title: IL-6 contributes to an immune tolerance checkpoint in post germinal center B cells.
abstract: The generation of a B cell repertoire involves producing and subsequently purging autoreactive B cells. Receptor editing, clonal deletion and anergy are key mechanisms of central B cell tolerance. Somatic mutation of antigen-activated B cells within the germinal center produces a second wave of autoreactivity; but the regulatory mechanisms that operate at this phase of B cell activation are poorly understood. We recently identified a post germinal center tolerance checkpoint, where receptor editing is re-induced to extinguish autoreactivity that is generated by somatic hypermutation. Re-induction of the recombinase genes RAG1 and RAG2 in antigen-activated B cells requires antigen to engage the B cell receptor and IL-7 to signal through the IL-7 receptor. We demonstrate that this process requires IL-6 to upregulate IL-7 receptor expression on post germinal center B cells. Diminishing IL-6 by blocking antibody or haplo-insufficiency leads to reduced expression of the IL-7 receptor and RAG and increased titers of anti-DNA antibodies following immunization with a peptide mimetope of DNA. The dependence on IL-6 to initiate receptor editing is B cell intrinsic. Interestingly, estradiol decreases IL-6 expression thereby increasing the anti-DNA response. Our data reveal a novel regulatory cascade to control post germinal center B cell autoreactivity.
authors.affiliation: The Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yan
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D019138:Antibodies, Blocking / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000974:Antibodies, Antinuclear; D019138:Antibodies, Blocking; D004268:DNA-Binding Proteins; D004967:Estrogens; D018398:Homeodomain Proteins; D015850:Interleukin-6; D009842:Oligopeptides; C499308:Rag2 protein, mouse; D020395:Receptors, Interleukin-7; C526794:aspartyl-tryptophyl-glutamyl-tyrosyl-seryl-valyl-tryptophyl-leucyl-seryl-asparagine; C064658:RAG-1 protein