozi Citokin pg/mlDjecanMean + SD Min-Maks tpIL-1Ispitivani293,5 + 2,760,0  9,5- 1,480,146Kontrola262,4 + 1,420,1 - 4,9IL-2Ispitivani2926,5 + 6,2518 - 43,52,370,021Kontrola2629,4 + 3,6718 - 43,2IL-3Ispitivani2954,2 + 16,7719,5 - 83- 0,770,445Kontrola2648,5 + 9,5340,2 - 74,2IL-4Ispitivani2911,6 + 7,767,7 - 32,5-1,910,062Kontrola268,5 + 0,317,9 - 8,9IL-6Ispitivani296,1 + 5,153 25-1,210,233Kontrola264,5 + 0,983,2 - 7,1IL-10Ispitivani2918,3 + 6,238 34,90,610,554Kontrola2618,2 + 2,9916,2 - 28,8TNF-Ispitivani2920,1 + 4,837,9  302,710,009Kontrola2622,9 + 3,2819  33IFN-Ispitivani2947,4 + 6,4236,2  63,30.220,830Kontrola2647,3 + 2,2244,1  51,2IFN-Ispitivani2953,8 + 35,356 - 150-1,160,252Kontrola2643,6 + 26,659,87  89 Nije bilo statisti ki zna ajne razlike u serumskim koncentracijama IL-1 (t = - 1,48; p = 0,146), IL-3 (t = - 0,77; p = 0,445), IL-6 (t = - 1,21; p = 0,233), IL-10 (t = 0,61; p = 0,554), IFN- (t = 0,22; p = 0,830) i IFN- (t = - 1,16; p = 0,252) (tablica 6). 4.3. Koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u serumu odraslih s trombocitopenijom pri dijagnozi Analiza usporedbe serumskih vrijednosti citokina meu skupinama izvraena je parametrijskim t-testom za nezavisne uzorke s logaritamski transformiranim varijablama. Rezultati su prikazani u tablici 7. kao srednja vrijednost + SD, minimum, maksimum, t i p vrijednost. Tablica 7. Prikaz razlika serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u odraslih s AITP pri dijagnozi i kontrolne skupine Citokin pg/mlOdraslinMean + SD Min-Maks tpIL-1Ispitivani183,8 + 2,660,0  11,3- 2,070,045Kontrola242,7 + 1,081 - 5,8IL-2Ispitivani1925,8 + 4,1317,5  31,20,440,660Kontrola2426,1 + 2,5817 31IL-3Ispitivani1961,0 + 27,2924,5 1371,220,230Kontrola2470,5 + 29,9031,2 150IL-4Ispitivani1916,6 + 11,318,1 48,9- 2,650,011Kontrola2410,4 + 2,127,3 - 14,9IL-6Ispitivani197,9 + 2,133,5 13,5- 0,680,503Kontrola247,4 + 1,583,12 - 9,54IL-10Ispitivani1916,3 + 3,539,3 27,52,110,041Kontrola2418,0 + 2,914,7 - 29,8TNF-Ispitivani1920,2 + 6,4115,7  410,700,494Kontrola2420,6 + 3,3217 - 29,4IFN-Ispitivani1958,8 + 14,3136,3  82,8- 0,970,336Kontrola2454,4 + 10,736 - 68,3IFN-Ispitivani1930,1 + 22,475,3  87,9- 0,620,537Kontrola2427,7 + 21,474  89 Analizom usporedbe serumskih koncentracija odabranih citokina u zdravih i odraslih s AITP pri dijagnozi uo ena je zna ajnost razlike serumskih koncentracija IL-1 (t = - 2,07; p = 0,045), IL-4 (t = - 2,65; p = 0,011) i IL-10 (t = 2,11; p = 0,041). Odrasli s AITP su imali statisti ki zna ajno vee vrijednosti IL-1 (slika 6) i IL-4 (slika 7), a statisti ki zna ajno manje koncentracije IL-10 (slika 8) od zdravih ispitanika. Nije bilo statisti ki zna ajne razlike u serumskim koncentracijama IL-2 (t = 0,44; p = 0,660), IL-3 (t = 1,22; p = 0,230), IL-6 (t = - 0,68; p = 0,503), TNF- (t = 0,70; p = 0,494), IFN- (t = - 0,97; p = 0,336) i IFN-( (t = - 0,62; p = 0,537) (tablica 7).  Slika 6. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-1 u zdravih i odraslih s AITP pri dijagnozi  Slika 7. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-4 u zdravih i odraslih s AITP pri dijagnozi Slika 8. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-10 u zdravih i odraslih s AITP pri dijagnozi 4.4. Koncentracije citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( i njihove razlike u djece i odraslih s trombocitopenijom pri dijagnozi Koncentracije citokina pri dijagnozi i njihove razlike u djece i odraslih prikazuje tablica 8. Dokazana je statisti ki zna ajna razlika u serumskim koncentracijama IL-4 (t = - 2,20; p = 0,033), IL-6 (t = - 3,01; p = 0,004), IFN- (t = - 3,46; p = 0,001) i IFN- (t = 2,81; p = 0,007). Djeca s AITP su imala statisti ki zna ajno manje koncentracije IL-4 (slika 9), IL-6 (slika 10) i IFN- (slika 11), a statisti ki zna ajno vee koncentracije IFN- (slika 12). Nije bilo statisti ki zna ajne razlike u serumskim koncentracijama IL-1 (t = - 0,79; p = 0,432), IL-2 (t = 0,21; p = 0,838), IL-3 (t = - 0,73; p = 0,468), IL-10 (t = 0,97; p = 0,338) i TNF- (t = 0,02; p = 0,987) (tablica 8). Tablica 8. Prikaz razlika serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u djece i odraslih s AITP pri dijagnozi Citokin pg/mlBolesninMean + SD Min-Maks tpIL-1Djeca293,5 + 2,760,0  9,5- 0,790,432Odrasli193,8 + 2,660,0  11,3IL-2Djeca2926,5 + 6,2518 - 43,50,210,838Odrasli1925,8 + 4,1317,5 31,2IL-3Djeca2954,2 + 16,7719,5 - 83- 0,730,468Odrasli1961,0 + 27,2924,5 137IL-4Djeca2911,6 + 7,777,7 - 32,5- 2,200,033Odrasli1916,6 + 11,38,1 48,9IL-6Djeca296,1 + 5,153 25- 3,010,004Odrasli197,9 + 2,133,5 13,5IL-10Djeca2918,3 + 6,238 34,90,970,338Odrasli1916,3 + 3,539,3 27,5TNF-Djeca2920,1 + 4,837,9  300,020,987Odrasli1920,2 + 6,4115,7  41IFN-Djeca2947,4 + 6,4236,2  63,3- 3.460,001Odrasli19 58,8 + 14,3136,3  82,8IFN-Djeca2953,8 + 35,356 - 1502,810,007Odrasli1930,1 + 22,47 5,3 87,9 Slika 9. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-4 u djece i odraslih s AITP pri dijagnozi Slika 10. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-6 u djece i odraslih s AITP pri dijagnozi  Slika 11. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN- u djece i odraslih s AITP pri dijagnozi  Slika 12. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN- u djece i odraslih s AITP pri dijagnozi 4.5. Povezanost serumskih koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( s apsolutnim brojem limfocita, postotkom cirkulirajuih limfocita T, B, T4, T8 i NK stanica u djece i odraslih s trombocitopenijom pri dijagnozi Analiza apsolutnog broja limfocita (n = 29), postotka cirkulirajuih limfocita T (n = 33), B (n = 33), T4 (n = 34), T8 (n = 34) i NK stanica (n = 32) u perifernoj krvi djece i odraslih s AITP, te njihova povezanost sa serumskim koncentracijama citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u sva tri mjerenja (/1, /2, /3) zajedno prikazani su u tablici 9. Apsolutni broj limfocita ispod 4000/L imalo je 25 (86%) od 29 oboljelih od AITP - 14 (87,5%) od 16 djece i 11 (84,5%) od 13 odraslih. U djece i odraslih apsolutni broj limfocita u perifernoj krvi je u visokom postotku bio ispod granice normale pri dijagnozi (slika 13). Postotak cirkulirajuih limfocita T u perifernoj krvi ispod granice normale imalo je jedno dijete s AITP (5%) od ukupno 18 djece, dok je u 17 (95%) djece postotak bio u granicama normale. U odraslih jedan (6,6%) je imao postotak cirkulirajuih limfocita T ispod granice normale, jedan (6,6%) iznad granice normale, dok je u njih 13 (86,8%) ovaj postotak bio u granicama normale. U etvero djece (22%) postotak cirkulirajuih limfocita B je bio iznad granice normale dok je u njih 14 (78%) bio u granicama normale. U odraslih 2 (13,3%) je imalo postotak cirkulirajuih limfocita B ispod granica normale, a 13 (86,7%) u granicama normale.  EMBED StaticEnhancedMetafile   EMBED StaticEnhancedMetafile  Slika 13. Prikaz apsolutnog broja limfocita u djece i odraslih s AITP pri dijagnozi  EMBED StaticEnhancedMetafile   EMBED StaticEnhancedMetafile  Slika 14. Prikaz postotka cirkulirajuih limfocita T4 u djece i odraslih s AITP pri dijagnozi Postotak cirkulirajuih limfocita T4 u 10 (52,6%) djece i u 4 (27,6%) odrasla je bio ispod granice normale, dok je u 9 (47,4%) djece i u 11 (72,4%) odraslih bio u granicama normale. U djece s AITP postotak cirkulirajuih limfocita T4 je u zna ajnom postotku bio ispod granica normale pri dijagnozi, za razliku od odraslih u kojih je taj postotak, u odnosu na djecu, bio neato ni~i (slika 14). Postotak cirkulirajuih limfocita T8 u dvoje djece s AITP (10,5%) je bio iznad granice normale, dok je u 17 (89,5%) bio u granicama normale. U odraslih jedan (6,6%) je imao postotak cirkulirajuih limfocita T8 ispod granice normale, jedan (6,6%) iznad granice normale, dok je njih 13 (86,8%) isti postotak imalo u granicama normale. Postotak cirkulirajuih NK stanica ispod normale imalo je jedno dijete s AITP (5,8%), dok je u njih 16 (94,2%) taj postotak bio u granicama normale. U 2 (13,3%) odrasla je postotak cirulirajuih NK stanica bio ispod granica normale, u 1 (6,6%) iznad granica normale, dok je u njih 11 (73,3%) taj postotak bio u granicama normale. Razlike imunoloaih parametara: apsolutnog broja limfocita, postotka cirkulirajuih limfocita T, B, T4, T8 i NK stanica pri dijagnozi izmeu djece i odraslih s AITP ispitane su student t-testom za nezavisne uzorke (tablica 9). Nije bilo statisti ki zna ajne razlike u apsolutnom broju limfocita u perifernoj krvi (t = 1,59; p = 0,123). Apsolutni broj limfocita u djece s AITP iznosio je 2810,2 + 1248,89/L (medijan: 2509/L; minimum 1460/L; maksimum 5772/L), a u odraslih 2110,2 + 1081,43 /L (medijan: 1992/L; minimum 759/L; maksimum 4430/L). Nije bilo statisti ki zna ajne razlike u postotku cirkulirajuih limfocita T (t = 0,20; p = 0,984), koji je u djece s AITP iznosio 65,6 + 9,59 % (medijan 66%; minimum 42%; maksimum 82%), a u odraslih 65,5 + 12,67% (medijan 66%; minimum 27%; maksimum 86%). Nije bilo statisti ki zna ajne razlike u postotku cirkulirajuih limfocita B djece i odraslih s AITP (t = 0,68; p = 0,503). U djece postotak cirkulirajuih limfocita B je iznosio 20,2 + 8,71% (medijan 22%; minimum 7%; maksimum 43%), a u odraslih 17,3 + 15,51% (medijan 14%; minimum 6%; maksimum 68%). Dokazana je statisti ki zna ajna razlika u postotku cirkulirajuih limfocita T4 (t = - 1,97; p = 0,057), koji je u djece s AITP iznosio je 32,5 + 7,65% (medijan 30%; minimum 19%; maksimum 48%), a u odraslih 39,5 + 12,91% (medijan 43%; minimum 17%; maksimum 60%). Postotak cirkulirajuih limfocita T4 u djece je bio statisti ki zna ajno ni~i. Izmeu ispitivanih skupina nije bilo statisti ki zna ajne razlike u postotku cirkulirajuih limfocita T8 (t = 0,62; p = 0,540), koji je u djece s AITP iznosio 28,3 + 9,69 % (medijan 24%; minimum 16%; maksimum 51%), a u odraslih 26,3 + 8,69% (medijan 25%; minimum 9%; maksimum 43%). Nije bilo statisti ki zna ajne razlike u postotku cirkulirajuih NK stanica izmeu djece i odraslih s AITP (t = - 0,81; p = 0,423), jer je postotak cirkulirajuih NK stanica u djece s AITP iznosio 13,4 + 5,36 % (medijan 13%; minimum 4%; maksimum 24%), a u odraslih 15,5 + 9,49% (medijan 16%; minimum 3%; maksimum 33%). U djece postotak cirkulirajuih limfocita T je pokazivao statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-1/1 (r = 0,46; p = 0,098) i IL-1/2 (r = 0,48; p = 0,081). Vrijednosti limfocita B su pokazivale statisti ki zna ajno negativnu povezanost sa serumskim koncentracijama IL-6/3 (r = - 0,88; p = 0,021), IL-10/3 (r = - 0,91; p = 0,013). Postotak limfocita T4 je pokazivao statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-1/1 (r = 0,54; p = 0,036). U djece su vrijednosti limfocita T8 pokazivale statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-4/3 (r = 0,68; p = 0,094). Vrijednosti NK stanica su pokazivale statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-2/1 (r = 0,55; p = 0,052), IL-10/3 (r = 0,78; p = 0,066), TNF-(/2 (r = 0,49; p = 0,092) i IL-6/3 (r = 0,81; p = 0,057), a statisti ki zna ajno negativnu povezanost sa serumskim koncentracijama IL-1/1 (r = - 0,49; p = 0,089). U odraslih su limfociti T pokazivali statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-3/1 (r = 0,51; p = 0,054) i IL-10/2 (r = 0,70; p = 0,024). Cirkulirajui limfociti B su pokazivali statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-4/3 (r = 0,94; p = 0,005), a statisti ki zna ajno negativnu sa serumskim koncentracijama IFN-(/2 (r = - 0,71; p = 0,020). Postotak cirkulirajuih limfocita T4 je pokazivao statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-10/2 (r = 0,57; p = 0,082). Vrijednosti NK stanica su pokazivale statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IFN-(/2 (r = 0,56; p = 0,095), IFN-(/3 (r = 0,78; p = 0,070) i IFN-(/3 (r = 0,84; p = 0,036). SHAPE \* MERGEFORMAT  Tablica 9. Prikaz razlika apsolutnog broja limfocita, postotka cirkulirajuih limfocita T, B, T4, T8 i NK stanica pri dijagnozi u perifernoj krvi djece i odraslih s AITP