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* Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at the Medical College of Wisconsin, and Children’s Research Institute of the Children’s Hospital of Wisconsin, Milwaukee, WI 53226;
Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226; and
Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, WA 98195
Human type 1 diabetes mellitus (T1DM) arises through autoimmune destruction of pancreatic β cells and is modeled in many respects by the lymphopenic and spontaneously diabetic BioBreeding (BB) DRlyp/lyp rat. Previously, preonset expression profiling of whole DRlyp/lyp pancreatic lymph nodes (PLN) revealed innate immune activity, specifically that of mast cells and eosinophils. Furthermore, we observed that pancreatic islets of DRlyp/lyp rats as well as those of diabetes-inducible BB DR+/+ rats potentially recruit innate cells through eotaxin expression. Here we determine that lifelong eotaxin expression begins before 40 days of life and is localized specifically to β cells. In this report, we find that PLN mast cells are more abundant in DRlyp/lyp compared with related BB DR+/+ rats (2.1 ± 0.9% vs 0.9 ± 0.4% of total cells, p < 0.0001). DRlyp/lyp PLN mast cell gene expression profiling revealed an activated population and included significant overrepresentation of transcripts for mast cell protease 1, cationic trypsinogen, carboxypeptidase A, IL-5, and phospholipase C
. In the DR+/+ rat, which develops T1DM upon depletion of T regulator cells, mast cells displayed gene expression consistent with the negative regulation of degranulation, including significant overrepresentation of transcripts encoding tyrosine phosphatase SHP-1, lipid phosphatase SHIP, and E3 ubiquitin ligase c-Cbl. To recapitulate the negative mast cell regulation observed in the DR+/+ rats, we treated DRlyp/lyp rats with the mast cell "stabilizer" cromolyn, which significantly (p < 0.05) delayed T1DM onset. These findings are consistent with a growing body of evidence in human and animal models, where a role for mast cells in the initiation and progression of autoimmune disease is emerging.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant EB001421 (to M.J.H.), National Institute of Allergy and Infectious Diseases Grant P01-AI-42380 (to Å.L.), and a special fund from the Children’s Hospital of Wisconsin Foundation.
2 Address correspondence and reprint requests to Dr. Martin J. Hessner, Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics, Medical College of Wisconsin and Children’s Hospital of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail address: mhessner{at}mcw.edu
3 Abbreviations used in this paper: T1DM, type 1 diabetes mellitus; BB, BioBreeding (rat); Dusp, dual specificity phosphatase; GO, Gene Ontology (project); IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; MS, multiple sclerosis; PLN, pancreatic lymph node; qRT-PCR; quantitative RT-PCR; SHP, Src homology 2-containing protein tyrosine phosphatase; TREG, regulatory T cell.
4 The online version of this article contains supplemental material.
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  C. Louvet, G. L. Szot, J. Lang, M. R. Lee, N. Martinier, G. Bollag, S. Zhu, A. Weiss, and J. A. Bluestone Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice PNAS, December 2, 2008; 105(48): 18895 - 18900. [Abstract] [Full Text] [PDF]
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