title: The Receptor for Advanced Glycation Endproducts Drives T Cell Survival and Inflammation in Type 1 Diabetes Mellitus.
abstract: The ways in which environmental factors participate in the progression of autoimmune diseases are not known. After initiation, it takes years before hyperglycemia develops in patients at risk for type 1 diabetes (T1D). The receptor for advanced glycation endproducts (RAGE) is a scavenger receptor of the Ig family that binds damage-associated molecular patterns and advanced glycated endproducts and can trigger cell activation. We previously found constitutive intracellular RAGE expression in lymphocytes from patients with T1D. In this article, we show that there is increased RAGE expression in T cells from at-risk euglycemic relatives who progress to T1D compared with healthy control subjects, and in the CD8+T cells in the at-risk relatives who do versus those who do not progress to T1D. Detectable levels of the RAGE ligand high mobility group box 1 were present in serum from at-risk subjects and patients with T1D. Transcriptome analysis of RAGE+versus RAGE-T cells from patients with T1D showed differences in signaling pathways associated with increased cell activation and survival. Additional markers for effector memory cells and inflammatory function were elevated in the RAGE+CD8+cells of T1D patients and at-risk relatives of patients before disease onset. These studies suggest that expression of RAGE in T cells of subjects progressing to disease predates dysglycemia. These findings imply that RAGE expression enhances the inflammatory function of T cells, and its increased levels observed in T1D patients may account for the chronic autoimmune response when damage-associated molecular patterns are released after cell injury and killing.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Sean P
authors.identifier: 0000-0002-5183-8802
authors.initials: SP
authors.lastname: Durning
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Paula
authors.initials: P
authors.lastname: Preston-Hurlburt
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clark
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.|Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York at Buffalo, Buffalo, NY 14214; and.
authors.forename: Ding
authors.identifier: 0000-0001-9380-2712
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; kevan.herold@yale.edu.|Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Kevan C
authors.identifier: 0000-0003-1534-6613
authors.initials: KC
authors.lastname: Herold
mesh_terms: D000293:Adolescent; D000328:Adult; D058070:Asymptomatic Diseases; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007156:Immunologic Memory; D007249:Inflammation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D012306:Risk; D015398:Signal Transduction; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000067759:Receptor for Advanced Glycation End Products