Islet autoantigens: structure, function, localization, and regulation.
Islet autoantigens associated with autoimmune type 1 diabetes (T1D) are expressed in pancreatic β cells, although many show wider patterns of expression in the neuroendocrine system. Within pancreatic β cells, every T1D autoantigen is in one way or another linked to the secretory pathway. Together, these autoantigens play diverse roles in glucose regulation, metabolism of biogenic amines, as well as the regulation, formation, and packaging of secretory granules. The mechanism(s) by which immune tolerance to islet-cell antigens is lost during the development of T1D, remains unclear. Antigenic peptide creation for immune presentation may potentially link to the secretory biology of β cells in a number of ways, including proteasomal digestion of misfolded products, exocytosis and endocytosis of cell-surface products, or antigen release from dying β cells during normal or pathological turnover. In this context, we evaluate the biochemical nature and immunogenicity of the major autoantigens in T1D including (pro)insulin, GAD65, ZnT8, IA2, and ICA69.
Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA. Parrvan@umich.edu
Peter
P
Arvan
Massimo
M
Pietropaolo
David
D
Ostrov
Christopher J
CJ
Rhodes
D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D027682:Cation Transport Proteins / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004195:Disease Models, Animal; D005968:Glutamate Decarboxylase / Q000276:immunology; D018398:Homeodomain Proteins / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057165:Proteostasis Deficiencies / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D022142:Secretory Vesicles / Q000378:metabolism; D000074122:Short Stature Homeobox Protein; D000075703:Zinc Transporter 8
D001324:Autoantigens; D027682:Cation Transport Proteins; D018398:Homeodomain Proteins; C087054:ICA1 protein, human; D007328:Insulin; C106071:SHOX protein, human; C492522:SLC30A8 protein, human; D000074122:Short Stature Homeobox Protein; D000075703:Zinc Transporter 8; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2