Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice

The intrafollicular location of B6.TC MZB cells starts before disease manifestations and puts MZB cells in direct contact with CD4+ T cells. Two different autoreactive B cell receptor (BCR) transgenic models showed that the expression of the Sle susceptibility loci enhances the presence of MZB cells inside the follicles. In vitro, B6.TC MZB cells were better effectors than B6 MZB cells with enhanced proliferation and antibody (Ab) production, including anti-DNA Ab, in response to stimulation with TLR ligands, immune complexes or anti-CD40. Furthermore, B6.TC MZB and CD4+ T cells showed a reciprocally enhanced activation, which indicated that their contacts inside B6.TC follicles have functional consequences that suggest an amplification loop between these two cell types.These results showed that the NZM2410 susceptibility loci induce MZB cells to locate into the follicles, and that this breach of follicular exclusion occurs early in the development of the autoimmune pathogenesis. The enhanced responses to stimulation and increased effector functions of MZB cells from lupus-prone mice as compare to non-autoimmune MZB cells provide a mechanism by which the failure of MZB cell follicular exclusion contributes to the autoimmune process.Systemic lupus erythematosus (SLE) is an autoimmune disease in which defects in multiple B cell subsets have long been recognized [1]. Marginal zone (MZ) B cells are enriched for autoreactive specificities through the expression of self-reactive germline-encoded BCRs [2]. MZB cells transport antigen inside the follicles [3] and are potent T-cell activators that respond more rapidly than follicular (FO) B cells to T-dependent antigen [4]. MZB cells also differentiate rapidly into plasma cells [5-9]. Finally, MZB cells respond better to T cells than FOB cells in vitro but not in vivo [10], showing that physiological barriers prevent in vivo activation of MZB cells [11]. These observations have led to hypothesize the existence of a tolerance