Advanced

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

Geoffrey, Rhonda; Jia, Shuang; Kwitek, Anne E.; Woodliff, Jeffrey; Ghosh, Soumitra; Lernmark, Åke LU ; Wang, Xujing and Hessner, Martin J (2006) In Journal of Immunology 177(10). p.7275-7286
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
in
Journal of Immunology
volume
177
issue
10
pages
12 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:33750840512
ISSN
0022-1767
language
English
LU publication?
no
id
3b7d2536-e392-4112-8ebd-bfe4d067991f
date added to LUP
2017-09-07 09:59:55
date last changed
2018-08-19 04:37:53
@article{3b7d2536-e392-4112-8ebd-bfe4d067991f,
  abstract     = {<p>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) DR<sup>lyp-lyp</sup> rat Previously, preonset expression profiling of whole DR<sup>lyp-lyp</sup> pancreatic lymph nodes (PLN) revealed innate immune activity, specifically that of mast cells and eosinophils. Furthermore, we observed that pancreatic islets of DR <sup>lyp/lyp</sup> rats as well as those of diabetes-inducible BB DR <sup>+/+</sup> 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 DR<sup>lyp-lyp</sup> compared with related BB DR<sup>+/+</sup> rats (2.1 ± 0.9% vs 0.9 ± 0.4% of total cells, p &lt; 0.0001). DR<sup>lyp/lyp</sup> 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<sup>+/+</sup> 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<sup>+/+</sup> rats, we treated DR <sup>lyp/lyp</sup> rats with the mast cell "stabilizer" cromolyn, which significantly (p &lt; 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.</p>},
  author       = {Geoffrey, Rhonda and Jia, Shuang and Kwitek, Anne E. and Woodliff, Jeffrey and Ghosh, Soumitra and Lernmark, Åke and Wang, Xujing and Hessner, Martin J},
  issn         = {0022-1767},
  language     = {eng},
  number       = {10},
  pages        = {7275--7286},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the biobreeding rat},
  volume       = {177},
  year         = {2006},
}