Immune Cell–Derived C3 Is Required for Autoimmune Diabetes Induced by Multiple Low Doses of Streptozotocin
- Marvin Lin1,
- Na Yin2,
- Barbara Murphy1,3,
- M. Edward Medof4,
- Stephan Segerer5,
- Peter S. Heeger1,3 and
- Bernd Schröppel1,3
- 1Division of Nephrology, Mount Sinai School of Medicine, New York, New York;
- 2Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York;
- 3Transplantation Institute, Mount Sinai School of Medicine, New York, New York;
- 4Institute of Pathology, Case Western Reserve University, Cleveland, Ohio;
- 5Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
- Corresponding author: Bernd Schröppel, .
OBJECTIVE The complement system contributes to autoimmune injury, but its involvement in promoting the development of autoimmune diabetes is unknown. In this study, our goal was to ascertain the role of complement C3 in autoimmune diabetes.
RESEARCH DESIGN AND METHODS Susceptibility to diabetes development after multiple low-dose streptozotocin treatment in wild-type (WT) and C3-deficient mice was analyzed. Bone marrow chimeras, luminex, and quantitative reverse transcription PCR assays were performed to evaluate the phenotypic and immunologic impact of C3 in the development of this diabetes model.
RESULTS Coincident with the induced elevations in blood glucose levels, we documented alternative pathway complement component gene expression within the islets of the diabetic WT mice. When we repeated the experiments with C3-deficient mice, we observed complete resistance to disease, as assessed by the absence of histologic insulitis and the absence of T-cell reactivity to islet antigens. Studies of WT chimeras bearing C3-deficient bone marrow cells showed that bone marrow cell–derived C3, and not serum C3, is involved in the induction of diabetes in this model.
CONCLUSIONS The data reveal a key role for immune cell–derived C3 in the pathogenesis of murine multiple low-dose streptozotocin-induced diabetes and support the concept that immune cell mediated diabetes is in part complement-dependent.
P.S.H. and B.S. both served as senior authors for this article.
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- Received January 12, 2010.
- Accepted June 21, 2010.
- © 2010 by the American Diabetes Association.
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