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NF?B1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells.

ABSTRACT: We examined the role of NF?B1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NF?B1 (Nf?b1(-/-)) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nf?b1(-/-)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 Nf?b1(-/-)mice. Bone marrow chimeric mice revealed that the Fo B cell-intrinsic loss of NF?B1 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(+)Nf?b1(-/-)Fo B cells. We demonstrate that p50-NF?B1 represses Il-6 transcription in Fo B cells, with the loss of NF?B1 also resulting in the uncontrolled RELA-driven transcription of Il-6.Collectively, our findings identify a previously unrecognized role for NF?B1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in Fo B cells.

SUBMITTER: de Valle E

PROVIDER: S-EPMC4821646 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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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 Elisha E Grigoriadis George G O'Reilly Lorraine A LA Willis Simon N SN Maxwell Mhairi J MJ Corcoran Lynn M LM Tsantikos Evelyn E Cornish Jasper K S JK Fairfax Kirsten A KA Vasanthakumar Ajithkumar A Febbraio Mark A MA Hibbs Margaret L ML Pellegrini Marc M Banerjee Ashish A Hodgkin Philip D PD Kallies Axel A Mackay Fabienne F Strasser Andreas A Gerondakis Steve S Gugasyan Raffi R

The Journal of experimental medicine 20160328 4

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. ...[more]

PMID: 27022143

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Project description:BackgroundTurner syndrome, a congenital condition that affects 1/2,500 births, results from absence or structural alteration of the second sex chromosome. Turner syndrome is usually associated with short stature, gonadal dysgenesis and variable dysmorphic features. The classical 45,X karyotype accounts approximately for half of all patients, the remainder exhibit mosaicism or structural abnormalities of the X chromosome. However, complex intra-X chromosomal rearrangements involving more than three breakpoints are extremely rare.ResultsWe present a unique case of a novel complex X chromosome rearrangement in a young female patient presenting successively a wide range of autoimmune diseases including insulin dependent diabetes mellitus, Hashimoto's thyroiditis, celiac disease, anaemia perniciosa, possible inner ear disease and severe hair loss. For the genetic evaluation, conventional cytogenetic analysis and FISH with different X specific probes were initially performed. The complexity of these results and the variety of autoimmune problems of the patient prompted us to identify the exact composition and breakpoints of the rearranged X as well as methylation status of the X chromosomes. The high resolution array-CGH (assembly GRCh37/hg19) detected single copy for the whole chromosome X short arm. Two different sized segments of Xq arm were present in three copies: one large size of 80,3 Mb from Xq11.1 to Xq27.3 region and another smaller (11,1 Mb) from Xq27.3 to Xq28 region. An 1,6 Mb Xq27.3 region of the long arm was present in two copies. Southern blot analysis identified a skewed X inactivation with ≈ 70:30 % ratios of methylated/unmethylated fragments. The G-band and FISH patterns of the rearranged X suggested the aspect of a restructured i(Xq) chromosome which was shattered and fortuitously repaired. The X-STR genotype analysis of the family detected that the patient inherited intact maternal X chromosome and a rearranged paternal X chromosome. The multiple Xq breakages and fusions as well as inverted duplication would have been expected to cause a severe Turner phenotype. However, the patient lacks many of the classic somatic features of Turner syndrome, instead she presented multiorgan autoimmune diseases.ConclusionsThe clinical data of the presented patient suggest that fragmentation of the i(Xq) chromosome elevates the risk of autoimmune diseases.

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NF?B1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells.

Publications

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

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