title: Molecular pathway alterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phase of autoimmune diabetes.
abstract: Type 1 diabetes (T1D) is a multigenic disease caused by T-cell mediated destruction of the insulin producing pancreatic islet ß-cells. The earliest sign of islet autoimmunity in NOD mice, islet leukocytic infiltration or insulitis, is obvious at around 5 weeks of age. The molecular alterations that occur in T cells prior to insulitis and that may contribute to T1D development are poorly understood. Since CD4 T-cells are essential to T1D development, we tested the hypothesis that multiple genes/molecular pathways are altered in these cells prior to insulitis. We performed a genome-wide transcriptome and pathway analysis of whole, untreated CD4 T-cells from 2, 3, and 4 week-old NOD mice in comparison to two control strains (NOR and C57BL/6). We identified many differentially expressed genes in the NOD mice at each time point. Many of these genes (herein referred to as NOD altered genes) lie within known diabetes susceptibility (insulin-dependent diabetes, Idd) regions, e.g. two diabetes resistant loci, Idd27 (tripartite motif-containing family genes) and Idd13 (several genes), and the CD4 T-cell diabetogenic activity locus, Idd9/11 (2 genes, KH domain containing, RNA binding, signal transduction associated 1 and protein tyrosine phosphatase 4a2). The biological processes associated with these altered genes included, apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks); inflammation and cell signaling/activation (predominant at 3 weeks); and innate and adaptive immune responses (predominant at 4 weeks). Pathway analysis identified several factors that may regulate these abnormalities: eight, common to all 3 ages (interferon regulatory factor 1, hepatic nuclear factor 4, alpha, transformation related protein 53, BCL2-like 1 (lies within Idd13), interferon gamma, interleukin 4, interleukin 15, and prostaglandin E2); and two each, common to 2 and 4 weeks (androgen receptor and interleukin 6); and to 3 and 4 weeks (interferon alpha and interferon regulatory factor 7). Others were unique to the various ages, e.g. myelocytomatosis oncogene, jun oncogene, and amyloid beta (A4) to 2 weeks; tumor necrosis factor, transforming growth factor, beta 1, NF?B, ERK, and p38MAPK to 3 weeks; and interleukin 12 and signal transducer and activator of transcription 4 to 4 weeks. Thus, our study demonstrated that expression of many genes that lie within several Idds (e.g. Idd27, Idd13 and Idd9/11) was altered in CD4 T-cells in the early induction phase of autoimmune diabetes and identified their associated molecular pathways. These data offer the opportunity to test hypotheses on the roles played by the altered genes/molecular pathways, to understand better the mechanisms of CD4 T-cell diabetogenesis, and to develop new therapeutic strategies for T1D.
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Tennessee Health Science Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA ; Research Service, Veterans Affairs Medical Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA.
authors.forename: Dorothy N
authors.initials: DN
authors.lastname: Kakoola
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Tennessee Health Science Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA ; Research Service, Veterans Affairs Medical Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Curcio-Brint
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Tennessee Health Science Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA ; Research Service, Veterans Affairs Medical Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA.
authors.forename: Nataliya I
authors.initials: NI
authors.lastname: Lenchik
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Tennessee Health Science Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA ; Research Service, Veterans Affairs Medical Center, VAMC Research 151, 1030 Jefferson Avenue, Memphis, TN 38104, USA.
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Gerling
keywords: CD4 T-cells; Genome-wide gene expression profiling; Molecular pathway analysis; NOD mice; Preinsulitis; Type 1 diabetes susceptibility regions