Faculty Collaboration Database

Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat. J Immunol 2006 Nov 15;177(10):7275-86

Date

11/04/2006

Pubmed ID

17082646

DOI

10.4049/jimmunol.177.10.7275

Scopus ID

2-s2.0-33750840512 (requires institutional sign-in at Scopus site)   66 Citations

Abstract

Human type 1 diabetes mellitus (T1DM) arises through autoimmune destruction of pancreatic beta 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 beta 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 Cgamma. 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.

Author List

Geoffrey R, Jia S, Kwitek AE, Woodliff J, Ghosh S, Lernmark A, Wang X, Hessner MJ

Authors

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Shuang Jia Biostatistician III in the Pediatrics department at Medical College of Wisconsin
Anne E. Kwitek PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Count
Chemokine CCL11
Chemokines, CC
Cromolyn Sodium
Diabetes Mellitus, Type 1
Female
Gene Expression Profiling
Genetic Predisposition to Disease
Hypoglycemic Agents
Immunity, Innate
Immunoglobulin E
Immunophenotyping
Islets of Langerhans
Lymph Nodes
Lymphopenia
Mast Cells
Rats
Rats, Inbred BB
Rats, Inbred WF
Reverse Transcriptase Polymerase Chain Reaction