title: Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat.
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.
authors.affiliation: 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, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Geoffrey
authors.forename: Shuang
authors.initials: S
authors.lastname: Jia
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kwitek
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Woodliff
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
authors.forename: Xujing
authors.initials: X
authors.lastname: Wang
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hessner
mesh_terms: D000818:Animals; D002452:Cell Count; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D004205:Cromolyn Sodium / Q000008:administration & dosage; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007113:Immunity, Innate / Q000235:genetics; D007073:Immunoglobulin E / Q000097:blood; D016130:Immunophenotyping; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011913:Rats, Inbred BB; D011920:Rats, Inbred WF; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C515456:CCL11 protein, human; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D007004:Hypoglycemic Agents; D007073:Immunoglobulin E; D004205:Cromolyn Sodium