The role of IL-27 in normal and autoimmune antibody responses

摘要

IL-27 is a heterodimeric cytokine belonging to the IL-12 family, a family knownto have an important influence on immune responses and the development ofautoimmune diseases. Previous studies in our laboratory have shown that IL-27plays a critical role in supporting germinal centers (GCs) at least partly throughpromoting follicular helper T (TFH) cell function. However, the effects of IL-27signalling directly on B cells, which also express the IL-27 receptor, are poorlyunderstood. Here, we aim to investigate the role of IL-27 signalling on B cells invivo and in vitro and its contribution to antibody mediated autoimmune disease.In vitro experiments using mouse and human B cells were performed toinvestigate the effects of IL-27 on cytokine production and transcription factorexpression. Although both chains of the IL-27 receptor are expressed by Bcells, its effect on these cells during the antibody response is poorlycharacterized. We found that IL-27 stimulation of purified B cells in vitroenhances expression of the transcription factor Bcl-6 and promotes phenotypicfeatures of GC B cells. We have also compared Il27ra+/+ and Il27ra-/- B cellreceptor (BCR) transgenic mice (SWHEL) after antigen specific activation usingflow cytometry, serum ELISA and histological analysis. Both Il27ra+/+ and Il27ra-/- SWHEL B cells form functional GC producing class-switched antibodies. Wethen investigated whether IL-27 is critical for the progression of autoimmunedisease mediated by T-dependent B cell responses. Using the Lupus-likemouse model, Roquinsan/san, we found that Il27ra-/-Roquinsan/san mice havereduced numbers of GC and ameliorated some aspects of disease in thismodel. Thus, we have examined the effects of IL-27 signalling on GC B cellfunction, and found IL-27 has a clear proinflammatory effect during antibodydependent autoimmune responses, and should be considered as a noveltherapeutic target against certain autoimmune diseases, such as lupus.