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B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies

Nature Medicine volume 17, pages 610617 (2011) | Download Citation

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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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  • 06 June 2011

     In the version of this article initially published, the authors did not acknowledge Canadian Institutes of Health Research grant 111156 (H.M.D.), which also supported the study. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank D. Jones for secretarial assistance; C. Benike for critical review of the manuscript; A. Chawla for critical review of the figures; C. Wang, L. Tolentino and K. Heydari for assistance with flow cytometry; and Y. Yang and L. Herzenberg for help in developing macrophage and B cell subset gates. These studies were supported by US National Institutes of Health grants CA141468 and DK082537 (E.G.E) and Canadian Institutes of Health Research Grant 111156 (H.M.D.).

Author information

Author notes

    • Daniel A Winer
    • , Shawn Winer
    •  & Lei Shen

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology, Stanford University, Palo Alto, California, USA.

    • Daniel A Winer
    • , Lei Shen
    • , Matthew G Davidson
    • , Michael N Alonso
    • , Hwei X Leong
    • , Maria Caimol
    • , Justin A Kenkel
    •  & Edgar G Engleman
  2. Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.

    • Daniel A Winer
    •  & Shawn Winer
  3. Neuroscience & Mental Health Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Shawn Winer
    • , Jason Yantha
    • , Geoffrey Paltser
    • , Hubert Tsui
    • , Ping Wu
    •  & H-Michael Dosch
  4. Department of Medicine, Stanford University, Palo Alto, California, USA.

    • Persis P Wadia
    •  & David B Miklos
  5. Division of Endocrinology, Stanford University School of Medicine, Palo Alto, California, USA.

    • Alec Glassford
    •  & Tracey McLaughlin
  6. Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.

    • Thomas F Tedder

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Contributions

D.A.W. and S.W. conceived the study, did experimental work and wrote the manuscript. L.S. was involved in experimental work, project planning and manuscript preparation. P.P.W., A.G., T.M. and D.B.M. contributed the human array data. J.Y., G.P., M.G.D., M.N.A., H.T., P.W., H.X.L., J.A.K. and M.C. did experimental work; T.F.T. contributed the CD20-specific mAb and was involved in manuscript preparation. H.M.D. supervised parts of the project and was involved in manuscript preparation; E.G.E. was involved in project planning, financing, supervision, data analysis and manuscript preparation. E.G.E. and H.M.D. are both senior authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Daniel A Winer or Edgar G Engleman.

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    Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Methods

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DOI

https://doi.org/10.1038/nm.2353

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