Dynamic interaction between T cell-mediated beta-cell damage and beta-cell repair in the run up to autoimmune diabetes of the NOD mouse.
In type 1 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 nonobese diabetic (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, Reg3alpha, Reg3beta, and Reg3gamma. 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-alpha 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.
Vukkadapu
Sankaranand S
SS
Diabetes Research Center, Division of Endocrinology, Cincinnati Children's Hospital Research Foundation and College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229-3039, USA.
Belli
Jenine M
JM
Ishii
Koji
K
Jegga
Anil G
AG
Hutton
John J
JJ
Aronow
Bruce J
BJ
Katz
Jonathan D
JD
D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016023:Integrins / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D016688:Mice, Inbred NOD; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D013601:T-Lymphocytes / Q000378:metabolism* / Q000502:physiology
D001324:Autoantigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D016023:Integrins; D003165:Complement System Proteins