LimfocitinIspitaniciMean + SDMin-MakstpApsolutni 16Djeca2810,2 + 1248,91460  57721,59 0,123broj /L13Odrasli2110,2 + 1081,4 759  4430T (%)18Djeca 65,1 + 9,5 42  820,20 0,98415Odrasli 65,5 + 12,727 86B (%)18Djeca 20, 2 + 8,77 43 0,68 0,50315Odrasli 17,3 + 15,56 68 T4 (%)19Djeca 32,5 + 7,6 19 48 - 1,97 0,05715Odrasli39,5 + 12,9 17 60 T8 (%)19Djeca28,3 + 9,716 51 0,620,54015Odrasli26,3 + 8,79 43NK (%)17Djeca13,4 + 5,44 24- 0,81 0,423 15Odrasli15,5 + 9,53 33 Analizirajui Pearsonovim testom korelacije povezanost izmeu apsolutnog broja limfocita, postotka cirkulirajuih limfocita T, B, T4, T8 i NK stanica pri dijagnozi s brojem trombocita u perifernoj krvi u sva tri mjerenja u djece nije dokazana statisti ki zna ajna povezanost meu varijablama (tablica 10). U odraslih bolesnika broj trombocita u perifernoj krvi pri dijagnozi nije bio statisti ki zna ajno povezan s postotkom cirkulirajuih limfocita T i T4, ali je bio statisti ki zna ajno pozitivno povezan s postotkom cirkulirajuih limfocita B (r = 0,49, p = 0,065), T8 (r = 0,49; p = 0,064) i NK stanica (r = 0,45; p = 0,096). Dokazana je statisti ki zna ajna negativna povezanost izmeu apsolutnog broja limfocita i broja trombocita pri dijagnozi (r = - 0,75; p = 0,003) (slika 15) i statisti ki zna ajna negativna povezanost postotka cirkulirajuih NK stanica pri dijagnozi i broja trombocita nakon 8 tjedana (r = - 0.66; p = 0,039) (tablica 10). Tablica 10. Prikaz povezanosti apsolutnog broja limfocita, postotka cirkulirajuih limfocita T, B, T4, T8 i NK stanica s brojem trombocita u djece i odraslih s AITP DjecaTrombocitiKorelacijaApsolutni broj limfocitaLimfociti TLimfociti BLimfociti T4Limfociti T8NK stanicePri r- 0,130,27- 0,140,260,24- 0,30dijagnozip0,6280,2850,5700,2880,3290,242n 16 1818 1919 17r- 0,060,19- 0,240,090,0000,018 tjedanp0,8520,5060,3910,7460,9990,973n131515161614r0,220,37- 0,240,450,18- 0,276 mjesecip0,5090,2070,4330,1080,5500,399n111313141412 OdrasliPri r- 0,750,210,49- 0,080,490,45dijagnozip0,0030,4570,0650,7710,0640,096n131515151515r0,570,280,100,42- 0,03- 0,668 tjedanp0,1080,4340,7860,2290,9370,039n91010101010r0,480,050,640,232- 0,12- 0,696 mjesecip0,4110,9210,1680,6580,8270,132n566666  EMBED StaticEnhancedMetafile  Slika 15. Prikaz negativne povezanosti broja trombocita i apsolutnog broja limfocita u perifernoj krvi u odraslih s AITP pri dijagnozi 4.6. Povezanost serumskih koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( s prisustvom serumskih IgM i IgG protutijela na CMV, EBV, HHV-6, adenovirus i parvovirus B19 u djece i odraslih s trombocitopenijom pri dijagnozi Serumske vrijednosti IgM i IgG protutijela na CMV, EBV, HHV-6, adenovirus i parvovirus B19 odreene su u 56 bolesnika, 39 djece i 17 odraslih s AITP, a rezultati prikazani u tablici 11. Pozitivna IgM serumska protutijela na bilo koji od odabranih virusa imalo je 33 (59%) bolesnika (slika 16). Sveukupno je bilo 7 (12%) bolesnika, koji su imali pozitivna IgM serumska protutijela istovremeno na dva ili vie virusa. Prisustvo serumskih IgM i IgG protutijela na CMV analizirano je u 56 bolesnika, 39 djece i 17 odraslih i prikazano u tablici 11. Negativna serumska CMV IgM protutijela imalo je 55 bolesnika (98%), 38 (97,4%) djece i 17 (100%) odraslih. Od svih bolesnika samo je jedno dijete (2%) imalo serumska CMV IgM protutijela pozitivna (slika 16). Pozitivna serumska CMV IgG protutijela imalo je 42 (75%) bolesnika, 28 (72%) djece i 14 (82%) odraslih. Negativna protutijela imalo je 11 (28%) djece i 3 (17,6%) odrasla. Nije bilo statisti ki zna ajne razlike u estalosti pozitivnih CMV IgG serumskih protutijela u djece i odraslih s AITP (2 = 0,7; p = 0,4). Serumska protutijela na EBV (EBV EA IgM, EBV EA IgG, EBV VCA IgM, EBV VCA IgG, EBNA IgG) analizirana su u 56 bolesnika, 39 djece i 17 odraslih i prikazala u tablici 11. Seroloaki potvrenu akutnu EBV infekciju imalo je 9 (16%) djece i odraslih s AITP (slika 16). EBV EA IgM serumska protutijela dokazana su u 6 (11%), a u 50 (89%) djece i odraslih s AITP nisu. EBV EA IgM pozitivna serumske protutijela imalo je etvero djece i dvoje odraslih, a negativna 35 (90%) djece i 15 (88,2%) odraslih. EBV EA IgG serumska protutijela su u 51(91%) djece i odraslih s AITP bila negativna, a u 5 (9%) pozitivna. Serumska EBV EA IgG protutijela je imalo dvoje djece i 3 odrasla s AITP. Serumska EBV VCA IgM protutijela su u 53 (95%) bolesnika, od toga u 37 (94,9 %) djece i 16 (94 %) odraslih s AITP bila negativna. Troje je bilo pozitivno, od toga dvoje djece i jedan odrasli. EBV VCA IgG serumska protutijela su u 36 (64%) bolesnika bila pozitivna, od toga 22 (56%) djeteta i 14 (82%) odraslih s AITP. Serumska EBV VCA IgG protutijela su u odraslih bila eae pozitivna (2 = 3,5; p = 0,062). EBNA IgG negativno bilo je 17 (44%) djece s AITP, a svega 1 (6%) odraslih s AITP. EBNA IgG serumska protutijela su u 38 (68%) bolesnika bila pozitivna, od toga 22 (56%) djeteta i 16 (94%) odraslih. Djeca s AITP su eae imala serumska EBNA IgG protutijela negativna nego odrasli (2 = 7,7; p = 0,005). Serumska IgG protutijela na HHV-6 analizirana su u 56 bolesnika, 39 djece i 17 odraslih. Pozitivna HHV-6 IgG protutijela imalo je 49 (87,5%) bolesnika, 33 (85%) djece i 16 (94%) odraslih. Negativna HHV-6 IgG protutijela imalo je 7 (12,5%) bolesnika (6 djece i jedan odrasli). Od ukupno 49 bolesnika koji su imali pozitivna serumska HHV-6 IgG protutijela u njih 11 (22%), 8 (20%) djece i 3 (17%) odrasla, vrijednosti HHV-6 IgG serumskih protutijela su bile tri puta vee od granice normale ato je ukazivalo na akutnu HHV-6 infekciju (slika 16). Nije bilo statisti ki zna ajne razlike u estalosti akutne HHV-6 infekcije izmeu djece i odraslih s AITP (2 = 0,42; p = 0,838). Tablica 11. Prikaz serumskih protutijela na CMV, EBV, HHV-6, adenovirus i parvovirus B19 u djece s AITP, odraslih i ukupno pri dijagnozi VirusSvi bolesniciDjecaOdraslipozitivnanegativnapozitivnanegativnapozitivnanegativnaCMV IgM1 (2%)55 (98%)1(3%)38 (97%)017(100%)CMV IgG42 (75%)14(25%)28 (72%)11 (28%) 14 (82%)3 (18%)EBV EA IgM6 (11%)50 (89%)4 (10%)34 (90%) 2 (12%)15 (88%)EBV EA IgG5 (9%) 51 (91%)2 (5%)37 (95%)3 (18%)14 (82%)EBV VCA IgM3 (5%)53 (95%)2 (5%)37(94%) 1 (6%)16(94%)EBV VCA IgG36(64%)20 (36%)22(56%)17 (44%)14 (82%).3 (18%)EBNA IgG38(68%)18 (32%)22(56%)17 (44%)16 (94%).1 (6%)HHV-6 IgG49 (87%)7 (13%)33 (85%)6 (15%)16 (94%)1 (6%)Adenovirus IgM14 (25%) 42 (75%)11(28%)28 (72%)3 (18%)14 (82%)Adenovirus IgG52 (93%) 4 (7%)35(90%)4 (10%)17 (100%)0Parvovirus B19 IgM 4 (7%)52 (93%)3 (8%)36 (92%)1 (6%)16 (94%)Parvovirus B19 IgG20 (36%)36 (64%)9 (23%)30 (77%)17 (100%)0 Serumska IgM i IgG protutijela na adenovirus analizirana su u 56 bolesnika, 39 djece i 17 odraslih s AITP. Serumska adenovirus IgM protutijela dokazana su u 14 (25%) bolesnika (slika 16), od toga 11 (28%) djece i 3 (18%) odrasla s AITP. Adenovirus IgM serumska protutijela nisu dokazana u 42 (75%) bolesnika, 28 (72%) djece i 14 (82%) odraslih. Nije bilo statisti ki zna ajne razlike u pozitivnosti serumskih adenovirus IgM protutijela izmeu djece i odraslih s AITP (2 = 0,71; p = 0,401). Serumska adenovirus IgG protutijela dokazana su u 52 (93%) bolesnika, 35 (89,7%) djece i 17 (100%) odraslih, za razliku od etvero djece s AITP u koje su bila negativna.  EMBED MSGraph.Chart.8 \s Slika 16. Prikaz postotka bolesnika s AITP sa seroloaki dokazanom akutnom virusnom infekcijom pri dijagnozi Serumska IgM i IgG protutijela na parvovirus B19 analizirana su u 56 bolesnika, 39 djece i 17 odraslih. Parvovirus B19 IgM su bila negativna u 52 (93%) bolesnika, 36 (92%) djece i 16 (94%) odraslih, a pozitivna u troje djece i jednog odraslog (7%) (slika 16). Serumska parvovirus B19 IgG pozitivna protutijela imalo je 20 (36%) ispitanika, od toga 9 (23%) djece i 11 (65%) odraslih. Odrasli s AITP su statisti ki zna ajno eae bili parvovirus B19 IgG pozitivni od djece (2 = 8,9; p = 0,003). U djece serumska CMV IgG protutijela pokazivala su statisti ki zna ajno negativnu povezanost sa serumskim koncentracijama IL-2/1 (r = - 0,35; p = 0,062), IL-10/3 (r = - 0,96; p < 0,001) i IFN-(/1 (r = - 0,33; p = 0,077). Serumska EBV EA IgM protutijela pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-10/1 (r = 0,35; p = 0,060), IFN-(/1 (r = 0,33; p = 0,080), IFN-(/1 (r = 0,35; p = 0,066) i IFN-(/2 (r = 0,33; p = 0,082). Serumska EBV EA IgG protutijela pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-4/2 (r = 0,36; p = 0,059), a negativnu s TNF-(/1 (r = - 0,49; p = 0,007) i TNF-(/2 (r = - 0,43; p = 0,020). Statisti ki zna ajna pozitivna povezanost uo ena je izmeu EBV VCA IgM serumskih protutijela i serumskih koncentracija IL-4/2 (r = 0,36; p = 0,059), a negativna sa serumskim koncentracijama TNF-(/1 (r = - 0,49; p = 0,007) i TNF-(/2 (r = - 0,43; p = 0,020). Serumska EBV VCA IgG protutijela pokazivala su statisti ki zna ajno negativnu povezanost sa serumskim koncentracijama IL-6/1 (r = - 0,32; p = 0,092) i TNF-(/2 (r = - 0,33; p = 0,079). EBNA IgG serumska protutijela pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-3/1 (r = 0,39; p = 0,038), IL-3/2 (r = 0,38; p = 0,044) i IFN-/1 (r = 0,42; p = 0,025), a statisti ki zna ajno negativnu povezanost sa serumskim koncentracijama IL-1 /1 (r = - 0,43; p = 0,020), IL-4/1 (r = - 0,37; p = 0,046), IL-4/2 (r = - 0,44; p = 0,017), IL-6/1 (r = - 0,43; p = 0,020), IL-6/2 (r = - 0,37; p = 0,047) i IFN-( /1 (r = - 0,33; p = 0,080). HHV-6 IgG serumska protutijela pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-10/3 (r = 0,54; p = 0,089). Serumska adenovirus IgM protutijela pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-2/1 (r = 0,51; p = 0,005), IL-10/3 (r = 0,96; p < 0,001) i IFN-/1 (r = 0,33; p = 0,079), a negativnu s IL-1/1 (r = - 0,49; p = 0,007). Serumska adenovirus IgG protutijela pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-1/3 (r = 0,69; p = 0,018), a negativnu s IL-10/2 (r = - 0,43; p = 0,021). Statisti ki zna ajno pozitivnu povezanost pokazivala su serumska parvovirus B19 IgM protutijela sa serumskim koncentracijama TNF-(/2 (r = 0,35; p = 0,063), dok su serumska parvovirus B19 IgG protutijela pokazivala zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-6/3 (r = 0,90; p < 0,01), a negativnu s IL-2/2 (r = - 0,31; p = 0,099) i IL-2/3 (r = - 0,61; p = 0,047). U odraslih s AITP dokazana je statisti ki zna ajna negativna povezanost serumskih CMV IgG protutijela i serumskih koncentracija IL-10/1 (r = - 0,53; p = 0,027), IL-4/2 (r = - 0,59; p = 0,045) i IL-4/3 (r = - 0,996; p < 0,01). Serumska protutijela EBV EA IgM pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama TNF-(/3 (r = 0,91; p = 0,004) i IFN-(/2 (r = 0,52; p = 0,081), a EBV EA IgG s TNF-(/3 (r = 0,91; p = 0,004) i IFN-(/2 (r = 0,52; p = 0,081). Serumska protutijela EBV VCA IgM pokazivala su statisti ki zna ajno negativnu povezanost s IL-2/3 (r = - 0,78; p = 0,038), IL-6/1 (r = - 0,46; p = 0,065 i pozitivno s IFN-(/1 (r = 0,66; p = 0,004) i IFN-(/2 (r = 0,56; p = 0,057). Serumska protutijela EBV VCA IgG pokazivala su statisti ki zna ajno negativnu povezanost sa serumskim koncentracijama TNF-(/2 (r = - 0,75; p = 0,005). Serumska protutijela EBNA IgG pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-(/2 (r = 0,51; p = 0,091) i IL-6/1 (r = 0,51; p = 0,035). Serumska protutijela IgG na HHV-6 pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-1/2 (r = 0,53; p = 0,077) i IFN-(/1 (r = 0,68; p = 0,002), a statisti ki zna ajno negativnu povezanost s IL-2/3 (r = - 0,78; p = 0,038). Adenovirus IgM serumska protutijela pokazivala su statisti ki zna ajno negativnu povezanost sa serumskim koncentracijama IL-2/3 (r = - 0,78; p = 0,038). Serumska parvovirus B19 IgM protutijela pokazivala su statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-4/3 (r = 0,996; p < 0,001), dok su parvovirus B19 IgG serumska protutijela pokazivala statisti ki zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-4/2 (r = 0,78; p = 0,003), a negativnu s IL-3/1 (r = - 0,55; p = 0,023). 