부산대학교 도서관

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by heterogeneous cellular abnormalities contributing to the disease pathogenesis. Plasmacytoid dendritic cells (pDCs) are innate immune cells that specialize in rapid secretion of large amounts of IFNNα in response to toll-like receptor (TLR) activation. In patients with SLE, chronic activation of these receptors results in overproduction of IFNα by pDCs that contributes to inflammation and pathogenesis of disease. The mechanism dictating the dysregulation of IFNα production by pDCs in SLE is yet to be defined. Regulatory B cells (Bregs) are important contributors to the maintenance of tolerance in healthy individuals, primarily via the production of IL-10. CD24hiCD38hi Bregs have previously been identified as defective in patients with SLE, with an impaired ability to suppress inflammation resulting from a defect in IL-10 production and STAT3 signalling. In this study, I investigate the outcome of interaction between pDCs and CD24hiCD38hi Bregs in healthy individuals, and assess whether this interaction is dysfunctional in SLE patients. Here, I report a novel feedback mechanism between pDCs and Bregs. In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24hiCD38hi Bregs and plasmablasts, via the release of IFNα and CD40 engagement. Bregs, in turn, restrain IFNα production by pDCs via IL-10 release. In patients with SLE, this cross-talk is compromised; pDCs promote plasmablast differentiation but fail to expand CD24hiCD38hi Bregs. Of interest, this defect was recapitulated in healthy B cells upon exposure to a high concentration of IFNα. Defective pDC-mediated expansion of CD24hiCD38hi Bregs in SLE patients was associated with altered STAT1 and STAT3 activation, signals downstream of IFNα/β-receptor. Both altered pDC-Breg interaction and STAT1/STAT3 activation, were normalized in SLE patients responding to rituximab therapy. Thus, this study suggests that alteration in the pDC-Breg interaction contributes to the pathogenesis of SLE.