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Modulation of B cell TLR9 expresssion and IL-10 and BAFF production in newly-discovered sle patients throughout chloroquine treatment

Introduction. Success of B cell-targeted treatments in autoimmune diseases like systemic lupus erythematosus (SLE) has brought into focus B cell hyperactivity as a dominant disorder. Dual nature of B cells - armed with pattern-recognition receptors but capable for antigen-specific response – can become detrimental if an autoantigen elicits both pathways in a self-sustained fashion. One such antigen is DNA, recognized by B cells via Toll-like receptor 9 (TLR9). Anti-DNA antibodies are prototypic for SLE, and activate self-reactive B cells when complexed with DNA in murine models. B cell activation is also augmented by IL-10 (produced in B cells upon TLR9 signaling) and their survival maintained by BAFF (B cell activating factor produced by myeloid cells). Both cytokines are often found increased in SLE patients’ sera. Patients and Methods. Since some aspects of SLE are effectively controlled by chloroquine, a drug that inhibits TLR9 signaling, we investigated whether chloroquine modulates TLR9, IL-10 and BAFF levels in newly discovered SLE patients. TLR9 expression was measured in peripheral blood B cells by flow cytometry, and IL-10 and BAFF determined in sera by ELISA in 3 time-points: before treatment, after 3 weeks on corticosteroids, and after 3 months when steroids were tapered and chloroquine introduced. We also examined how chloroquine and steroids modulate TLR9 activation and B cell IL-10 production induced by synthetic CpG DNA, as well as BAFF levels and BAFF-receptor expression in cultures of isolated peripheral blood mononuclear cells. Samples for analysis were obtained both from patients and healthy controls. Autoantibody levels were also measured, and disease activity calculated with SLEDAI score. Results and Conclusion. Measured parameters (except BAFF release in vitro) didn’ t correlate with disease activity or autoantibody production. However, ex vivo and in vitro experiments suggested that immunomodulatory drugs substantially influence TLR9, IL-10 and perhaps BAFF serum levels. Therefore, treatment is an important parameter to be considered in interpretation of immunological studies in humans, and possible modulatory effect of therapy should be included in study design and determined prior to sample collection.

systemic lupus erythematosus; Toll-like receptors; TLR9; BAFF; IL-10; autoimmunity; chloroquine; corticosteroids

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