title: B cell-derived IL-10 does not regulate spontaneous systemic autoimmunity in MRL.Fas(lpr) mice.
abstract: B cells contribute to the pathogenesis of chronic autoimmune disorders, like systemic lupus erythematosus (SLE), via multiple effector functions. However, B cells are also implicated in regulating SLE and other autoimmune syndromes via release of IL-10. B cells secreting IL-10 were termed "Bregs" and were proposed as a separate subset of cells, a concept that remains controversial. The balance between pro- and anti-inflammatory effects could determine the success of B cell-targeted therapies for autoimmune disorders; therefore, it is pivotal to understand the significance of B cell-secreted IL-10 in spontaneous autoimmunity. By lineage-specific deletion of Il10 from B cells, we demonstrated that B cell-derived IL-10 is ineffective in suppressing the spontaneous activation of self-reactive B and T cells during lupus. Correspondingly, severity of organ disease and survival rates in mice harboring Il10-deficient B cells are unaltered. Genetic marking of cells that transcribe Il10 illustrated that the pool of IL-10-competent cells is dominated by CD4 T cells and macrophages. IL-10-competent cells of the B lineage are rare in vivo and, among them, short-lived plasmablasts have the highest frequency, suggesting an activation-driven, rather than lineage-driven, phenotype. Putative Breg phenotypic subsets, such as CD1d(hi)CD5(+) and CD21(hi)CD23(hi) B cells, are not enriched in Il10 transcription. These genetic studies demonstrated that, in a spontaneous model of murine lupus, IL-10-dependent B cell regulation does not restrain disease and, thus, the pathogenic effects of B cells are not detectably counterbalanced by their IL-10-dependent regulatory functions.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Lino L
authors.initials: LL
authors.lastname: Teichmann
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr / Q000235:genetics / Q000276:immunology*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013045:Species Specificity; D013577:Syndrome; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: C556062:IL10 protein, mouse; D019014:fas Receptor; D016753:Interleukin-10