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J Immunol. 2015 Feb 15;194(4):1489-502. doi: 10.4049/jimmunol.1401880. Epub 2015 Jan 16.

Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction.

Author information

1
Center for Comparative Medicine, University of California, Davis, Davis, CA 95616; Graduate Group in Immunology, University of California, Davis, Davis, CA 95616;
2
Center for Comparative Medicine, University of California, Davis, Davis, CA 95616; Microbiology Graduate Group, University of California, Davis, Davis, CA 95616;
3
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.

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.

PMID:
25595791
PMCID:
PMC4324358
DOI:
10.4049/jimmunol.1401880
[Indexed for MEDLINE]
Free PMC Article

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