Molecular pathwayalterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phaseof autoimmune diabetes

Dorothy N. Kakoola, Anita Curcio-Brint, Nataliya I. Lenchik, Ivan Gerling

Research output: Contribution to journalArticle

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Abstract

Type 1 diabetes (T1D) is a multigenic disease caused by T-cell mediated destruction of the insulin producing pancreatic islet β-cells. The earliest sign of islet autoimmunity in NOD mice, islet leukocytic infiltration or insulitis, is obvious at around 5weeks 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 4week-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 2weeks); inflammation and cell signaling/activation (predominant at 3weeks); and innate and adaptive immune responses (predominant at 4weeks). 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 4weeks (androgen receptor and interleukin 6); and to 3 and 4weeks (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 2weeks; tumor necrosis factor, transforming growth factor, beta 1, NFκB, ERK, and p38MAPK to 3weeks; and interleukin 12 and signal transducer and activator of transcription 4 to 4weeks. 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.

Original languageEnglish (US)
Pages (from-to)30-45
Number of pages16
JournalResults in Immunology
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2014

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Inbred NOD Mouse
Type 1 Diabetes Mellitus
T-Lymphocytes
Genes
Islets of Langerhans
Interferon-alpha
Proto-Oncogene Proteins c-bcl-2
STAT4 Transcription Factor
Interferon Regulatory Factor-7
Interferon Regulatory Factor-1
jun Genes
Insulin
Biological Phenomena
Interleukin-15
Protein Tyrosine Phosphatases
Androgen Receptors
Gene Expression Profiling
Adaptive Immunity
Interleukin-12
Metabolic Networks and Pathways

All Science Journal Classification (ASJC) codes

  • Immunology

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Molecular pathwayalterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phaseof autoimmune diabetes. / Kakoola, Dorothy N.; Curcio-Brint, Anita; Lenchik, Nataliya I.; Gerling, Ivan.

In: Results in Immunology, Vol. 4, No. 1, 01.01.2014, p. 30-45.

Research output: Contribution to journalArticle

Kakoola, Dorothy N. ; Curcio-Brint, Anita ; Lenchik, Nataliya I. ; Gerling, Ivan. / Molecular pathwayalterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phaseof autoimmune diabetes. In: Results in Immunology. 2014 ; Vol. 4, No. 1. pp. 30-45.
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N2 - Type 1 diabetes (T1D) is a multigenic disease caused by T-cell mediated destruction of the insulin producing pancreatic islet β-cells. The earliest sign of islet autoimmunity in NOD mice, islet leukocytic infiltration or insulitis, is obvious at around 5weeks 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 4week-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 2weeks); inflammation and cell signaling/activation (predominant at 3weeks); and innate and adaptive immune responses (predominant at 4weeks). 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 4weeks (androgen receptor and interleukin 6); and to 3 and 4weeks (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 2weeks; tumor necrosis factor, transforming growth factor, beta 1, NFκB, ERK, and p38MAPK to 3weeks; and interleukin 12 and signal transducer and activator of transcription 4 to 4weeks. 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.

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