IL10 and B Cell Activation in Humans

One predicted role of IL-10 in SLE is its ability to promote B cell differentiation and auto-antibody production (Fig. 2). IL-10 is a cofactor for these activities and requires B cell activation via the B cell receptor or costimulatory molecules such as CD40. Due to the constant presence of nuclear antigens such as dsDNA, and antibodies directed against them, B cells in SLE patients are continuously primed for costimulation by IL-10. One might then expect decreased auto-antibody production upon blocking of IL-10 in vivo. Llorente et al tested this hypothesis by transferring PBMC from SLE patients into SCID mice, resulting in auto-antibody production in these mice.56 Treatment of the reconstituted mice with anti-human IL-10 mAb resulted in a drop of anti-dsDNA auto-antibodies in 10 of12 mice to undetectable levels. Using the same SCID model, Kalechman et al treated reconstituted mice with the immunomodulator AS101 in order to decrease IL-10 levels, and observed also a decrease in auto-antibody production.11 Another possible role for IL-10 in SLE could stem from its ability to promote survival of B cells. IL-10 has been shown to prevent spontaneous cell death of germinal center B cells in vitro by inducing BCL-2 expression.57 Over expression of BCL-2 in transgenic mice results in an excess of B lymphocytes and immunoglobulin-producing cells, and development of an autoimmune disease similar to transgenic mice spontaneously produce auto-antibodies to nuclear antigens, and 60% develop terminal immune complex-mediated glomerulonephritis between 3 and 12 months of age. However, efforts to demonstrate a role for BCL-2 in SLE have met with mixed results.38'46'47'49'59-63 In a recent study, Miret et al found that serum level of IL-10 and amount of BCL-2 protein in PBMC lysates did not correlate in SLE patients.38 However, increased BCL-2 and increased IL-10 did individually correlate with higher SLEDAI disease index. Further study is necessary to understand the importance of a role for IL-10 mediated prevention of spontaneous B cell apoptosis in SLE. In a small, open-label clinical trial, anti-IL-10 treatment of lupus patients with cutaneous and joint manifestations resulted in improvement to clinically inactive disease in five of six patients within 6 months of the 3-week treatment regimen.64 Though anti-dsDNA auto-antibody levels, C3 and C4 levels, and lymphocyte count did not change, other markers of biological activity were affected. By day 10 of treatment, serum markers of T lymphocyte and endothelial cell activation were decreased, and T lymphocyte function, as measured by responsiveness to PHA stimulation, was partially restored. Thus, IL-10 is likely to play a role in many facets of SLE development and progression.

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