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&#39;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

Author(s): 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;
Details: Publication Year 2016-04-04,Volume 213,Issue #4,Page 621-41
Journal Title: J Exp Med
Publication Type: Journal Article
Abstract: 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.
Publisher: RUP
Research Division(s): Immunology; Infection And Immunity; Molecular Medicine; Molecular Immunology; Molecular Genetics Of Cancer
PubMed ID: 27022143
Publisher's Version: https://doi.org/10.1084/jem.20151182
NHMRC Grants: NHMRC/1020363, NHMRC/101670, NHMRC/1009145,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-04-05 01:43:59

Last Modified: 2016-08-19 10:27:11