title: Reduced CD4+ T-cell-specific gene expression in human type 1 diabetes mellitus.
abstract: Type 1 diabetes mellitus (T1DM) in humans is characterized by the T-cell-dependent destruction of the insulin producing pancreatic beta cells; however, the precise pathogenesis of the disease, especially the initiation of pathologic immune response, is still largely unknown. We hypothesized that the function of human CD4+ T cells is altered in T1DM and analyzed unstimulated human peripheral blood CD4+ T-cell gene expression. We used a novel three-way comparison of DNA microarray data of CD4+ T cells isolated from patients with new onset T1DM, patients with long-term Type 2 diabetes (T2DM), and from healthy control subjects in order to eliminate any possible influence of glucose homeostasis on our findings. We analyzed the T1DM specific gene-expression changes and their functional relevance to T1DM autoimmunity. Our genetic and functional data show that T1DM CD4+ T cells are down-regulated specifically affecting key immune functions and cell cycle. Histone deacetylase gene expression, a key regulator of epigenetic modification is also reduced. The CD4+ T cells showed impaired function, including an abnormal immune response, which may be a key element that leads to the breakdown of self-tolerance.
authors.affiliation: Section of Immunology and Immunogenetics, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA. torban@joslin.harvard.edu
authors.forename: Tihamer
authors.initials: T
authors.lastname: Orban
authors.forename: Janos
authors.initials: J
authors.lastname: Kis
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szereday
authors.forename: Peter
authors.initials: P
authors.lastname: Engelmann
authors.forename: Klara
authors.initials: K
authors.lastname: Farkas
authors.forename: Heyam
authors.initials: H
authors.lastname: Jalahej
authors.forename: Andras
authors.initials: A
authors.lastname: Treszl
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male
chemical_list: D006655:Histone Deacetylases