Autoregulatory function of interleukin-10-producing pre-naïve B cells is defective in systemic lupus erythematosus

Abstract

Introduction: Pre-naive B cells represent an intermediate stage in human B-cell development with some functions of mature cells, but their involvement in immune responses is unknown. The aim of this study was to determine the functional role of normal pre-naive B cells during immune responses and possible abnormalities in systemic lupus erythematosus (SLE) that might contribute to disease pathogenesis. Methods: Pre-naive, naive, and memory B cells from healthy individuals and SLE patients were stimulated through CD40 and were analyzed for interleukin-10 (IL-10) production and co-stimulatory molecule expression and their regulation of T-cell activation. Autoreactivity of antibodies produced by pre-naive B cells was tested by measuring immunoglobulin M (IgM) autoantibodies in culture supernatants after differentiation. Results: CD40-stimulated pre-naive B cells produce larger amounts of IL-10 but did not suppress CD4(+) T-cell cytokine production. Activated pre-naive B cells demonstrated IL-10-mediated ineffective promotion of CD4(+) T-cell proliferation and induction of CD4(+)FoxP3(+) T cells and IL-10 independent impairment of co-stimulatory molecule expression and tumor necrosis factor-alpha (TNF-alpha) and IL-6 production. IgM antibodies produced by differentiated pre-naive B cells were reactive to single-stranded deoxyribonucleic acid. SLE pre-naive B cells were defective in producing IL-10, and co-stimulatory molecule expression was enhanced, resulting in promotion of robust CD4(+) T-cell proliferation. Conclusions: There is an inherent and IL-10-mediated mechanism that limits the capacity of normal pre-naive B cells from participating in cellular immune response, but these cells can differentiate into autoantibody-secreting plasma cells. In SLE, defects in IL-10 secretion permit pre-naive B cells to promote CD4(+) T-cell activation and may thereby enhance the development of autoimmunity.