NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells

We examined the role of NF kappa B1 in the homeostasis and function of peripheral follicular (F-0) B cells. Aging mice lacking NF kappa B1 (Nf kappa b1(-/-)) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nf kappa b1(-/-) Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in the Nf kappa b1(-/-) mice. Bone marrow chimeric mice revealed that the F-0 B cell-intrinsic loss of NF kappa B1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4(+) T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM(+) Nf kappa b1(-/-) Fo B cells. We demonstrate that p50-NF kappa B1 represses Il-6 transcription in F-0 B cells, with the loss of NF kappa B1 also resulting in the uncontrolled RELA-driven transcription of Il-6. Collectively, our findings identify a previously unrecognized role for NF kappa B1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in F-0 B cells.