4.7. Povezanost serumskih koncentracija citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u djece i odraslih s te~inom trombocitopenije, njenim trajanjem i terapijskim odgovorom 4.7.1. Povezanost serumskih koncentracija IL-1, -2, -3, -4, -6, 10, TNF-(, IFN-( i IFN-( u djece i odraslih s brojem trombocita Broj trombocita u perifernoj krvi (n = 29) pri dijagnozi (slika 17) pokazivao je statisti ki zna ajnu negativnu povezanost jedino sa serumskim koncentracijama IL-3 pri dijagnozi (r = - 0,43; p = 0,021) (tablica 12). Nije bilo statisti ki zna ajne povezanosti broja trombocita u perifernoj krvi i serumskih koncentracija IL-1 (r = 0,01; p = 0,963), IL-2 (r = 0,09; p = 0,662), IL-4 (r = 0,06; p = 0,756), IL-6 (r = 0,21; p = 0,275), IL-10 (r = - 0,20; p = 0,297), TNF-( (r = - 0,10; p = 0,604), IFN-( (r = - 0,18; p = 0,359) i IFN-( (r = 0,13; p = 0,511) (tablica 12).  EMBED StaticEnhancedMetafile  Slika 17. Prikaz negativne povezanosti broja trombocita u perifernoj krvi i serumskih koncentracija IL-3 u djece s AITP pri dijagnozi U djece s AITP dokazana je statisti ki zna ajna negativna povezanost broja trombocita nakon 8 tjedana s IL-1/2 (r = - 0,38; p = 0,045) i broja trombocita nakon 6 mjeseci s IL-1/2 (r = - 0,41; p = 0,043), IL-2/2 (r = - 0,045; p = 0,025), IL-4/1 (r = - 0,042; p = 0,035), TNF-/1 (r = - 0,41; p = 0,048), IFN-/2 (r = - 0,41; p = 0,042) i s IFN-/3 (r = - 0,66; p = 0,029), a statisti ki zna ajna pozitivna povezanost broja trombocita nakon 6 mjeseci s IL-3/1 (r = 0,42; p = 0,035). U odraslih s AITP pri dijagnozi (n = 19) nije bilo statisti ki zna ajne povezanosti serumskih koncentracija IL-1 (r = 0,21; p = 0,391), IL-2 (r = 0,08; p = 0,730), IL-3 (r = - 0,23; p = 0,336), IL-4 (r = - 0,25; p = 0,310), IL-6 (r = 0,34; p = 0,151), IL-10 (r = 0,33; p = 0,166), TNF-( (r = - 0,33; p = 0,166), IFN-( (r = - 0,02; p = 0,927) i IFN-( (r = - 0,10; p = 0,692) i broja trombocita u perifernoj krvi (tablica 12). Tablica 12. Prikaz povezanosti serumskih koncentracija IL-1, -2, -3, -4, -6, 10, TNF-(, IFN-( i IFN-( s brojem trombocita u perifernoj krvi u djece i odraslih s AITP pri dijagnozi DjecaOdrasliCitokiniKorelacijaTrombocitiTrombocitiIL-1r 0,010,21p0,9630,391IL-2r0,090,08p0,6620,730IL-3r- 0,43- 0,23p0,0210,336IL-4r0,06- 0,25p0,7560,310IL-6r0,210,34p0,2750,151IL-10r- 0,200,33p0,2970,166TNF-(r- 0,10- 0,33p0,6040,166IFN-(r- 0,18- 0,02p0,3590,927IFN-(r0,13- 0,10p0,5110,692 U odraslih s AITP broj trombocita pri dijagnozi i broj trombocita nakon 8 tjedana nije bio povezan sa serumskim koncentracijama odabranih citokina u sva tri mjerenja, dok je broj trombocita nakon 6 mjeseci bio statisti ki zna ajno pozitivno povezan s IL-4/2 (r = 0,81; p = 0,028) i IL-4/3 (r = 0,77; p = 0,045), a statisti ki zna ajno negativno povezan s IFN-/3 (r = - 0,85; p = 0,015) i IL-3/3 (r = - 0,79; p = 0,034). 4.7.2. Usporedba serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u djece i odraslih s AITP Rezultate usporedbe koncentracije citokina pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci (n = 11) u djece prikazuje tablica 13. U djece s AITP serumske koncentracije IL-1 se nisu statisti ki zna ajno promijenile nakon 8 tjedana i nakon 6 mjeseci u odnosu na koncentracije pri dijagnozi (2 = 2,9; p = 0,234). Promjene nisu dokazane ni kod IL-2 (2 = 3,8; p = 0,150), IL-3 (2 = 0,88; p = 0,643), IFN- (2 = 1,64; p = 0,441) i IFN- (2 = 0,54; p = 0,761), ali su dokazane kod IL-4, IL-6, IL-10 i TNF- . Promijenile su se statisti ki zna ajno serumske koncentracije IL-4 (2 = 9,14; p = 0,010). Nije dokazana razlika u serumskim koncentracijama IL-4 pri dijagnozi i nakon 8 tjedana (z = 0,29; p = 0,78). Serumske koncentracije IL-4 bile su statisti ki zna ajno vee nakon 6 mjeseci od vrijednosti pri dijagnozi (z = 2,5; p = 0,013) i od vrijednosti nakon 8 tjedana (z = 2,5; p = 0,013). Promijenile su se i serumske koncentracije IL-6 (2 = 11,09; p = 0,004). Nije dokazana razlika u serumskim koncentracijama IL-6 nakon 8 tjedana prema koncentracijama pri dijagnozi (z = 0,63; p = 0,53). Serumske koncentracije IL-6 bile su statisti ki zna ajno vee nakon 6 mjeseci od koncentracija pri dijagnozi (z = 2,4; p = 0,016) i od koncentracija nakon 8 tjedana (z = 2,4; p = 0,016). Promijenile su se i serumske koncetracije IL-10 (2 = 5,44; p = 0,066). Nije dokazana razlika u koncentracijama IL-10 nakon 8 tjedana prema koncentracijama pri dijagnozi (z = - 0,41; p = 0,684) i nakon 6 mjeseci (z = - 1,33; p = 0,182). Serumske koncetracije IL-10 bile su statisti ki zna ajno ni~e nakon 6 mjeseci od koncetracija pri dijagnozi (z = - 1,79; p = 0,075). Promijenile su se i serumske koncetracije TNF- (2 = 14,0; p = 0,001). Nije dokazana razlika serumskih koncentracija TNF- nakon 8 tjedana prema koncentracijama pri dijagnozi (z = 0,34; p = 0,73). Serumske koncentracije TNF- bile su nakon 6 mjeseci statisti ki zna ajno ni~e nego pri dijagnozi (z = 2,9; p = 0,034) i nakon 8 tjedana (z = 2,8; p = 0,044). Tablica 13. Prikaz serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( mjerenih pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u djece s AITP CitokiniMean +SD pg/mlMedijan pg/mlMin-Maks pg/ml2pPri Dg4,6 + 2,584,00,4 - 8,0IL-18 tjedan3,7 + 2,812,70,2 - 9,02,910,2346 mjeseci5,5 + 2,995,50,8 - 10,0Pri Dg25,3 + 7,7522,018,0 - 43,5IL-28 tjedan26,9 + 3,9628,119,5 - 31,23,800,1506 mjeseci24,1 + 2,2324,020,0 - 27,4Pri Dg49,9 + 12,9946,921,0 - 65,1IL-38 tjedan56,2 + 29,7147,121,0 - 137,70,880,6436 mjeseci41,2 + 22,3129,918,0 - 72,0Pri Dg12,1 + 8,748,27,9 - 31,0IL-48 tjedan12,5 + 8,798,27,7 - 30,09,140,0106 mjeseci29,3 + 14,8629,014,4 - 61,5Pri Dg6,3 + 6,29 4,23,1 - 25,0IL-68 tjedan7,8 + 8,754,53,0 - 30,011,090,0046 mjeseci17,3 + 16,839,97,3 - 63,0Pri Dg20,1 + 4,5418,615,4 - 29,8IL-108 tjedan20,3 + 6,4919,58,9 - 29,35,440,0666 mjeseci17,6 + 5,3216,713,0 - 33,0Pri Dg20,9 + 3,7819,916,1 - 29,7TNF-8 tjedan21,0 + 2,9921,015,6 - 28,014,000,0016 mjeseci17,8 + 1,1418,016,0 - 19,5Pri Dg45,6 + 4,8945,036,2 - 57,0IFN-8 tjedan50,4 + 13,1345,843,9 - 88,31,640,4406 mjeseci54,3 + 17,5247,736,2 - 98,8Pri Dg51,4 + 24,7944,017,5 - 89,0IFN-8 tjedan44,9 + 32,2943,412,5 - 92,20,550,7616 mjeseci45,5 + 25,0243,013,0 - 105,0 Rezultati usporedbe koncentracija citokina pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u odraslih s AITP (n = 6) prikazani su u tablici 14. Tablica 14. Prikaz serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( mjerenih pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u odraslih s AITP CitokiniMean + SD pg/mlMedian pg/mlMin-Maks pg/ml2pPri Dg2,6 + 2,022,50 - 5,7IL-18 tjedan2,0 + 1,422,20,05  3,90,610,7386 mjeseci3,3 + 1,123,32,0 5,2Pri Dg28,8 + 1,3527,527,4 - 27,4IL-28 tjedan27,9 + 0,928,526,5 - 29,01,830,4016 mjeseci25,4 + 4,62616,9 - 30,2Pri Dg62,3 + 4,716056,9 - 70IL-38 tjedan57,4 + 14,296030,5 - 702,330,3116 mjeseci50,0 + 15,836130,9 69,7Pri Dg10,1 + 2,389,48,1 14,4IL-48 tjedan26,8 + 25,1513,57,5 - 61,32,330,3116 mjeseci17,8 + 18,7510,87,6 - 55,9Pri Dg6,8 + 2,567,53,4 - 9,6IL-68 tjedan8,0 + 2,928,53,7 12,43,00,2236 mjeseci13,3 + 8,789,17,3  30,4Pri Dg16,7 + 0,6117,015,5 - 17,1IL-108 tjedan14,8 + 2,7715,010,9  17,71,330,5136 mjeseci19,6 + 6,5817,216,3-33,0Pri Dg19,6 + 2,4619,616,6  22,7TNF-8 tjedan21,3 + 6,0919,916,0 - 32,73,550,1706 mjeseci20,2 + 6,3218,015,6  32,0Pri Dg56,8 + 14,2455,643,0 - 81,3IFN-8 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$$Ifa$prt*$$$IfkdUC$$Ifl4֞"[ g9\:0 64 lalf4’ $$Ifa$’ĒВ*$$$IfkdD$$Ifl4֞"[ g9\:0 64 lalf4(4 $$Ifa$468L*$$$Ifkd]F$$Ifl4֞"[ g9\:0 64 lalf4Ldn $$Ifa$*$$$IfkdG$$Ifl4֞"[ g9\:0 64 lalf4ԓ֓ؓ $$Ifa$ؓړ*$$$IfkdWI$$Ifl4֞"[ g9\:0 64 lalf44>J $$Ifa$JLN*! $$Ifa$kdJ$$Ifl4֞"[ g9\:0 64 lalf4Nb| $$Ifa$ $$Ifa$$If*$<dh^<`a$kd5L$$Ifl4֞"[ g9\:0 64 lalf4na: IL-1 (2 = 0,61; p = 0,738), IL-2 (2 = 1,83; p = 0,401), IL-3 (2 = 2,33; p = 0,311), IL-4 (2 = 2,33; p = 0,311), IL-6 (2 = 3,00; p = 0,223), IL-10 (2 = 1,33; p = 0,513), TNF- (2 = 3,54; p = 0,170), IFN- (2 = 4,33; p = 0,115) i IFN- (2 = 0,26; p = 0,878). 4.7.3. Razlike serumskih koncentracija citokina izmeu ispitanika s akutnom AITP, kroni nom AITP pri dijagnozi i kontrolne skupine Nije bilo statisti ki zna ajne razlike u serumskim koncentracijama IL-1 izmeu zdravih ispitanika i onih s akutnom i kroni nom AITP (F = 1,48; p = 0,234) (slika 18). U zdravih ispitanika srednja vrijednost serumskih koncentracija IL-1 bila je 2,6 + 1,27 pg/ml (minimum 0,1 pg/ml; maksimum 5,80 pg/ml), u bolesnika s kroni nom AITP 3,5 + 2,29 pg/ml (minimum 0; maksimum 7,83 pg/ml), a u bolesnika s akutnom AITP 2,8 + 2,42 pg/ml (minimum 0; maksimum 8,0 pg/ml). Nije bilo statisti ki zna ajne razlike u serumskim koncentracijama IL-2 izmeu zdravih ispitanika i onih s akutnom i kroni nom AITP (F = 0,45; p = 0,637) (slika 19). U zdravih ispitanika srednja vrijednost serumskih koncentracija IL-2 bila je 27,9 + 3,57 pg/ml (minimum 17,0 pg/ml; maksimum 43,2 pg/ml), u bolesnika s kroni nom AITP 26,9 + 5,46 pg/ml (minimum 18,0 pg/ml; maksimum 34,60 pg/ml), a u bolesnika s akutnom AITP 26,8 + 6,53 pg/ml (minimum 17,50 pg/ml; maksimum 43,50 pg/ml). Nije bilo statisti ki zna ajne razlike u serumskim koncentracijama IL-3 izmeu zdravih ispitanika i onih s akutnom i kroni nom AITP (F = 0,45; p = 0,344) (slika 20). U zdravih ispitanika srednja vrijednost serumskih koncentracija IL-3 bila je 59,1 + 24,26 pg/ml (minimum 31,2 pg/ml; maksimum 150,0 pg/ml), u bolesnika s kroni nom AITP 52,2 + 14,79 pg/ml (minimum 21,0 pg/ml; maksimum 70,0 pg/ml), a u bolesnika s akutnom AITP 63,7 + 19,81 pg/ml (minimum 40,0 pg/ml; maksimum 137,0 pg/ml).  Slika 18. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-1 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi Slika 19. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-2 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi  Slika 20. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-3 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi Slika 21. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-4 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi Izmeu serumskih koncentracija IL-4 u zdravih ispitanika i onih s akutnom i kroni nom AITP dokazana je statisti ki zna ajna razlika (F = 5,29; p = 0,007) (slika 21). U zdravih ispitanika srednja vrijednost serumskih koncentracija IL-4 bila je 9,4 + 1,76 pg/ml (minimum 7,3 pg/ml; maksimum 14,9 pg/ml), u bolesnika s kroni nom AITP 12,5 + 8,06 pg/ml (minimum 7,8 pg/ml; maksimum 31,0 pg/ml), a u bolesnika s akutnom AITP 8,6 + 1,47 pg/ml (minimum 7,7 pg/ml; maksimum 14,4 pg/ml). Bolesnici s kroni nom AITP su imali statisti ki zna ajno vee serumske koncentracije IL-4. Izmeu serumskih koncentracija IL-6 u zdravih ispitanika i onih s akutnom i kroni nom AITP nije dokazana statisti ki zna ajna razlike (F = 1,44; p = 0,243) (slika 22). U zdravih ispitanika srednja vrijednost serumskih koncentracija IL-6 bila je 5,9 + 1,92 pg/ml (minimum 3,2 pg/ml; maksimum 9,5 pg/ml), u bolesnika s kroni nom AITP 6,8 + 5,8 pg/ml (minimum 3,0 pg/ml; maksimum 25,0 pg/ml), a u bolesnika s akutnom AITP 5,1 + 1,9 pg/ml (minimum 3,0 pg/ml; maksimum 9,6 pg/ml). Slika 22. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-6 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi Izmeu serumskih koncentracija IL-10 u zdravih ispitanika i onih s akutnom i kroni nom AITP nije dokazana statisti ki zna ajna razlika (F = 2,29; p = 0,108) (slika 23). U zdravih ispitanika srednja vrijednost serumskih koncentracija IL-10 bila je 18,2 + 2,9 pg/ml (minimum 14,7 pg/ml; maksimum 29,8 pg/ml), u bolesnika s kroni nom AITP 20,2 pg/ml + 6,8 pg/ml (minimum 13,0 pg/ml; maksimum 34,9 pg/ml), a u bolesnika s akutnom AITP 17,1 + 4,4 pg/ml (minimum 10,5 pg/ml; maksimum 30,5 pg/ml).  Slika 23. