Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the biobreeding rat
(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.
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- author
- Geoffrey, Rhonda ; Jia, Shuang ; Kwitek, Anne E. ; Woodliff, Jeffrey ; Ghosh, Soumitra ; Lernmark, Åke LU ; Wang, Xujing and Hessner, Martin J
- publishing date
- 2006
- 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
-
- pmid:17082646
- 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
- 2024-05-26 22:31:21
@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 < 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 < 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}}, }