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Åke Lernmark

Principal investigator

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Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the biobreeding rat

Author

  • Rhonda Geoffrey
  • Shuang Jia
  • Anne E. Kwitek
  • Jeffrey Woodliff
  • Soumitra Ghosh
  • Åke Lernmark
  • Xujing Wang
  • Martin J Hessner

Summary, in English

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 DR lyp/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 Cγ. 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 DR lyp/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.

Publishing year

2006

Language

English

Pages

7275-7286

Publication/Series

Journal of Immunology

Volume

177

Issue

10

Document type

Journal article

Publisher

American Association of Immunologists

Status

Published

ISBN/ISSN/Other

  • ISSN: 0022-1767