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.
authors.affiliation: Burnet Institute, Melbourne, VIC 3004, Australia Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Elisha
authors.initials: E
authors.lastname: de Valle
authors.affiliation: School of Clinical Sciences, Monash University, Melbourne, VIC 3004, Australia Center for Cancer Research, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia Clinical Haematology, Monash and Alfred Health, Melbourne, VIC 3168, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Grigoriadis
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Willis
authors.affiliation: Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Mhairi J
authors.initials: MJ
authors.lastname: Maxwell
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Corcoran
authors.affiliation: Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tsantikos
authors.affiliation: Burnet Institute, Melbourne, VIC 3004, Australia Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Jasper K S
authors.initials: JK
authors.lastname: Cornish
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Fairfax
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Ajithkumar
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Center for Cancer Research, Hudson Institute of Medical Research, Melbourne, VIC 3168, Australia.
authors.forename: Ashish
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hodgkin
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Infection and Immunity Program, Monash Biomedical Discovery Institute, Monash University, Melbourne, VIC 3004, Australia Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Gerondakis
authors.affiliation: Burnet Institute, Melbourne, VIC 3004, Australia Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia gugasyan@burnet.edu.au.
authors.forename: Raffi
authors.initials: R
authors.lastname: Gugasyan
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018858:Germinal Center / Q000276:immunology* / Q000473:pathology; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*
chemical_list: D007075:Immunoglobulin M; D015850:Interleukin-6; D052002:NF-kappa B p50 Subunit; C073701:Nfkb1 protein, mouse