engleski

ene Expression Profiling of the T-cell Receptor Signalosome Reveals Novel Immune-Endocrine Interactions in Hashimoto's Thyroiditis

CD28/TCR/CTLA-4 complex controls T-cell homeostasis, tolerance and autoimmunity in Hashimoto’s thyroiditis (HT). Many other receptors, CD45 protein tyrosine phosphatase and vitamin D receptor (VDR) in particular, are indispensable for CD28/TCR signaling efficiency and affect Th1/Th17/Treg processes central to the pathogenesis of HT. However, their role has been less well established. Aim: To explore disease- modifying effects of the expression levels of selected mRNAs, centered around T-cell pathways involving CTLA-4, in patients with HT. Methods: 44 HT patients and 46 euthyroid, thyroid peroxidase autoantibodies (TPOAb)negative controls without a personal or family history of autoimmune disorders were recruited. HT was diagnosed by positive TPOAb-IgG, characteristic ultrasonographic and cytopathologic findings on fine needle aspiration biopsy and/or biochemical hypothyroidism. Untouched T-lymphocytes were negatively isolated from peripheral blood mononuclear cells by use of magnetic beads. Total mRNA was extracted and gene expression studied by RT-PCR and ImageQuant method relative to GAPDH products (%). Biochemical data were compared to gene expression levels by robust regression procedures. Results: Total VDR, CTLA-4, CD28, CD45RABC and CD45R0 mRNA expression did not differ by case-control status, gender and need for hormone replacement therapy. CTLA-4 mRNA expression was related to both CD28 (β=0.758±0.283, P=0.011, R2a~13%) and VDR mRNA expression (β=0.311±0.148, P=0.042, R2a~7%), irrespective of the thyroid function level (unsorted T-cells, HT patients). Log-transformed TSH values at diagnosis were inversely correlated with T-cell CTLA-4 mRNA levels in untreated patients (β=-0.0047±0.002, P=0.026, R2a~5%), independent of the serum free thyroxine and age. Increased CD45RABC expression, a characteristic of naïve Tcells, was associated with younger age and higher VDR mRNA (β=0.093±0.045, P=0.04, R2a~5%), independent of the case-control status. At the same time, ageing (β=0.54±0.151, P<0.001, R2a~11%) and decreased VDR mRNA expression (β=0.212±0.07, P=0.003, R2a~8%) were associated with accumulation of CD45R0 transcripts characteristic of activated and memory T-cells.Conclusion: Thyroid dysfunction is associated with down-regulation of CTLA-4 mRNA in peripheral blood T-cells of untreated HT patients. T-cell VDR mRNA abundance is linked to CTLA-4 mRNA expression and involved in attenuation of an age-related shift from naïve to memory T- cell mRNA signature in HT patients. A cross talk between endocrine and immune functions apparently exists in chronic thyroiditis: thyroid function, ageing and VDR mRNA expression seem to play a role in the maintenance of peripheral T-cell subpopulations in affected individuals. Thus, transcriptome profiling of the TCR signalosome in selected T-cell populations holds promise to unravel novel, therapeutically amenable disease- modifying networks in autoimmune thyroid disorders.

T-lymphocyte ; CTLA-4 ; Hashimoto's thyroiditis ; calcitriol receptor

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