title: Involvement of eotaxin, eosinophils, and pancreatic predisposition in development of type 1 diabetes mellitus in the BioBreeding rat.
abstract: Allergy and autoimmunity are both examples of deregulated immunity characterized by inflammation and injury of targeted tissues that have until recently been considered disparate disease processes. However, recent findings have implicated mast cells, in coordination with granulocytes and other immune effector cells, in the pathology of these two disorders. The BioBreeding (BB) DRlyp/lyp rat develops an autoimmune insulin-dependent diabetes similar to human type 1 diabetes mellitus (T1DM), whereas the BBDR+/+ rat does not. To better understand immune processes during development of T1DM, gene expression profiling at day (d) 40 (before insulitis) and d65 (before disease onset) was conducted on pancreatic lymph nodes of DRlyp/lyp, DR+/+, and Wistar-Furth (WF) rats. The eosinophil-recruiting chemokine, eotaxin, and the high-affinity IgE receptor (FcepsilonRI) were up-regulated >5-fold in d65 DRlyp/lyp vs d65 DR+/+ pancreatic lymph nodes by microarray (p < 0.05) and quantitative RT-PCR studies (p < 0.05). DR+/+, WF, and d40 DRlyp/lyp animals possessed normal pancreatic histology; however, d65 DRlyp/lyp animals possessed eosinophilic insulitis. Therefore, immunohistochemistry for pancreatic eotaxin expression was conducted, revealing positive staining of d65 DRlyp/lyp islets. Islets of d65 DR+/+ rats also stained positively, consistent with underlying diabetic predisposition in the BB lineage, whereas WF islets did not. Other differentially expressed transcripts included those associated with eosinophils, mast cells, and lymphocytes. These data support an important role for these inflammatory mediators in BB rat T1DM and suggest that the lymphopenia due to the Ian5/(lyp) mutation may result in a deregulation of cells involved in insulitis and beta cell destruction.
authors.affiliation: The Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at the Medical College of Wisconsin and the Children's Research Institute of the Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA. mhessner@mcw.edu
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hessner
authors.forename: Xujing
authors.initials: X
authors.lastname: Wang
authors.forename: Lisa
authors.initials: L
authors.lastname: Meyer
authors.forename: Rhonda
authors.initials: R
authors.lastname: Geoffrey
authors.forename: Shuang
authors.initials: S
authors.lastname: Jia
authors.forename: Jessica
authors.initials: J
authors.lastname: Fuller
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004804:Eosinophils / Q000473:pathology*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000276:immunology* / Q000473:pathology; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011913:Rats, Inbred BB; D011920:Rats, Inbred WF; D017455:Receptors, IgE / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C515456:CCL11 protein, human; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D017455:Receptors, IgE; C516765:PTPN22 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases