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

Citation

de Valle, E and Grigoriadis, G and O'Reilly, LA and Willis, SN and Maxwell, MJ and Corcoran, LM and Tsantikos, E and Cornish, JK and Fairfax, KA and Vasanthakumar, A and Febbraio, MA and Hibbs, ML and Pellegrini, M and Banerjee, A and Hodgkin, PD and Kallies, A and Mackay, F and Strasser, A and Gerondakis, S and Gugasyan, R, NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells, The Journal of Experimental Medicine, 213, (4) pp. 621-641. ISSN 0022-1007 (2016) [Refereed Article]


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© 2016 de Valle et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial– Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

DOI: doi:10.1084/jem.20151182

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.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Cell Development, Proliferation and Death
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Immune System and Allergy
UTAS Author:Fairfax, KA (Dr Kirsten Fairfax)
ID Code:134797
Year Published:2016
Web of Science® Times Cited:20
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-09-05
Last Modified:2019-10-14
Downloads:2 View Download Statistics

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