B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies |
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Authors: | Winer Daniel A Winer Shawn Shen Lei Wadia Persis P Yantha Jason Paltser Geoffrey Tsui Hubert Wu Ping Davidson Matthew G Alonso Michael N Leong Hwei X Glassford Alec Caimol Maria Kenkel Justin A Tedder Thomas F McLaughlin Tracey Miklos David B Dosch H-Michael Engleman Edgar G |
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Affiliation: | Department of Pathology, Stanford University, Palo Alto, California, USA. dan.winer@uhn.on.ca |
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Abstract: | Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease. |
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