65: Nuclear Factor-kappa B1 is a critical regulator of mature B cell homeostasis and serves to prevent chronic inflammatory disease

Abstract

The transcriptional regulator Nuclear Factor-kappa B1 (NF-kB1) plays an essential role in immune function and controls key aspects of cell survival, differentiation and proliferation. Polymorphisms and mutations in the NF-kB1 gene are linked to various human autoimmune diseases and malignancies. Due to its duplicitous roles in the activation and repression of gene transcription, the precise function of NF-kB1 has remained unclear. Through various murine models, we show that NF-kB1 is critical for the normal maintenance of mature follicular B cells. As the loss of NF-kB1 in Fo B cells lowers their activation threshold, and enhances proliferation and survival in vivo . This is largely attributed to the finding that NF-kB1-deficient Fo B cells produce excessive amounts of the proinflammatory cytokine interleukin-6, which promotes the enhanced differentiation of follicular helper CD4 + T cells. In aged mice this culminates in a severe multi-organ autoimmune disease characterized by the spontaneous formation of germinal center B cells, the presence of class-switched antibodies and tissue-specific autoantibodies. Finally, we demonstrate that NF-kB1 is an essential regulator of IL-6 expression in Fo B cells. Collectively, our findings show that NF-kB1 plays a crucial role in maintaining the normal homeostasis of mature B cells and prevents the development of chronic diseases, such as autoimmunity and cancer, through its regulation of the IL-6 gene.