Cellular and molecular pathogenic mechanisms of insulin-dependent diabetes mellitus.
Insulin-dependent diabetes mellitus (IDDM), also known as type 1 diabetes, is an organ-specific autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells. The hypothesis that IDDM is an autoimmune disease has been considerably strengthened by the study of animal models such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, both of which spontaneously develop a diabetic syndrome similar to human IDDM. Beta cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T cells have been shown to be involved in the pathogenesis of autoimmune diabetes. Among the beta cell autoantigens identified, glutamic acid decarboxylase (GAD) has been extensively studied and is the best characterized. Beta cell-specific suppression of GAD expression in NOD mice results in the prevention of IDDM. Macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages play an essential role in the development and activation of beta cell-cytotoxic T cells. B lymphocytes play a role as antigen-presenting cells, and T cells have been shown to play a critical role as final effectors that kill beta cells. Cytokines secreted by immunocytes, including macrophages and T cells, may regulate the direction of the immune response toward Th1 or Th2 as well as cytotoxic effector cell or suppressor cell dominance. Beta cells are destroyed by apoptosis through Fas-Fas ligand and TNF-TNF receptor interactions and by granzymes and perforin released from cytotoxic effector T cells. Therefore, the activated macrophages and T cells, and cytokines secreted from these immunocytes, act synergistically to destroy beta cells, resulting in the development of autoimmune IDDM.
Yoon
J W
JW
Department of Microbiology and Infectious Disease, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, The University of Calgary, Alberta, Canada. yoon@ucalgary.ca
Jun
H S
HS
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology; D016207:Cytokines / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D012697:Serine Endopeptidases / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; C096322:ICA512 autoantibody; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; C516864:Ptprn protein, rat; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2