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

Research output: Contribution to journalArticleResearchpeer-review

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, Elisha ; Grigoriadis, George ; O'Rielly, Lorraine A. ; Willis, Simon N. ; Maxwell, Mhairi J. ; Corcoran, Lynn M. ; Tsantikos, Evelyn ; Cornish, Jasper K. S. ; Fairfax, Kirsten A. ; Vasanthakumar, Ajithkumar ; Febbraio, Mark A. ; Hibbs, Margaret L. ; Pellegrini, Marc ; Banerjee, Ashish ; Hodgkin, Philip D. ; Kallies, Axel ; Mackay, Fabienne ; Strasser, Andreas ; Gerondakis, Steven ; Gugasyan, Raffi. / NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells. In: Journal of Experimental Medicine. 2016 ; Vol. 213, No. 4. pp. 621-641.
@article{e03bffc7df824bc8bf60cd68edd1cda6,
title = "NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells",
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.",
author = "{de Valle}, Elisha and George Grigoriadis and O'Rielly, {Lorraine A.} and Willis, {Simon N.} and Maxwell, {Mhairi J.} and Corcoran, {Lynn M.} and Evelyn Tsantikos and Cornish, {Jasper K. S.} and Fairfax, {Kirsten A.} and Ajithkumar Vasanthakumar and Febbraio, {Mark A.} and Hibbs, {Margaret L.} and Marc Pellegrini and Ashish Banerjee and Hodgkin, {Philip D.} and Axel Kallies and Fabienne Mackay and Andreas Strasser and Steven Gerondakis and Raffi Gugasyan",
year = "2016",
month = "4",
day = "4",
doi = "10.1084/jem.20151182",
language = "English",
volume = "213",
pages = "621--641",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "4",

}

de Valle, E, Grigoriadis, G, O'Rielly, LA, Willis, SN, Maxwell, MJ, Corcoran, LM, Tsantikos, E, Cornish, JKS, 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, 'NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells' Journal of Experimental Medicine, vol. 213, no. 4, PMC4821646, pp. 621-641. https://doi.org/10.1084/jem.20151182

NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells. / de Valle, Elisha; Grigoriadis, George; O'Rielly, Lorraine A.; Willis, Simon N.; Maxwell, Mhairi J.; Corcoran, Lynn M.; Tsantikos, Evelyn; Cornish, Jasper K. S.; Fairfax, Kirsten A.; Vasanthakumar, Ajithkumar; Febbraio, Mark A.; Hibbs, Margaret L.; Pellegrini, Marc; Banerjee, Ashish; Hodgkin, Philip D.; Kallies, Axel; Mackay, Fabienne; Strasser, Andreas; Gerondakis, Steven; Gugasyan, Raffi.

In: Journal of Experimental Medicine, Vol. 213, No. 4, PMC4821646, 04.04.2016, p. 621-641.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells

AU - de Valle, Elisha

AU - Grigoriadis, George

AU - O'Rielly, Lorraine A.

AU - Willis, Simon N.

AU - Maxwell, Mhairi J.

AU - Corcoran, Lynn M.

AU - Tsantikos, Evelyn

AU - Cornish, Jasper K. S.

AU - Fairfax, Kirsten A.

AU - Vasanthakumar, Ajithkumar

AU - Febbraio, Mark A.

AU - Hibbs, Margaret L.

AU - Pellegrini, Marc

AU - Banerjee, Ashish

AU - Hodgkin, Philip D.

AU - Kallies, Axel

AU - Mackay, Fabienne

AU - Strasser, Andreas

AU - Gerondakis, Steven

AU - Gugasyan, Raffi

PY - 2016/4/4

Y1 - 2016/4/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85015622116&partnerID=8YFLogxK

U2 - 10.1084/jem.20151182

DO - 10.1084/jem.20151182

M3 - Article

VL - 213

SP - 621

EP - 641

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 4

M1 - PMC4821646

ER -