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


de Valle, E; Grigoriadis, G; O'Reilly, LA; Willis, SN; Maxwell, MJ; Corcoran, LM; Tsantikos, E; Cornish, JK; Fairfax, KA; Vasanthakumar, A; Febbraio, MA; Hibbs, ML; Pellegrini, M; Banerjee, A; Hodgkin, PD; Kallies, A; Mackay, F; Strasser, A; Gerondakis, S; Gugasyan, R
2016-04-04
2016-03-28
J Exp Med
Journal Article
213
4
621-41
We examined the role of NFkappaB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFkappaB1 (Nfkappab1-/-) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity ofNfkappab1-/-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 theNfkappab1-/-mice. Bone marrow chimeric mice revealed that the Fo B cell-intrinsic loss of NFkappaB1 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+Nfkappab1-/-Fo B cells. We demonstrate that p50-NFkappaB1 repressesIl-6transcription in Fo B cells, with the loss of NFkappaB1 also resulting in the uncontrolled RELA-driven transcription ofIl-6.Collectively, our findings identify a previously unrecognized role for NFkappaB1 in preventing multiorgan autoimmunity through its negative regulation ofIl-6gene expression in Fo B cells.
RUP
Molecular Genetics of Cancer; Molecular Immunology; Molecular Medicine; Infection and Immunity; Immunology
10.1084/jem.20151182
27022143
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2016-04-05 01:43:59 Last Modified 2016-08-19 10:27:11