title: Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction.
abstract: It is unclear why selective deficiency in secreted (s)IgM causes Ab-mediated autoimmunity. We demonstrate that sIgM is required for normal B cell development and selection. The CD5(+) B cells that were previously shown to accumulate in body cavities of sIgM(-/-) mice are not B-1a cells, but CD19(int), CD43(-), short-lived, BCR signaling-unresponsive anergic B-2 cells. Body cavity B-1 cells were >10-fold reduced, including VH11(+) and phosphotidylcholine-specific B-1a cells, whereas splenic B-1 cells were unaffected and marginal zone B cells increased. Follicular B cells had higher turnover rates, survived poorly after adoptive transfer, and were unresponsiveness to BCR stimulation in vitro. sIgM bound to B cell precursors and provided a positive signal to overcome a block at the pro/pre-B stage and during IgVH repertoire selection. Polyclonal IgM rescued B cell development and returned autoantibody levels to near normal. Thus, natural IgM deficiency causes primary autoimmune disease by altering B cell development, selection, and central tolerance induction.
authors.affiliation: Center for Comparative Medicine, University of California, Davis, Davis, CA 95616; Graduate Group in Immunology, University of California, Davis, Davis, CA 95616;
authors.forename: Trang T T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Center for Comparative Medicine, University of California, Davis, Davis, CA 95616; Microbiology Graduate Group, University of California, Davis, Davis, CA 95616;
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Elsner
authors.affiliation: Center for Comparative Medicine, University of California, Davis, Davis, CA 95616; Graduate Group in Immunology, University of California, Davis, Davis, CA 95616; Microbiology Graduate Group, University of California, Davis, Davis, CA 95616; Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616 nbaumgarth@ucdavis.edu.
authors.forename: Nicole
authors.initials: N
authors.lastname: Baumgarth
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D061167:Central Tolerance / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance; D007075:Immunoglobulin M / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D001323:Autoantibodies; D007075:Immunoglobulin M