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-10 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi Izmeu serumskih koncentracija TNF-( u zdravih ispitanika i onih s akutnom i kroni nom AITP dokazana je statisti ki zna ajna razlika (F = 4,36; p = 0,016). U zdravih ispitanika srednja vrijednost serumskih koncentracija TNF-( bila je 21,8 + 3,47 pg/ml (minimum 17,0 pg/ml; maksimum 33,0 pg/ml), u bolesnika s kroni nom AITP 21,8 + 6,1 pg/ml (minimum 7,9 pg/ml; maksimum 30,0 pg/ml), a u bolesnika s akutnom AITP 18,9 + 3,03 pg/ml (minimum 15,0 pg/ml; maksimum 28,0 pg/ml). Bolesnici s akutnom AITP su imali statisti ki zna ajno manje serumske koncentracije TNF-( (slika 24).  Slika 24. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD TNF-( u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi  Slika 25. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN- u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi Izmeu serumskih koncentracija IFN- u zdravih ispitanika i onih s akutnom i kroni nom AITP nije dokazana statisti ki zna ajna razlika (F = 0,39; p = 0,674) (slika 25). U zdravih ispitanika srednja vrijednost serumskih koncentracija IFN- bila je 50,7 + 8,3 pg/ml (minimum 36,0 pg/ml; maksimum 68,3 pg/ml), u bolesnika s kroni nom AITP 52,0 + 11,7 pg/ml (minimum 36,2 pg/ml; maksimum 82,8 pg/ml), a u bolesnika s akutnom AITP 49,2 + 9,4 pg/ml (minimum 43,0 pg/ml; maksimum 81,3 pg/ml). Izmeu serumskih koncentracija IFN-( u zdravih ispitanika i onih s akutnom i kroni nom AITP dokazana je statisti ki zna ajna razlika (F = 3,74; p = 0,028) (slika 26). U zdravih ispitanika srednja vrijednost serumskih koncentracija IFN-( bila je 36,1 + 25,37 pg/ml (minimum 4,0 pg/ml; maksimum 89,0 pg/ml), u bolesnika s kroni nom AITP 60,2 + 44,71 pg/ml (minimum 8,8 pg/ml; maksimum 150,0 pg/ml), a u bolesnika s akutnom AITP 44,1 + 23,71 pg/ml (minimum 12,5 pg/ml; maksimum 88,0 pg/ml). Bolesnici s kroni nom AITP su imali statisti ki zna ajno vee serumske koncentracije IFN-(. Slika 26. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN-( u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi 4.8. Povezanost promjena i prognosti kih vrijednosti serumskih citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u odnosu na prelazak bolesti u kroni ni oblik u djece i odraslih s akutnom AITP Upotrijebljena je viaestruka regresija kako bi se dobio optimalni broj regresorskih varijabli (prediktora), koje utje u na regresand varijablu, trombocite mjerene nakon 6 mjeseci od dijagnoze u djece s AITP. Za regresorske varijable koriatene su serumske koncentracije IL-3, IL-4, TNF-, postotak cirkulirajuih limfocita T4 u krvi pri dijagnozi i broj trombocita mjeren nakon 8 tjedana u perifernoj krvi djece s AITP. Koeficijent determinacije iznosio je 0,953, ato zna i da je protuma enost modela bila 95,3%. F-testom testirana je njegova zna ajnost, pa je koeficijent determinacije bio zna ajan na razini od 0,002. Mo~emo zaklju iti da bi se ovaj model mogao koristiti u svrhu prognoziranja vrijednosti trombocita mjerenih nakon 6 mjeseci od dijagnoze (Tr/3) u djece s AITP znajui vrijednost varijabli prediktora serumske koncentracije IL-3, IL-4, TNF- i postotak cirkulirajuih limfocita T4 u krvi mjerenih pri dijagnozi kao i broj trombocita mjeren nakon 8 tjedana. Pri tome mo~emo upotrijebiti jednad~bu viaestruke regresije: w =107508 + 1462 x X1  7462 x X2  8361 x X3 + 3655 x X4 + 0,899 x X5 gdje je w = Tr/3; X1 = IL-3/1; X2 = IL-4/1; X3 = TNF-/1; X4 = postotak limfocita T4 pri dijagnozi; X5 = Tr/2. Pearsonovim testom korelacije broj trombocita mjeren u perifernoj krvi nakon 6 mjeseci od dijagnoze statisti ki je zna ajno pozitivno korelirao sa serumskom koncentracijom IL-3/1 (r = 0,42; p = 0,035), postotkom cirkulirajuih limfocita T4 pri dijagnozi (r = 0,45; p = 0,054) i brojem trombocita u perifernoj krvi mjerenim nakon 8 tjedana (r = 0,51; p = 0,005), a statisti ki zna ajno negativno sa serumskom koncentracijom IL-4/1 (r = - 0,42; p = 0,035) i TNF-/1 (r = - 0,41; p = 0,048). To zna i da e u djece broj trombocita u perifernoj krvi 6 mjeseci od dijagnoze biti vei ako su serumske koncentracije IL-3, postotak cirkulirajuih limfocita T4 pri dijagnozi i broj trombocita mjerenih nakon 8 tjedana bili vei, a serumske koncentracije IL-4 i TNF- pri dijagnozi bile manje. Upotrijebljena je viaestruka regresija kako bi se dobio optimalni broj regresorskih varijabli (prediktora) koje utje u na regresand varijablu, broj trombocita u perifernoj krvi mjeren nakon 8 tjedana od dijagnoze (Tr/2) u odraslih s AITP. Za regresorske varijable koriatene su vrijednosti apsolutnog broja limfocita, postotak cirkulirajuih limfocita B i NK stanica i serumske koncentracije IFN- pri dijagnozi. Koeficijent determinacije iznosio je 0,933, ato zna i da je protuma enost modela bila 93,3%. F-testom testirana je njegova zna ajnost, pa je koeficijent determinacije bio zna ajan na razini od 0,046. Ovaj bi se model mogao koristiti u svrhu prognoziranja vrijednosti trombocita mjerenih nakon 8 tjedana od dijagnoze u odraslih s AITP znajui vrijednost varijabli prediktora apsolutnog broja limfocita, postotka cirkulirajuih limfocita B i NK stanica i serumskih koncentracija IFN- pri dijagnozi. Pri tome mo~emo upotrijebiti jednad~bu viaestruke regresije: w = 43766 - 7194 x X1  6326 x X2 + 0,103 x X3 + 2793 x X4 gdje je w = Tr/2; X1 = postotak cirkulirajuih limfocita B pri dijagnozi; X2 = postotak cirkulirajuih NK stanica pri dijagnozi; X3 = apsolutni broj limfocita pri dijagnozi; X4 = serumske koncentracije IFN-/1. Broj trombocita u perifernoj krvi mjeren nakon 8 tjedana od dijagnoze statisti ki je zna ajno pozitivno korelirao s apsolutnim brojem limfocita pri dijagnozi (p = 0,040), a negativno s postotkom cirkulirajuih limfocita B pri dijagnozi (p = 0,028). Negativna povezanost je postojala, ali nije bila statisti ki zna ajna s postotkom cirkulirajuih NK stanica (p = 0,112) i pozitivna ali ne statisti ki zna ajna sa serumskim koncentracijama IFN-/1 (p = 0,268). To zna i da e u odraslih broj trombocita u perifernoj krvi 8 tjedana od dijagnoze biti vei ako su apsolutni broj limfocita i serumske koncentracije IFN- pri dijagnozi bili vei i ako je postotak cirkulirajuih limfocita B i NK stanica u krvi bili ni~i. 5. RASPRAVA AITP je relativno rijetka bolest koja se klini ki mo~e podijeliti u dvije forme dje ju AITP i onu u odraslih. Mo~e trajati godinama pa i cijeli ~ivot. Neki su bolesnici praeni i 30 godina. Incidencija kroni ne AITP u USA je 10 na 1.000.000 godianje i eaa je u odraslih (196). Javlja se u jednog djeteta od 25000 djece godianje (197). Kroni na AITP u djece javlja se u 0,46 na 100 000 djece godianje (198). Ispitujui morbiditet i mortalitet u odraslih s AITP u grupi od 152 bolesnika u dobi od 15 godina i viae Portielje je zaklju ila da je veina imala dobru prognozu uz rijetke hospitalizacije (199). Dje ja AITP se javlja u dva oblika: akutna bolest koja prestaje sama od sebe i kroni na bolest s brojem trombocita u perifernoj krvi < 150 x 109/L du~e od 6 mjeseci (200). U oko 20% ispitanika s akutnom AITP bolest e prei u kroni an oblik, a specifi ni biljezi koji bi ukazivali na mogunost razvoja kroni nog oblika bolesti, joa nam nisu poznati.  HYPERLINK "C:\Documents and Settings\Administrator\Desktop\AITP-DOK\Liter IL,virusi\ovidweb.cgi?T=dirlink&Q=Bolton%2dMaggs+PH%2eau%2e&D=medall&S=AIPPPPOPPHPJPL" Bolton-Maggs tvrdi da ak 20-30% djece s AITP ne posti~e remisiju nakon 6 mjeseci i to prete~no starija djeca-djevoj ice, dok Karpatkin navodi da 7-28% djece razvije kroni nu AITP (201,202). Rezultati analize prezentirane doktorske disertacije su pokazali da je nakon 6 mjeseci 65,5% djece i 62,5% odraslih postiglo remisiju bolesti. Djeca su pri dijagnozi imala zna ajno (p = 0,004) ni~i prosje ni broj trombocita u perifernoj krvi (17,4 x 109 /L), za razliku od odraslih (36,8 x 109/L). Broj trombocita u perifernoj krvi pri dijagnozi < 10 x 109/L imalo je 58% djece i 26% odraslih, a 10-30 x 109/L 18% djece i 16% odraslih, a 18% djece i 21% odraslih 30-50 x 109/L i 6% djece i 37% odraslih 50-80 x 109/L. Broj trombocita u perifernoj krvi nakon 6 mjeseci zna ajno je porastao u djece s AITP (p < 0,001) i u odraslih (p = 0,006) u odnosu na vrijednosti pri dijagnozi. Broj trombocita pri dijagnozi nije se zna ajno razlikovao u svih bolesnika s akutnom i kroni nom AITP (p = 0,615). Razli iti patogenetski mehanizmi mogu biti odgovorni za nastanak akutnog ili kroni nog oblika ove bolesti. Jedan od moguih etioloakih faktora je poremeaj citokinske ravnote~e, koji je zamijeen u tih bolesnika (3). Utjecaj poremeaja citokinske ravnote~e na nastanak autoimunih bolesti, pa tako i AITP postaje sve viae predmetom interesa, ali se danas joa uvijek malo zna o ulozi citokina u autoimunoj patogenezi ove bolesti. Veina analiza se bazira na usporedbi pojedinih imunoloakih parametara djece i odraslih s ciljem da se otkrije zbog ega je ova bolest razli itog tijeka i prognoze u ove dvije skupine bolesnika. Hipoteza od koje polazi ovo istra~ivanje je da u AITP poremeaj citokinske ravnote~e igra va~nu ulogu u patogenetskom mehanizmu nastanka bolesti, koji se vjerojatno razlikuje u djece i odraslih ljudi. Analizom serumskih koncentracija citokina to je i dokazano. Djeca s AITP pri dijagnozi su imala zna ajno vee serumske koncentracije IL-4 (p = 0,062) i zna ajno ni~e koncentracije IL-2 (p = 0,021) i TNF- (p = 0,009) od zdrave djece. Izmeu zdrave djece i one s AITP nije bilo zna ajne razlike u serumskim koncentracijama IL-1 (p = 0,146), IL-3 (p = 0,445), IL-6 (p = 0,233), IL-10 (p = 0,554), IFN- (p = 0,830) i IFN- (p = 0,252). Odrasli s AITP pri dijagnozi su imali zna ajno vee serumske koncentracije IL-1 (p = 0,045) i IL-4 (p = 0,011), a zna ajno manje koncentracije IL-10 (p = 0,041) od zdravih ispitanika, za razliku od serumskih koncentracija IL-2 (p = 0,660), IL-3 (p = 0,230), IL-6 (p = 0,503), TNF- (p = 0,494), IFN- (p = 0,336) i IFN- (p = 0,537) koje se nisu zna ajno razlikovale. Takoer je dokazana razlika u serumskim koncentracijama pojedinih citokina u djece i odraslih. Djeca s AITP su pri dijagnozi imala zna ajno ni~e serumske koncentracije IL-4 (p = 0,033), IL-6 (p = 0,004) i IFN- (p = 0,001), a zna ajno viae serumske koncentracije IFN- (p = 0,007) od odraslih s AITP, za razliku od serumskih koncentracija IL-1 (p = 0,432), IL-2 (p = 0,838), IL-3 (p = 0,468), IL-10 (p = 0,333) i TNF- (p = 0,987), koje nisu pokazivale zna ajnu razliku. Iz rezultata je vidljiva zna ajna negativna povezanost broja trombocita u djece mjerenih nakon 8 tjedana od dijagoze sa serumskim koncentracijama IL-1/2, a mjerenih nakon 6 mjeseci sa serumskim koncentracijama IL-1/2, IL-2/2, IL-4/1, TNF-/1, IFN-/2 i s IFN-/3. U odraslih s AITP broj trombocita u perifernoj krvi pri dijagnozi i nakon 8 tjedana nije pokazivao zna ajnu povezanost ni s jednim od odabranih citokina u sva tri mjerenja, dok je broj trombocita nakon 6 mjeseci pokazivao zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-4, a zna ajnu negativnu s IFN- i IL-3. U mnogim je studijama ispitivana uloga IL-2 kod autoimunih bolesti. Najnovije studije ukazuju da je funkcija IL-2 u apoptozi limfocita iznimno va~na (203). Shenoy sa suradnicima je pokazao da u 25% bolesnika s imunom citopenijom postoji defekt u induciranoj stani noj smrti limfocita zbog Fas mutacije uslijed ega je blokirana eliminacija limfocita (204). IL-2 igra sredianju ulogu u humanom imunom odgovoru i poveane vrijednosti ovog citokina su pronaene kod razli itih autoimunih bolesti kao ato su multipla skleroza, RA i SLE (205-207). Hipersekrecija endogenog IL-2 mo~e voditi u autoagresiju na viae na ina, primjerice inducirajui ostale citokine, kao IFN- i IL-10 (64). Abdel-Raheem i suradnici opisuju nastanak Evansova sindroma u bolesnika koji je lije en sa IL-2 (65). Erduran je mjerio solubilni IL-2 receptor (sIL-2R) u bolesnika s AITP i zdravih ispitanika i pronaaao je da postoji negativna povezanost izmeu broja trombocita i nivoa sIL-2R, ato su mjereni nivoi sIL-2R bili vei broj trombocita je bio manji (208). Poveane vrijednosti citokina, zajedno s in vitro trombocitima stimuliranim stvaranjem IL-2, mogu biti va~an test u otkrivanju razlike u patofiziologiji akutne i kroni ne forme