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

Elisha de Valle, George Grigoriadis, Lorraine A. O'Rielly, Simon N. Willis, Mhairi J. Maxwell, Lynn M. Corcoran, Evelyn Tsantikos, Jasper K. S. Cornish, Kirsten A. Fairfax, Ajithkumar Vasanthakumar, Mark A. Febbraio, Margaret L. Hibbs, Marc Pellegrini, Ashish Banerjee, Philip D. Hodgkin, Axel Kallies, Fabienne Mackay, Andreas Strasser, Steven Gerondakis, Raffi Gugasyan

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Abstract

We examined the role of NFκB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFκB1 (Nfκb1(-/-)) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nfκb1(-/-)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 Nfκb1(-/-)mice. Bone marrow chimeric mice revealed that the Fo B cell-intrinsic loss of NFκB1 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(+)Nfκb1(-/-)Fo B cells. We demonstrate that p50-NFκB1 represses Il-6 transcription in Fo B cells, with the loss of NFκB1 also resulting in the uncontrolled RELA-driven transcription of Il-6.Collectively, our findings identify a previously unrecognized role for NFκB1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in Fo B cells.

Original languageEnglish
Article numberPMC4821646
Pages (from-to)621-641
Number of pages21
JournalJournal of Experimental Medicine
Volume213
Issue number4
DOIs
Publication statusPublished - 4 Apr 2016

Cite this

de Valle, E., Grigoriadis, G., O'Rielly, L. A., Willis, S. N., Maxwell, M. J., Corcoran, L. M., Tsantikos, E., Cornish, J. K. S., Fairfax, K. A., Vasanthakumar, A., Febbraio, M. A., Hibbs, M. L., Pellegrini, M., Banerjee, A., Hodgkin, P. D., Kallies, A., Mackay, F., Strasser, A., Gerondakis, S., & Gugasyan, R. (2016). NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells. Journal of Experimental Medicine, 213(4), 621-641. [PMC4821646]. https://doi.org/10.1084/jem.20151182