Journal Article

B Lymphocytes Promote Insulin Resistance through Modulation of T Lymphocytes and Production of Pathogenic IgG Antibody

Glassford, Alec, Wadia, Persis P., Alonso, Michael N., McLaughlin, Tracey, Tsui, Hubert, Davidson, Matthew G., Dosch, H.-Michael, Tedder, Thomas F., Shen, Lei, Engleman, Edgar G., Paltser, Geoffrey, Winer, Daniel A., Caimol, Maria, Yantha, Jason, Winer, Shawn, Wu, Ping, Leong, Hweixian, Miklos, David B, Kenkel, Justin A.

2011

Overview

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 demonstrate 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 activation of pro-inflammatory macrophages and T cells, and production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, while transfer of DIO-IgG 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 to manage the disease.