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1 Diabetes Research Center, Division of Endocrinology, Cincinnati Children's Hospital Research Foundation and College of Medicine, Cincinnati, OH, USA
2 Division of Pediatric Informatics, Cincinnati Children's Research Foundation and College of Medicine, Cincinnati, OH, USA
3 Division of Pediatric Informatics, Cincinnati Children's Research Foundation and College of Medicine, Cincinnati, OH, USA; Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation and College of Medicine, Cincinnati, OH, USA
4 Diabetes Research Center, Division of Endocrinology, Cincinnati Children's Hospital Research Foundation and College of Medicine, Cincinnati, OH, USA; Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and College of Medicine, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: jonathan.katz{at}cchmc.org.
In Type I diabetes mellitus (T1DM), also known as autoimmune diabetes, the pathogenic destruction of the insulin producing pancreatic beta cells is under the control of and influenced by distinct subsets of T lymphocytes. To identify the critical genes expressed by autoimmune T cells, antigen presenting cells and pancreatic beta cells during the evolution of T1DM in the NOD mouse, and the genetically-altered NOD mouse (BDC/N), we used functional genomics. Microarray analysis revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin (IL)-17, and islet cell regenerating genes - Reg 3
, Reg3
and Reg3
. Our data indicate that progression to insulitis was connected to marked changes in islet antigen expression, beta cell differentiation and T cell activation and signaling - all associated with tumor necrosis factor- and IL-6 expression. Overt diabetes saw a clear shift in cytokine, chemokine and T cell differentiation factor expression, consistent with a focused Th1 response, as well as a significant upregulation in genes associated with cellular adhesion, homing and apoptosis. Importantly, the temporal pattern of expression of key verified genes suggested that T1DM develops in a relapsing/remitting as opposed to a continuous fashion, with insulitis linked to hypoxia-regulated gene control and diabetes with C/EBP and Nkx2 gene control.
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