AITP i mogu pomoi da se otkrije koja djeca e iz akutne forme razviti kroni nu formu bolesti. Semple sa suradnicima je istra~ivao hipotezu da abnormalnosti membrane trombocita i abnormalne koncentracije citokina mogu biti zna ajne u patogenezi AITP (5). Semple navodi da 53% djece s kroni nom AITP i samo 9 % onih s akutnom AITP imaju poveane vrijednosti IL-2 u serumu (5). U prezentiranoj doktorskoj disertaciji nije dokazana zna ajna razlika u serumskim koncentracijama IL-2 izmeu ispitanika s akutnom, kroni nom AITP pri dijagnozi i kontrolne skupine. Ipak su serumske koncentracije IL-2 u djece bile ni~e od kontrolne skupine. IL-3 sam i u kombinaciji s ostalim imbenicima koji stimuliraju kolonije, koristan je u rekonstrukciji KS, poveava broj neutrofila i trombocita i podr~ava ranu megakariocitopoezu (209). Veoma je va~an u lije enju trombopenija, tako da primjena IL-3 nakon davanja IL-6 bitno popravlja broj trombocita u perifernoj krvi. IL-3 ima zna ajni u inak na megakariocitopoezu djelujui na megakariocite, pa bi trebalo ispitati da li postoji mehanizam povratne sprege izmeu broja trombocita i serumskih koncentracija IL-3. Bilo bi va~no procijeniti ulogu IL-3 u patogenezi imunotrombocitopenije posebno zbog toga ato se zna da sudjeluje u regulaciji i kontroli mijelopoetskog sustava. Brojni autori naglaaavaju ulogu IL-3 u megakariocitopoezi i djelovanje ovog citokina na poja ano stvaranja megakariocita i trombocita. Yang je, piaui o ulozi citokina na regulaciju magakariocitopeze i nastanku trombocita, naglasio da u megakariocitopoezi osim trombopoetina sudjeluju i IL-1, IL-3 i IL-6 (210). Bruno je pokazao da kombinacija IL-3+SCF+IL-6+TPO inducira zna ajno stvaranje megakariocita iz CD34+ stanica (211). Ispitujui da li postoji povezanost broja trombocita u perifernoj krvi i serumskih koncentracija IL-3 u djece s AITP u prezentiranoj disertaciji dokazano je, da je broj trombocita u perifernoj krvi pri dijagnozi i nakon 6 mjeseci bio zna ajno povezan sa serumskim koncentracijama IL-3 pri dijagnozi i to Tr/1 s IL-3/1 (p = 0,021) negativno, a Tr/3 s IL-3/1 (p = 0,035) pozitivno. `to su trombociti pri dijagnozi bili vei serumske koncentracije IL-3 su bile manje, za razliku od broja trombocita nakon 6 mjeseci, koji su bili vei ato je IL-3 pri dijagnozi bio vei. Nije bilo zna ajne razlike u serumskim koncentracijama IL-3 izmeu ispitanika s akutnom, kroni nom AITP i kontrolne skupine. U odraslih s AITP nije uo ena zna ajna povezanost broja trombocita sa serumskim koncentracijama IL-3 u sva tri mjerenja. Serumske koncentracije IL-3 u djece i odraslih nisu se zna ajno razlikovale u sva tri mjerenja. Svakako bi daljnja ispitivanja vezana uz IL-3 kod AITP mogla pomoi u razumijevanju biologije ove bolesti, jer je IL-3 va~an imbenik u megakariocitopoezi. Webber je dokazao u djece i odraslih s AITP, da serumske koncentracije Th2 citokina IL-4 su zna ajno vee u bolesnika s AITP nego u zdravih individua. Isti autor predla~e lije enje AITP djelovanjem na solubilni IL-4. Nije bilo povezanosti izmeu vrijednosti bolesnikovih trombocita i serumskih koncentracija IL-4, iako su koncentracije IL-4 u serumu bile poveane (212). Ovaj citokin, esencijalan za T zavisne limfocite B, mo~e igrati zna ajnu ulogu u stvaranju autoprotutijela. Serumske koncentracije IL-4 u ispitivane djece i odraslih s AITP, u prezentiranoj disertaciji, su takoer bile zna ajno vee nego u kontrolnoj skupini. Dokazano je da su i ispitanici s kroni nom AITP pri dijagnozi imali zna ajno vee serumske koncentracije IL-4 od ispitanika s akutnom AITP i kontrolne skupine. U djece je dokazano da su serumske koncentracije IL-4 mjerene 6 mjeseci od dijagnoze bile zna ajno vee od onih pri dijagnozi i nakon 8 tjedana, ato do sada nije opisano u literaturi. U odraslih te razlike nije bilo. U djece s AITP nije dokazana zna ajna povezanost broja trombocita u perifernoj krvi s istovremeno ispitivanim serumskim koncentracijama IL-4, ali je evidentna zna ajna negativna povezanost serumskih koncentracija IL-4 pri dijagnozi s brojem trombocita nakon 6 mjeseci (p = 0,035) kada se mo~e dijagnosticirati kroni na AITP. Ovo saznanje koriateno je u odabiru prediktora, pa su serumske koncentracije IL-4 pri dijagnozi upotrijebljene kao jedan od prediktora u modelu za prognozu AITP u djece. Istovremeno serumske koncentracije IL-4 pri dijagnozi pokazale su zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-4 (p < 0,001) mjerenim nakon 8 tjedana. U odraslih s AITP serumske koncentracije IL-4 nisu pokazivale zna ajnu povezanost s brojem trombocita istovremeno ispitivanim pri dijagnozi, ali je broj trombocita nakon 6 mjeseci, kada se mo~e dijagnosticirati kroni na AITP, pokazivao zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-4 u sva tri mjerenja. Ovo saznanje da bolesnici s AITP imaju poveane koncentracije IL-4 je zna ajno jer ovaj interleukin mo~e utjecati na nastanak patogenih protutijela i zna ajan je za diferencijaciju limfocita B ovisnih o limfocitima T. Osim toga mo~e potiskivati humanu megakariocitopoezu (102). Relativno visoke koncentracije IL-4 u plazmi bolesnika s AITP ukazuju da ovi bolesnici generiraju Th2 tip stanica, ato mo~e biti i primarni nedostatak u ovih bolesnika ili mo~da ukazuju na prisustvo stimulusa koji poti e nastanak Th2. Izgleda da ovi bolesnici razviju Th0 citokinski profil, koji se mo~e okrenuti u Th1 aktivaciju. Drugi profil citokina, koji nisu u Th1/Th2, mo~e biti prisutan, npr. TGF- sna~ni Th3 imunosupresivni citokin (213,214). Inobe je ispitivao utjecaj IL-4 u generaciji limfocita Th3 i dokazao da IL-4, ali ne i IL-2 i IFN- djeluju na nastanak limfocita Th3 iz nezrelih limfocita T, a ove stanice poma~u stvaranje IgA (215). Obzirom da su neki od serumskih citokina u bolesnika s AITP poviaeni, a neki sni~eni, manipulacija citokinima bi mogla biti jedan od na ina lije enja AITP. Ona se ve danas svakako koristi primjenom kortikosteroida i IVIG-a u autoimunim bolestima (216). AITP u djece obi no nestaje nakon prve episode. Akutna AITP se obi no prezentira s Th1, Th0/Th1, ili Th0 profilom. Mouzaki smatra da je stabilna remisija udru~ena s Th0 ili Th2 profilom, a Th0 ili Th2 profil nakon terapije IVIG-om je bolje prognoze dok visoka ekspresija IFN- i refrakternost na IVIG zna i loau prognozu bolesti (217). IL-4 serumski citokin mo~e biti potencijalni cilj u lije enju ove bolesti. Crossley je dokazao da IFN- ako se koristi u lije enju AITP poveava Th1 aktivnost i smanjuje stvaranje protutijela smanjujui visoke serumske koncentracije IL-4 i/ili IL-10 (218). Anderson i suradnici su prou avali serumske koncentracije Th citokina i limfocite T i B u kroni noj AITP i uo ili su da je Th2 citokin IL-4 bio vrlo nizak u oboljelih i u kontrolnoj skupini (214). Paleolog je pokazao da IL-4 poja ava stvaranje IL-6 (219). U prezentiranom istra~ivanju nije dokazana zna ajna razlika u serumskim koncentracijama IL-6 izmeu zdrave djece i djece s AITP (p = 0,233), zdravih i odraslih s AITP (p = 0,503), ali su u odraslih s AITP serumske koncentracije IL-6 bile zna ajno vee nego u djece s AITP (p = 0,004). U djece s AITP serumske koncentracije IL-6 su bile zna ajno vee nakon 6 mjeseci od koncentracija pri dijagnozi i nakon 8 mjeseci (p = 0,016), za razliku od odraslih u kojih te razlike nije bilo (p = 0,223). Serumske koncentracije IL-6 nisu se razlikovale izmeu bolesnika s akutnom i kroni nom AITP pri dijagnozi. Niti Olcay u svom ispitivanju nije naaao zna ajnu razliku u serumskim koncentracijama u bolesnika s akutnom i kroni nom AITP, ali je dokazao da je doalo do zna ajnog pada serumskih koncentracija IL-6 nakon lije enja metilprednisolonom (220). IL-6 djeluje na megakariocitopezu i mo~da vee serumske koncentracije poma~u oporavku djece s akutnom AITP. Williams smatra da IL-6 direktno djeluje na progenitore megakariocita, ali jedino zajedni kim djelovanjem s IL-3 poma~e u sazrijevanju megakariocita (221). IL-6 poti e rast megakariocitnih progenitora u prisutnosti IL-3, IL-4 i EPO, regulirajui rast progenitornih stanica u razli itom stadiju sazrijevanja ato je pokazao Rennick na eksperimentalnom miajem modelu (222). IL-6 stimulira megakariocitopoezu u KS poveavajui broj trombocita u cirkulaciji. Brojni autori naglaaavaju ulogu IL-6 u megakariocitopoezi i djelovanje ovog citokina na poja ano stvaranja megakariocita i trombocita (223,224). Rana proliferacija i razvoj megakariocita potaknuti su trombopetinom i brojnim drugim citokinima meu kojima je i IL-6. Tek zajedni kim djelovanjem mo~e se potaknuti maksimalna megakariocitopeza (225). IL-10 je imunoregulatorni citokin, koji mo~e modulirati imune procese inhibirajui upalni Th1 odgovor. U eksperimentalnom miajem modelu limfociti pod utjecajem IL-10 lu e manje IFN- i IL-2 (226). Panitsas i suradnici su u odraslih s AITP ukazali na jasnu polarizaciju Th1 imunog odgovora, a u bolesnika s aktivnom boleau na sni~ene serumske koncentracije TGF1 (227). IL-10 ima zna ajni imunostimulatorni u inak na limfocite B i supresivan u inak na monocite i makrofage ato dovodi do smanjenja upalnih citokina kao ato je IL-6 (228). Poveane koncentracije IL-10 naene su u nekih bolesnika s AITP. Andersson sa suradnicima je dokazao zna ajno ni~e koncetracija IL-10 u bolesnika s kroni nom AITP i trombocitima manjim od 50 x 109/L nego u zdravih osoba ili bolesnika ije su vrijednosti trombocita bile od 50-150 x 109/L (214). U ispitivanoj skupini nije bilo zna ajne razlike u serumskim koncentracijama IL-10 u djece s AITP pri dijagnozi i zdrave djece. U odraslih serumske koncentracije su bile zna ajno vee u zdravih ispitanika (p = 0,041). Izmeu djece i odraslih s AITP nije bilo zna ajne razlike u serumskim koncentracijama IL-10 (p = 0,338). Neki autori naglaaavaju da IVIG mo~e popraviti neravnote~u IL-10 u AITP. Nakon administracije IVIG-a rastu serumske koncentracije IL-10 koje koreliraju s porastom trombocita (229). U djece s AITP mo~emo pratiti dinamiku promjena serumskih koncentracija IL-10 kroz 8 tjedana i 6 mjeseci. Serumske koncentracije IL-10 bile su zna ajno ni~e nakon 6 mjeseci od koncentracija pri dijagnozi (p = 0,075), ato do sada u literaturi nije objavljeno. U odraslih nije bilo razlike u mjerenjima. Takoer nije bilo zna ajne razlike u mjerenjima izmeu ispitanika s akutnom, kroni nom AITP i kontrolne skupine. Koji imbenik je odgovoran za zna ajnu dinamiku IL-10 u djece s AITP, a koji da te dinamike u odraslih nema? IFN- poveava broj trombocita u bolesnika s AITP. U bolesnika koji su imali poveane koncentracije IL-4 i IL-10 nakon lije enja IFN- doalo je do smanjenja istih. NK stani na aktivnost, koja je bila ni~a prije lije enja poveava se, poja ava se i Th1 aktivnost i smanjuje stvaranje protutijela (230). Analizirajui serumske citokine u bolesnika s AITP Lazarus je pokazao da nisu imali poviaene koncentracije IL-10 (231). U djece s AITP serumske koncentracije TNF- su bile nakon 6 mjeseci zna ajno ni~e nego pri dijagnozi (p = 0,034) i nakon 8 tjedana (p = 0,044). Djeca s AITP su imala i zna ajno ni~e serumske koncentracije TNF- pri dijagnozi od kontrolne skupine. U odraslih nije bilo razlike u mjerenjima. Iz rezultata je vidljivo da nije bilo zna ajne razlike u serumskim koncentracijama TNF- izmeu djece i odraslih pri dijagnozi. Serumske koncentracije TNF- zna ajno su se razlikovale izmeu ispitanika s akutnom, kroni nom AITP pri dijagnozi i kontrolne skupine. Ispitanici s akutnom AITP su imali zna ajno manje koncentracije (p = 0,016). U radu Lazarusa i suradnika nisu dokazane poveane serumske koncentracije TNF- (231) Autoimuna bolest mo~e nastati dijelom zbog abnormalnog ispoljavanja HLA-DR molekula na povraini ciljnih stanica, ato mo~e aktivirati limfocite T i sintezu autoprotutijela. Prolazno ispoljavanje HLA-DR mo~e biti uzrokovano citokinima kao ato je IFN-. Gajewski je pokazao da IFN- mo~e inhibirati proliferaciju stanica KS stimuliranim s IL-3, IL-4 ili GM-CSF u miajem modelu i na taj na in dokazao antiproliferativni u inak IFN- u