Journal
CELL REPORTS
Volume 3, Issue 4, Pages 1187-1198Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.03.006
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Funding
- Global COE Research Program
- Health and Labor Sciences Research Grants (Ministry of Health, Labor and Welfare of Japan)
- Mitsubishi Pharma Research Foundation
- Natto Research Foundation
- Kanae Foundation for the Promotion of Medical Science
- Astellas Foundation for Research on Metabolic Disorders
- Ono Medical Research Foundation
- Banyu Foundation
- Grants-in-Aid for Scientific Research [24390196, 23390091, 25461494, 221S0001, 24659175, 23791107, 11J05522] Funding Source: KAKEN
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Natural immunoglobulin M (IgM) is reactive to autoantigens and is believed to be important for autoimmunity. Blood pentameric IgM loaded with antigens forms a large immune complex (IC) that contains various elements, including apoptosis inhibitor of macrophage (AIM). Here we demonstrate that this IgM-AIM association contributes to autoantibody production under obese conditions. In mice fed a high-fat diet, natural IgM increased through B cell TLR4 stimulation. AIM associated with IgM and protected AIM from renal excretion, increasing blood AIM levels along with the obesity-induced IgM augmentation. Meanwhile, the AIM association inhibited IgM binding to the Fc alpha/mu receptor on splenic follicular dendritic cells, thereby protecting the IgM IC from Fc alpha/mu receptor-mediated internalization. This supported IgM-dependent autoantigen presentation to B cells, stimulating IgG autoantibody production. Accordingly, in obese AIM-deficient (AIM(-/-)) mice, the increase of multiple IgG autoantibodies observed in obese wild-type mice was abrogated. Thus, the AIM-IgM association plays a critical role in the obesity-associated autoimmune process.
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