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Involvement of Eotaxin, Eosinophils, and Pancreatic Predisposition in Development of Type 1 Diabetes Mellitus in the BioBreeding Rat¹

Martin J. Hessner^2,*,, Xujing Wang^*,, Lisa Meyer^*, Rhonda Geoffrey, Shuang Jia^*,, Jessica Fuller, Ake Lernmark and Soumitra Ghosh^*

^* 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; The Human and Molecular Genetics Center, The Medical College of Wisconsin, Milwaukee, WI 53226; and Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, WA 98195

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 (FcRI) 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 cell destruction.

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