imunoj regulaciji (232). Da abnormalno stvaranje TNF- i IFN- mo~e utjecati na patogenezu AITP zaklju io je i Garcia-Suarez sa suradnicima primjetivai da su serumske koncentracije oba citokina zna ajno poviaene u bolesnika koji su ovisni o lije enju za razliku od zdravih ispitanika. Ovi citokini djeluju na limfocite B da se diferenciraju u stanice koje lu e imunoglobuline. Te~ina klini ke slike je povezana s poremeenom sekrecijom ova dva citokina (233). Serumske koncentracije IFN- nisu se zna ajno razlikovale izmeu djece i odraslih s AITP i kontrolne skupine, ali je dokazana zna ajna razlika izmeu djece i odraslih s AITP. Odrasli s AITP su imali zna ajno vee serumske koncentracije IFN- od djece s AITP (p = 0,001). Serumske koncentracije IFN- nisu se zna ajno razlikovale u ispitanika s akutnom, kroni nom AITP pri dijagnozi i kontrolne skupine. Nije bilo zna ajnih razlika u serumskoj koncentraciji IFN- mjerenih pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci ni u djece niti u odraslih. U djece akutna AITP se prezentira s Th1, Th0/Th1 ili Th0 ekspresijom citokina. U stabilnoj remisiji izra~eni su Th0 ili Th2 citokini uz kojih je, nakon lije enja IVIG-om, vezana bolja prognoza bolesti, dok visoke koncentracije IFN- i neosjetljivost na lije enje IVIG-om govori u prilog loaijoj prognozi bolesti. Semple navodi da 53% djece sa kroni nom AITP i samo 9 % onih sa akutnom AITP imaju poveane vrijednosti IFN- u serumu (5). Serumske koncentracije IFN- nisu se zna ajno razlikovale izmeu djece i odraslih s AITP i kontrolne skupine. Dokazano je da su u odraslih s AITP serumske koncentracije IFN- bile zna ajno ni~e nego u djece (p = 0,007). Nisu dokazane promjene u serumskim koncentracijama nakon 8 tjedana i nakon 6 mjeseci u odnosu na koncentracije pri dijagnozi ni u djece niti u odraslih s AITP. Iz rezultata je vidljivo da serumske koncentracije IL-4, IL-6 i TNF- 6 mjeseci od zaprimanja su bile zna ajno vee u djece s AITP, za razliku od odraslih s AITP u kojih nije bilo zna ajne razlike serumskih koncentracija svih citokina pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci. Do sada nije opisana u literaturi prezentirana dinamika serumskih koncentracija IL-4, IL-6 i TNF- u vremenu do 6 mjeseci od dijagnoze u djece s AITP. Izmeu zdravih ispitanika i onih s akutnom i kroni nom AITP nije bilo zna ajne razlike u serumskim koncentracijama IL-1, IL-2, IL-3, IL-6, IL-10 i IFN- pri dijagnozi. Zna ajno vee su bile serumske koncentracije IL-4 u bolesnika s kroni nom AITP nego u zdravih ispitanika i onih s akutnom AITP. Bolesnici s akutnom AITP su imali zna ajno manje serumske koncentracije TNF-( od zdravih ispitanika i onih s kroni nom AITP, dok su bolesnici s kroni nom AITP imali zna ajno vee serumske koncentracije IFN-( od zdravih ispitanika i onih s akutnom AITP. Distribuciju subpopulacija limfocita u bolesnika s AITP ispitivalo je viae istra~iva a, neki su otkrili zna ajno sni~enje postotka i apsolutnog broja cirkulirajuih limfocita T8 (234). Zna ajno sni~en postotak, funkciju sveukupnih limfocita T, postotak cirkulirajuih limfocita T4 i povean postotak cirkulirajuih limfocita T8, ali ne i promjene u postotku i funkciji limfocita B dokazao je Mylvaganam (235). Garcia-Suarez i suradnici su objavili izvjeataj o tri bolesnika s AITP koji su nakon splenektomije razvili apsolutnu limfocitozu s ekspanzijom NK stanica. Dvoje od ova tri bolesnika su bili refrakterni na splenektomiju (236). U prezentiranom ispitivanju postotak cirkulirajuih limfocita B iznad granice normale imalo je 22% djece dok je u 78% bio u granicama normale. U odraslih 13,3% je imalo postotak cirkulirajuih limfocita B ispod granica normale, a 86,7% u granicama normale. Najnovije studije ukazuju da je AITP vezana uz promjene u imunosnom sustavu koje nisu samo ograni ene na limfocite B nego takoer zahvaaju populaciju limfocita T. Zna ajan porast CD56+CD3+ citotoksi nih limfocita T i CD56+CD3+ NK stanica je uo io Garcia-Suarez sa suradnicima u bolesnika koji su bili refrakterni na standardno lije enje (237). Kroni na AITP je u odraslih bolesnika karakterizirana stvaranjem autoprotutijela ato je regulirano limfocitima T4. Viae studija ukazuje da u bolesnika s AITP postoji abnormalna limfocitna aktivacija i abnormalno Th1/Th2 stvaranje citokina. Lazarus smatra da se radi o poremeaju prenosa transmembranskog signala u limfocitima (238). Posljednjih desetljea brojne studije opisuju defekt limfocita T i pokuaavaju osvijetliti njihovu ulogu u patogenezi AITP. Neki autori su ispitivali receptore limfocita T, ali joa uvijek je nedovoljno studija koje bi potvrdile patofizioloaki mehanizam promjena. Potrebno je joa ispitivanja (239). U ispitivanoj skupini djece s AITP postotak cirkulirajuih limfocita T4 je u zna ajnom postotku (52,6%) bio ispod granica normale pri dijagnozi, za razliku od odraslih u kojih je taj postotak u odnosu na djecu bio neato ni~i (27,6%). Evidentno je da stvaranje protutijela pomou limfocita B zahtijeva pomo limfocita T. Autoreaktivne stanice su limfociti T4 poznati kao pomoni ke stanice koje selektivno poma~u limfocitima B u stvaranju protutijela (240). Kuwana sa suradnicima je identificirao autoreaktivne limfocite T, koji poma~u limfocitima B u stvaranju protutijela na trombocitni membranski GPIIb-IIIa, koji je najva~niji cilj antitrombocitnih protutijela. Autori naglaaavaju da su potrebna daljnja istra~ivanja autoreaktivnih limfocita T, koja e mo~da rasvijetliti patogenezu kroni ne AITP i pomoi u odabiru lije enja refrakternih bolesnika (241,242). Joa uvijek nema studija koje bi objasnile imunoregulaciju nastanka antitrombocitnih protutijela (243). Garcia-Suarez sa suradnicima je pronaaao u bolesnika s AITP povean postotak in vivo aktiviranih (CD25+/DR+) limfocita T, iji je proliferativni odgovor na poliklonalne mitogene signale oateen. On smatra da je funkcionalno oateenje udru~eno sa redistribucijom limfocita T u perifernoj krvi, gdje je evidentan nedostatak limfocita T4. Takoer je pronaaao da je oateenje funkcije limfocita T razli ito u razli itim periodima bolesti. U bolesnika sa stabilnom nelije enom boleau zna ajno je smanjen proliferativni odgovor limfocita T na mitogene, dok oni bolesnici koji ne odgovaraju na steroide i splenektomiju pokazuju zna ajno smanjenu blastogenezu nakon stimulacije limfocita T fitohemaglutininom (244). Evidentno je da je nastanak antitrombocitnih protutijela pod utjecajem razli itih abnormalnih mehanizama vezanih uz limfocite, poveanu aktivnost limfocita T4, a smanjenu aktivnost limfocita T8, o emu je pisao Semple sa suradnicima (245). Analizirao je fenotip limfocita u perifernoj krvi u bolesnika s AITP i ukazao na znatno smanjenje CD4+/Leu8+T supresorskih/inducirajuih stanica i istovremeno poveanje CD3+/DR+ aktiviranih limfocita T i CD19+ limfocita B. Isti autor smatra da su limfociti T4 u bolesnika s AITP stimulirani da lu e IL-2 i mogu modulirati poja ani antitrombocitni odgovor (246). Patoloaki stani ni imunoloaki odgovor u AITP je vezan uz defekt u populaciji limfocita T, dok populacija limfocita B nije zahvaena. U kroni noj AITP abnormalnost stani nog imuniteta je dokazao i Mylvaganam sa suradnicima kada je pokazao da su bolesnici s AITP u aktivnoj fazi imali zna ajno smanjen postotak limfocita T4 i povean postotak limfocita T8, ali nije dokazao odstupanja u funkciji i postotku limfocita B (247). Iz rezultata je vidljivo da nije bilo zna ajne razlike u apsolutnom broju limfocita u perifernoj krvi, postotku cirkulirajuih limfocita T, B, T8 i NK stanica izmeu djece i odraslih s AITP. Postotak cirkulirajuih limfocita T4 u djece s AITP je bio zna ajno manji nego u odraslih. Broj trombocita u perifernoj krvi u sva tri mjerenja u djece s AITP nije pokazivao zna ajnu povezanost s apsolutnim brojem limfocita, postotkom cirkulirajuih limfocita T, B, T8 i NK stanica. U odraslih bolesnika broj trombocita u perifernoj krvi pri dijagnozi nije pokazivao zna ajnu povezanost s postotkom cirkulirajuih limfocita T i T4, ali je pokazivao zna ajnu pozitivnu povezanost s postotkom cirkulirajuih limfocita B, T8 i NK stanica i zna ajnu negativnu povezanost s apsolutnim brojem limfocita (p = 0,003). Broj trombocita nakon 8 tjedana pokazivao je zna ajnu negativnu povezanost s postotkom cirkulirajuih NK stanica pri dijagnozi (p = 0,039). Iz rezultata je vidljivo da e u odraslih broj trombocita biti vei ako je apsolutni broj limfocita pri dijagnozi ni~i, a postotak limfocita B, T8 i NK stanica viai. Ovo saznanje je koriateno u odabiru prediktora u odraslih bolesnika i analizi modelom viaestruke regresije, ato do sada nije opisano u literaturi. Limfociti T4 i T8 mogu u razli itim okolnostima proizvoditi razli ite citokine i podjednako su va~ni u imunom odgovoru. U djece je dokazana zna ajno pozitivna povezanost limfocita T sa serumskim koncentracijama IL-1, a zna ajno negativna limfocita B sa serumskim koncentracijama IL-6 i IL-10. Zna ajnu pozitivnu povezanost u djece s AITP pokazivali su limfociti T4 s IL-1 kao i limfociti T8 s IL-4. Limfociti T8 proizvode Th1 i Th2 tip citokina i va~ni su u regulaciji imunog odgovora. Hoiden i suradnici su ispitivali postotak limfocita T4 i T8 u slezeni nakon stimulacije superantigenom. Dokazali su da IL-4 nastaje isklju ivo iz limfocita T4, dok su u viae od 80% slu ajeva IL-10 i IFN- proizvodili limfociti T8 (248). U djece s AITP NK stanice su pokazivale zna ajnu pozitivnu povezanost s IL-2, IL-10, TNF-( i IL-6 i zna ajnu negativnu povezanost s IL-1. Jewett i suradnici su istra~ivali djelovanje citokina IL-12 koji mo~e aktivirati citotoksi nu funkciju NK stanica. Dokazali su da je ova aktivacija ovisna o endogenom lu enju TNF-( i potisnuta endogenim lu enjem IFN-. U ovu aktivaciju nezrelih NK stanica mo~e biti djelomi no uklju en i IL-2 uz inhibiciju anti-TNF-( protutijelima, ali ne i lu enjem IFN- (249). U odraslih ispitanika limfociti T su pokazivali zna ajnu pozitivnu povezanost s IL-3 i IL-10, a cirkulirajui limfociti B s IL-4 i zna ajnu negativnu povezanost s IFN-(. Zna ajna pozitivna povezanost uo ena je izmeu postotka cirkulirajuih limfocita T4 i IL-10, a NK stanica s IFN-( i IFN-(. NK stanice mogu izlu ivati razli ite citokine koji sudjeluju u aktivaciji nezrelih stanica, a izlu ivanje je vezano uz stupanj zrelosti NK stanica (250). Lije enje IVIG-om mo~e modulirati Th1/Th2 ravnote~u. Yamada sa suradnicima je pokazao da infuzije IVIG-a mogu povisiti koncentracije citokina IFN-, TNF- (Th1 citokini) i IL-4 i IL-10 (Th2 citokini) u perifernoj krvi i smanjiti Th1/Th2 odnos limfocita. Visoke doze IVIG-a mogu promijeniti perifernu Th1/Th2 ravnote~u (251). Dvije treine djece imaju u anamnezi preboljelu infekcioznu bolest nekoliko dana ili tjedana prije nastanka AITP. Iz prezentiranih rezultata je vidljivo da je pozitivna IgM serumska protutijela na neki od odabranih virusa imalo 33 (59%) bolesnika. Sveukupno je bilo 7 (12%) bolesnika, koji su imali pozitivna IgM serumska protutijela istovremeno na dva ili viae virusa. Molekularna mimikrija izmeu viralnih antigena i proteina domaina mo~da je uzrokom nastanka protutijela u AITP (137,138), meutim izgleda da infekcija nekim od virusa nije najva~niji imbenik u nastanku bolesti. Seroloaki potvrenu akutnu EBV infekciju imalo je 9 (16%) djece i odraslih, a akutnu seroloaki dokazanu HHV-6 infekciju 11 (22%) bolesnika od toga 8 (20%) djece i 3 (17%) odrasla. Seroloaki dokazanu akutnu infekciju adenovirusom imalo je 14 (25%) bolesnika, od toga 11 (28%) djece i 3 (18%) odraslih s AITP, dok je seroloaki dokazanu akutnu infekciju parvovirusom B19 imalo troje djece i jedan odrasli (7%). Malo je izvjeataja u literaturi o utjecaju virusne infekcije na poremeaj u citokinskoj mre~i openito. Kerr sa suradnicima opisuje poveane serumske koncentracije TNF- i IFN- u bolesnika s parvovirus B19 infekcijom, a Corcoran sa suradnicima je dokazao da limfociti u odraslih bolesnika koji se oporavljaju od iste infekcije poja ano stvaraju IL-2 i IFN-, za razliku od djece u koje je primjeen zna ajan deficit stvaranja IFN-. Autori smatraju da neke autoimune bolesti vezane uz parvovirus B19 infekciju nastaju zbog poremeaja u ravnote~i citokina (252,253). Flamad sa suradnicima je istra~ivao utjecaj HHV-6 na sintezu citokina i dokazao da ovaj virus ima sna~an imunomodulatorni utjecaj stimulirajui stanice na stvaranje citokina (19,20). Va~no je istaknuti da je dokazana zna ajna povezanost serumskih koncentracija citokina i serumskih IgM protutijela na pojedine viruse u djece i odraslih. U djece serumska EBV EA IgM protutijela pokazivala su zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-10, IFN-( i IFN-( . Serumska EBV EA IgG protutijela pokazivala su zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-4, a negativnu s TNF-(, dok su EBV VCA IgM serumska protutijela pokazivala zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-4, a negativnu s TNF-(. HHV-6 IgG serumska protutijela pokazivala su zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-10 u djece s AITP, a serumska adenovirus IgM protutijela zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-2, IL-10 i IFN-, a zna ajnu negativnu s IL-1. Serumska parvovirus B19 IgM protutijela zna ajno su pozitivno bila povezana sa serumskim koncentracijama TNF-(. U odraslih s AITP serumska protutijela EBV EA IgM pokazivala su zna ajnu pozitivnu povezanost sa serumskim koncentracijama TNF-( i IFN-(, EBV EA IgG s TNF-( i IFN-(. Serumska protutijela EBV VCA IgM pokazivala su zna ajnu negativnu povezanost s IL-2, IL-6 i pozitivnu s IFN-(.. Serumska protutijela EBV VCA IgG pokazivala su zna ajnu negativnu povezanost sa serumskim koncentracijama TNF-( . Serumska protutijela IgG na HHV-6 virus pokazivala su zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-1 i IFN-(, a zna ajnu negativnu s IL-2. Adenovirus IgM serumska protutijela pokazivala su zna ajnu negativnu povezanost sa serumskim koncentracijama IL-2. Serumska parvovirus B19 IgM protutijela pokazivala su zna ajnu pozitivnu povezanost sa serumskim koncentracijama IL-4. Evidentno je da postoji zna ajna povezanost koncentracija serumskih citokina s pojavom protutijela na viruse u bolesnika s AITP ato do sada nije opisano u literaturi. Svakako e ovo saznanje biti predmetom brojnih znanstvenih istra~ivanja i rasprava da bi se ustanovio mehanizam djelovanja virusa na citokinsku mre~u u bolesnika s AITP. Joa uvijek je nemogue predvidjeti da li e dijete ili odrasli razviti akutnu ili kroni nu AITP (254). Prezentirani su rezultati modela viaestruke regresije, koji bi bio optimalan u predvianju broja trombocita u perifernoj krvi 6 mjeseci od dijagnoze u djece s AITP i broja trombocita u perifernoj krvi nakon 8 tjedana od dijagnoze u odraslih s AITP. Pomou modela viaestruke regresije mo~emo s 95,3% vjerojatnosti prognozirati broj trombocita u perifernoj krvi 6 mjeseci od dijagnoze pomou pet regresorskih varijabli, koje utje u na broj trombocita u perifernoj krvi djece nakon 6 mjeseci od dijagnoze. To su serumske koncentracije IL-3, IL-4, TNF- i postotak cirkulirajuih limfocita T4 pri dijagnozi kao i broj trombocita u perifernoj krvi nakon 8 tjedana. Znajui vrijednost varijabli prediktora serumskih koncentracija IL-3, IL-4, TNF- i postotak limfocita T4 u krvi mjerenih pri dijagnozi kao i broj trombocita mjeren nakon 8 tjedana mo~emo upotrijebiti jednad~bu viaestruke regresije. Broj trombocita u perifernoj krvi nakon 6 mjeseci od dijagnoze pokazivao je zna ajnu pozitivnu povezanost s IL-3/1 (p = 0,035), postotkom cirkulirajuih limfocita T4 pri dijagnozi (p = 0,054) i brojem trombocita u perifernoj krvi nakon 8 tjedana (p = 0,005), a zna ajnu negativnu s IL-4/1 (p = 0,035) i TNF-/1 (p = 0,048). To zna i da e u djece broj trombocita mjeren 6 mjeseci od dijagnoze biti vei ako su serumske koncentracije IL-3 i postotak cirkulirajuih limfocita T4 pri dijagnozi i broj trombocita mjerenih nakon 8 tjedana vei i ako su serumske koncentracije IL-4 i TNF- pri dijagnozi manje, ato do sada u literaturi nije opisano. U odraslih etiri regresorske varijable koje utje u na broj trombocita u perifernoj krvi nakon 8 tjedana od dijagnoze su vrijednosti apsolutnog broja limfocita, postotak cirkulirajuih limfocita B, NK stanica i serumske koncentracije IFN- pri dijagnozi. Znajui vrijednost varijabli prediktora upotrebom jednad~be viaestruke regresije mo~emo s 93,3% vjerojatnosti predvidjeti broj trombocita nakon 8 tjedana. Trombociti mjereni nakon 8 tjedana od dijagnoze zna ajno pozitivno koreliraju s apsolutnim brojem limfocita pri dijagnozi (p = 0,040), a negativno s postotkom limfocita B pri dijagnozi (p = 0,028). Negativna povezanost s NK stanicama (p = 0,112) i pozitivna sa serumskim koncentracijama IFN- pri dijagnozi (p = 0,268) postoji, ali nije zna ajna. To zna i da e u odraslih broj trombocita u perifernoj krvi 8 tjedana od dijagnoze biti vei ako je apsolutni broj limfocita i ako su serumske koncentracije IFN- pri dijagnozi bili vei, a postotak cirkulirajuih limfocita B i NK stanica u krvi bili ni~i, ato do sada u literaturi nije opisano. 6. ZAKLJU CI Djeca s AITP pri dijagnozi su imala zna ajno vee serumske koncentracije IL-4 i zna ajno ni~e IL-2 i TNF- od zdrave djece. Odrasli s AITP pri dijagnozi su imali zna ajno vee serumske koncentracije IL-1 i IL-4, a zna ajno manje koncentracije IL-10 od zdravih ispitanika. Djeca s AITP pri dijagnozi su imala zna ajno ni~e serumske koncentracije IL-4, IL-6 i IFN-, a zna ajno viae IFN- od odraslih s AITP. Zna ajno su se promijenile serumske koncentracije IL-4, IL-6, IL-10 i TNF- u djece u vremenu do 6 mjeseci od dijagnoze. Serumske koncentracije IL-4 i IL-6 su nakon 6 mjeseci bile zna ajno vee, a serumske koncentracije IL-10 i TNF- zna ajno ni~e od onih pri dijagnozi. Zna ajnih promjena nije bilo u serumskim koncentracijama IL-1, IL-2, IL-3, IFN- i IFN- u djece i IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, TNF-, IFN- i IFN- u odraslih s AITP. U djece s AITP broj trombocita u perifernoj krvi pri dijagnozi bio je zna ajno negativno povezan, a broj trombocita nakon 6 mjeseci zna ajno pozitivno povezan sa serumskim koncentracijama IL-3 pri dijagnozi. U odraslih broj trombocita odreen nakon 6 mjeseci od dijagnoze u perifernoj krvi je pokazivao zna ajno pozitivnu povezanost sa serumskim koncentracijama IL-4, a zna ajno negativnu povezanost s IFN- i IL-3. Pri dijagnozi izmeu zdravih ispitanika i onih s akutnom i kroni nom AITP nije bilo zna ajne razlike u serumskim koncentracijama IL-1, IL-2, IL-3, IL-6, IL-10 i IFN-. Serumske koncentracije IL-4 i IFN- bile su zna ajno vee u bolesnika s kroni nom AITP, dok su serumske koncentracije TNF- bile zna ajno manje u bolesnika s akutnom AITP. U djece s AITP broj trombocita u perifernoj krvi nije bio zna ajno povezan s apsolutnim brojem limfocita, postotkom limfocita T, B, T4, T8 i NK stanica za razliku od odraslih u kojih je bio zna ajno pozitivno povezan s postotkom cirkulirajuih limfocita B, T8 i NK stanica, a zna ajno negativo s apsolutnim brojem limfocita pri dijagnozi. U djece je dokazana zna ajna povezanost limfocita T s IL-1, limfocita B s IL-6 i IL-10, limfocita T4 s IL-1, T8 s IL-4, a NK stanica s IL-2, IL-10, IL-6 i TNF-, a u odraslih limfocita T s IL-3 i IL-10, limfocita B s IL-4 i IFN-, T4 s IL-10, a NK stanica s IFN- i IFN-. Seroloaki je dokazana akutna virusna infekcija u 59% bolesnika s AITP (16% EBV, 22% HHV-6, 25% adenovirus i 7% parvovirus B19). U djece je dokazana zna ajna pozitivna povezanost serumskih koncentracija IL-10, IFN-( i IFN-( i pojave serumskih protutijela EBV EA IgM, IL-4 i EBV EA IgG, kao i negativna povezanost EBV EA IgG s TNF-(. EBV VCA IgM protutijela su pokazivala zna ajno pozitivnu povezanost s IL-4, a negativnu s TNF-(. HHV-6 IgG protutijela pokazivala su zna ajno pozitivnu povezanost s IL-10, a adenovirus IgM zna ajno pozitivnu s IL-2, IL-10 i IFN-, a negativnu s IL-1. Dokazana je zna ajno pozitivna povezanost parvovirus B19 IgM protutijela s TNF-(. U odraslih EBV EA IgM i IgG protutijela pokazivala su zna ajno pozitivnu povezanost s TNF-( i IFN-(, dok su EBV VCA IgM pokazivala zna ajno negativnu povezanost s IL-2, IL-6, a pozitivnu s IFN-(. EBV VCA IgG protutijela pokazivala su zna ajno negativnu povezanost s TNF-(, dok su HHV-6 IgG pokazivala zna ajno pozitivnu povezanost s IL-1 i IFN-(, a zna ajno negativnu s IL-2. Dokazana je zna ajno negativna povezanost adenovirus IgM protutijela s IL-2 i zna ajno pozitivna parvovirus B19 IgM s IL-4. U djece s AITP, znajui vrijednost varijabli prediktora serumskih koncentracija IL-3, IL-4, TNF- i postotak cirkulirajuih T4 mjerenih pri dijagnozi, kao i broj trombocita u perifernoj krvi mjerenih nakon 8 tjedana, mo~emo prognozirati broj trombocita u perifernoj krvi 6 mjeseci nakon dijagnoze. U odraslih s AITP, znajui vrijednosti varijabli prediktora apsolutnog broja limfocita, postotka limfocita B, NK stanica i serumskih koncentracija IFN- pri dijagnozi, mo~emo prognozirati broj trombocita u perifernoj krvi nakon 8 tjedana od dijagnoze. Pri tome mo~emo upotrijebiti jednad~bu viaestruke regresije. 7. SA}ETAK Uvod: AITP je uzrokovana neadekvatnim imunim odgovorom nejasne etiologije. Trombociti oblo~eni protutijelima uklanjaju se iz cirkulacije pomou monocitno makrofagnog sustava zbog ega krae ~ive. Jedan od moguih etioloakih imbenika je poremeaj ravnote~e citokina, koji je zamijeen u tih bolesnika. Ciljevi: Odrediti da li je imunosni defekt povezan sa serumskim koncentracijama citokina u djece i odraslih s akutnom AITP. Usporediti citokine pri dijagnozi u ispitanika meusobno i prema kontrolnoj skupini i odrediti promjene nakon 8 tjedana i nakon 6 mjeseci u oboljele djece i odraslih. Utvrditi povezanost razine citokina s prisustvom protutijela za CMV, EBV, HHV-6, adenovirus i parvovirus B19 i razine citokina s apsolutnim brojem limfocita, postotkom limfocita T, B, T4, T8 i NK stanica u oboljele djece i odraslih. Odrediti prognosti ke vrijednosti razine citokina u odnosu na prelazak bolesti u kroni ni oblik u djece i odraslih. Ispitanici: Ispitivano je 48 djece i 19 odraslih s AITP. Kontrolnu skupinu sa injavalo je 26 zdrave djece, te 24 zdrava odrasla. Metode: Koncentracije citokina IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-(, IFN-(, protutijela na CMV, EBV, HHV-6, adenovirus i parvovirus B19 su odreeni u testu ELISA; apsolutni broj limfocita, postotak cirkulirajuih limfocita T, B, T4, T8 i NK stanice analizirani su pomou proto nog razvrstava a stanica u djece i odraslih s AITP pri dijagnozi. Rezultati su analizirani pomou statisti kih programa SPSS 11.0 PC i Statistica 6.0. Studentov t-test s logaritamski transformiranim varijablama koriaten je za usporedbu rezultata. Citokini i trombociti su mjereni pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci, a za evaluaciju promjena koriaten je Friedmanov test. Pearsonov koeficijent korelacije i model viaestruke regresije primijenjen je u predvianju broja trombocita. Kao razina zna ajnosti koriatena je vrijednost p < 0,05. Rezultati: Koncentracije IL-2 (p = 0,021), TNF- (p = 0,009) u djece i IL-10 (p = 0,041) u odraslih su bile ni~e, a IL-4 (p = 0,062) u djece i IL-1 (p = 0,0,045) u odraslih su bile viae od kontrolne skupine. Djeca s AITP su imala ni~i IL-4 (p = 0,033), IL-6 (p = 0,004) IFN- (p = 0,001), a viai IFN- (p = 0,007) od odraslih. Limfociti T4 u 52,6% djece i 27,6% odraslih su bili sni~eni. Broj trombocita u djece nakon 6 mjeseci bi se mogao predvidjeti pomou broja trombocita nakon 8 tjedana, a IL-3, IL-4 i TNF- pri dijagnozi. U odraslih bi se nakon 8 tjedana broj trombocita mogao predvidjeti pomou IFN-, apsolutnog broja limfocita, postotka limfocita B i NK stanica. Zaklju ak: U patogenezi AITP, pored autoprotutijela, sudjeluju i pomoni ki limfociti T, kao i citokini koje oni lu e . 8. SUMMARY Background: The etiology of AITP is unknown and it is caused by an inappropriate response of the immune system. Antibody-coated platelets are removed from circulation by the monocytic phagocytic system, resulting in a shortened platelet survival. Aims: This study was designed to determine if these defects are related to serum cytokine levels, to evaluate the differences in serum cytokines between children and adults, to determine the correlation between cytokine serum concentrations and circulating lymphocytes, and antibodies to viruses. Subjects: The study population consisted of 48 children and 26 healthy controls, 19 adults with AITP and 24 healthy controls. Methods: Serum concentrations of IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-(, and IFN-(, antibodies against CMV, EBV, HHV-6, adenovirus and parvovirus B19 were all determined by ELISA; absolute lymphocyte count, percentage of circulating lymphocyte T, B, T4, T8 and NK cells by flow cytometric analysis were measured in children and adults with AITP at diagnosis. Data were analyzed by SPSS 11.0 PC and Statistica 6.0 statistical programs. Student s t-test with logarithmic transformation comparing the data on cytokine levels was performed. Cytokines and platelets were measured at diagnosis, after 8 weeks and after 6 months while the Friedman test evaluated the changes. Pearson s correlation coefficients and multiple regression analysis were used to predict the platelet values (after 6 months in children, after 8 weeks in adults). A p < 0,05 value was considered as statistically significant. Results: Concentrations of IL-2 (p = 0,021), TNF- (p = 0,009) in children and IL-10 (p = 0,041) in adult patients were lower, while IL-4 (p = 0,062) in children and IL-1 (p = 0,0,045) in adults where higher, compared to healthy controls. Children with AITP had lower IL-4 (p = 0,033), IL-6 (p = 0,004) and IFN- (p = 0,001), and higher IFN- (p = 0,007) then adults. Th lymphocytes in 52,6% children and 27,6% adults were low. 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Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol 2001;82:3011-9. Corcoran A, Doyle S, Waldron D, Nicholson A, Mahon BP. Impaired gamma interferon responses against parvovirus B19 by recently infected children. J Virol 2000;74:9903-10. Chu YW, Korb J, Sakamoto KM. Idiopathic thrombocytopenic purpura. Pediatr Rev 2000;21:95-104. Popis tablica i slika Popis tablica strana Tablica 1. Podjela autoimmune trombocitopenije prema stadiju bolesti& & & & & & ...10 Tablica 2. Ispitanici s AITP...............................................................................................38 Tablica 3. Normalne koncentracije serumskih citokina.....................................................40 Tablica 4. Prikaz broja trombocita pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u perifernoj krvi djece i odraslih s AITP i ukupno& & & & & & & & & & & 44 Tablica 5. U estalost te~ine trombocitopenije u djece i odraslih& & & & & & & & & ...45 Tablica 6. Prikaz razlika serumskih kocentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u zdrave i djece s AITP pri dijagnozi pri dijagnozi& & & & .48 Tablica 7. Prikaz razlika serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u zdravih i odraslih s AITP pri dijagnozi& & & & & & & & 49 Tablica 8. Prikaz razlika serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( u djece i odraslih s AITP pri dijagnozi & & & & & & & & & 52 Tablica 9. Prikaz razlika apsolutnog broja limfocita, postotka cirkulirajuih limfocita T, B, T4, T8 i NK stanica pri dijagnozi u perifernoj krvi djece i odraslih s AITP& & & & & & & & & & & & & & & & & & ...& & & & & & & & & 60 Tablica 10. Prikaz povezanosti apsolutnog broja limfocita, postotka cirkulirajuih limfocita T, B, T4, T8 i NK stanica s brojem trombocita u djece i odraslih s AITP& & & & & & & & & & & & & & & & & & & & & & & & & & & .61 Tablica 11. Prikaz serumskih protutijela na CMV, EBV, HHV-6, adenovirus i parvovirus B19 u djece s AITP, odraslih i ukupno pri dijagnozi& & & & & 63 Tablica 12. Prikaz povezanosti serumskih koncentracija IL-1, -2, -3, -4, -6, 10, TNF-(, IFN-( i IFN-( s brojem trombocita u perifernoj krvi u djece i odraslih s AITP pri dijagnozi& .& & & & & & & & & & & & & & & & & ..68 Tablica 13. Prikaz serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( mjerenih pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u djece s AITP & & & & & & & & & & & & & & & & & & & & & & & & & & & .70 Tablica 14. Prikaz serumskih koncentracija IL-1, -2, -3, -4, -6, -10, TNF-(, IFN-( i IFN-( mjerenih pri dijagnozi, nakon 8 tjedana i nakon 6 mjeseci u odraslih s AITP& & & & & & & .& & & & & & & & & & & & & & & & ...71 Popis slika Slika 1. Zreli megakariocit.................................................................................................13 Slika 2. Plan ispitivanja .....................................................................................................42 Slika 3. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, standardne pogreake (SE) i SD IL-4 u zdrave i djece s AITP pri dijagnozi...........................47 Slika 4. Prikaz srednje logaritmirane vrijednosti serumske koncentracije, SE i SD IL-2 u zdrave i djece s AITP. pri dijagnozi........................................................ 47 Slika 5. Prikaz srednje logaritmirane vrijednosti serumske koncentracije, SE i SD TNF- u zdrave i djece s AITP. pri dijagnozi& ..................................................48 Slika 6. Prikaz srednje logaritmirane vrijednosti serumske koncentracije, SE i SD IL-1 u zdravih i odraslih s AITP pri dijagnozi...................................................50 Slika 7. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-4 u zdravih i odraslih s AITP pri dijagnozi....................................................51 Slika 8. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-10 u zdravih i odraslih s AITP pri dijagnozi...................................................51 Slika 9. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-4 u djece i odraslih s AITP pri dijagnozi.........................................................53 Slika 10. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-6 u djece i odraslih s AITP pri dijagnozi.......................................................53 Slika 11. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN- u djece i odraslih s AITP pri dijagnozi.....................................................54 Slika 12. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN- u djece i odraslih s AITP pri dijagnozi..& & & & ..................................54 Slika 13. Prikaz apsolutnog broja limfocita u djece i odraslih s AITP pri dijagnozi.........56 Slika 14. Prikaz postotka cirkulirajuih limfocita T4 u djece i odraslih s AITP pri dijagnozi& & & & & & & & & & & & & & & & & & & & & & & & & & & ..57 Slika 15. Prikaz negativne povezanosti broja trombocita i apsolutnog broja limfocita u perifernoj krvi u odraslih s AITP pri dijagnozi& & & & ................................61 Slika 16. Prikaz postotka bolesnika s AITP sa seroloaki dokazanom akutnom virusnom infekcijom pri dijagnozi& .............................& & & & & & & & & 64 Slika 17. Prikaz negativne povezanosti broja trombocita u perifernoj krvi i serumskih koncentracija IL-3 u djece s AITP pri dijagnozi...& & & & & & & & & & & .67 Slika 18. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-1 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi........................................................................................................73 Slika 19. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-2 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi....................................................................................................... .....73 Slika 20. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-3 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi& & & & & & & & & & & & & & & & & & & & & & & & & & 74 Slika 21. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-4 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi..& & & & & & & & & & & & & & & & & & & & & & & & & ..74 Slika 22. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-6 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi..............................................................................................................75 Slika 23. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IL-10 u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi & & & .& & & & & & & & & & & & & & & & & & & & & & & & 76 Slika 24. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD TNF-( u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi............................................................................................77 Slika 25. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN- u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi& & & & & & & & & & & & & & & & & & & & & & & & & ..77 Slika 26. Prikaz srednje logaritmirane vrijednosti serumskih koncentracija, SE i SD IFN-( u zdrave populacije, bolesnika s kroni nom i akutnom AITP pri dijagnozi.......................................................................................................78 Ova disertacija ostvarena je u : Klini koj bolnici Split Klini ki odjel za dje ju hematologiju, onkologiju, imunologiju i medicinsku genetiku Klinike za dje je bolesti 1.2. Laboratorij za imunogenetiku 1.3. Centralni laboratorij Kri~ine 2. Klinici za infektivne bolesti Dr. Fran Mihaljevi u Zagrebu Odjel za klini ku mikrobiologiju Odsjek za serologiju Mentor rada je prof . dr. sc. Boris Labar Rad ima: stranice 131 slika 26 tablica 14 } I V O T O P I S Roena 1949. u Splitu. Maturirala 1968, diplomirala na Medicinskom fakultetu u Zagrebu, 1974. Studentski rad: Citogenetske varijacije i njihovo genetsko zna enje uz Downov sindrom; nagrada rektora Sveu iliata 1972. (mentor prof. Zergollern). Godine 1974. razmjena studenata kirurgija, Regionalna bolnica Madrid. Sta~ist u Imunoloakom zavodu u Zagrebu; stru ni ispit 1975; u DZ Split 1976; specijalizacija pedijatrije 1977; poslijediplomski studij Klini ka pedijatrija, 1980; specijalisti ki ispit 1981; Klinika za dje je bolesti KB Split 1981; Odsjek za dje ju hemato/onkologiju, imunologiju 1983; magistarski rad Medicinski fakultet Zagreb, 1986: Sindrom oateenja hladnoom (mentor prof. `tambuk). Usavraavanje: Zavod za hemofiliju i hemoblastoze Medicinskog fakulteta Zagreb, 1985. (prof. Tiefenbach); Hemato/onkologija Otroake klinike Ljubljana, 1986. (prof. Jereb); Hematoloaka klinika i Centar za znanstvena istra~ivanja San Gerardo Monza, 1989-2001. (prof. Masera, prof. Biondi); pohaala viae meunarodnih seminara/ simpozija iz hemato/onkologije, imunologije, genetike, molekularne biologije. Predsjednica Pedijatrijske sekcije ZLH Split, 1984-1988; znanstveni asistent 1987; voditelj vje~bi/seminara na Medicinskom fakultetu Split, 1987; voditelj Odsjeka za hemato/onkologiju i imunologiju Klinike za dje je bolesti KB Split, 1987. Osnovala: klub roditelja "Sanus" 1991, podru~nicu HULL 1998, humanitarnim akcijama omoguila donacije za KB Split. Projekt psihosocijalne zaatite djece sa malignom boleau 1994. (mentor prof. Spineta). Tim za transplantaciju krvotvornih mati nih stanica KB Split, 2001. Asistent za predmet Pedijatrija Medicinskog fakulteta Split, 1994. Naziv primarius stekla 2002. Voditelj Klini kog odjela za dje ju hematologiju, onkologiju, imunologiju i medicinsku genetiku 2003. lan: Nacionalne skupine za leukemije, limfome i nasljedne koagulopatije, WFH, ISTH, ESID, SIOP, HS. Aktivna na viae znanstvenih/stru nih skupova/simpozija u zemlji i inozemstvu. Odr~ala viae predavanja na stru nim skupovima i javnim tribinama. Mentor viae diplomskih radova. Autor viae kongresnih priopenja i radova objavljenih u domaim/meunarodnim asopisima (CC, Medline/Index Medicus). Govori, piae engleski i talijanski, slu~i se francuskim i apanjolskim jezikom. Majka jednog sina.     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