IA-2 and IA-2β: the immune response in IDDM

Abstract

Pancreatic islet cell autoantigens associated with insulin-dependent diabetes mellitus (IDDM) include a recently identified family of protein tyrosine phosphatase-like molecules, notably IA-2 and IA-2beta. IA-2 is a 979 amino acid transmembrane protein located on human chromosome 2q35, whereas IA-2beta is 986 amino acids long located on human chromosome 7q36. Comparison of human IA-2 and IA-2beta showed 74% identity within the intercellular domains, but only 27% indentify within the extracellular domains. These IA-2 molecules are expressed predominantly in cells of neuroendocrine origin, particularly pancreatic islets and brain. Radioimmunoprecipitation with recombinant IA-2 and IA-2beta has been used to measure autoantibodies to these molecules and their intracellular fragments. Autoantibodies to IA-2 are detected in the majority (60% to 80%) of newly diagnosed IDDM patients and in less than 2% of controls. The major antigenic determinants of both IA-2 and IA-2beta reside within the C-terminus of their intracellular domains. In first-degree relatives of IDDM patients, the presence of autoantibodies to IA-2 is predictive of IDDM and in combination with autoantibodies to glutamic acid decarboxylase (GAD) the positive predictive value is in the 50% range. The role of IA-2 and IA-2beta in the pathogenesis of IDDM is still unclear. Identification of these antigens has extended our ability to predict the disease and may be valuable in the search for antigen-specific therapies to prevent IDDM.

Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk

“…Moreover, half of the ZnT8A-NH 2 -positive children did not develop other islet autoantibodies, and none of those progressed to diabetes. The high diabetes risk associated with the development of ZnT8A-COOH is similar to that seen in children with antibodies to the IA-2 and in particular IA-2β autoantigens [5,[25][26][27][28]. All of these antibody targets are the COOH-terminal cytosolic portion of secretory granule transmembrane proteins, suggesting a relative importance of autoimmunity to such proteins compared with other beta cell proteins in the pathogenesis of type 1 diabetes.…”

Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk

“…Moreover, half of the ZnT8A-NH 2 -positive children did not develop other islet autoantibodies, and none of those progressed to diabetes. The high diabetes risk associated with the development of ZnT8A-COOH is similar to that seen in children with antibodies to the IA-2 and in particular IA-2β autoantigens [5,[25][26][27][28]. All of these antibody targets are the COOH-terminal cytosolic portion of secretory granule transmembrane proteins, suggesting a relative importance of autoimmunity to such proteins compared with other beta cell proteins in the pathogenesis of type 1 diabetes.…”

Differential Gene Expression after Zinc Supplementation and Deprivation in Human Leukocyte Subsets

“…Hence, the change could also be a response to a disturbance of the cellular redox balance by zinc. The receptor type protein tyrosine phosphatase (PTP) RN, also known as IA-2, is an autoantigen in diabetes that is found in pancreatic islets and the brain (28). For KIAA1109 and HAX1, no functions have thus far been published.…”

Enterovirus infection can induce immune responses that cross‐react with β‐cell autoantigen tyrosine phosphatase IA‐2/IAR

“…Tyrosine phosphatases IA-2 and IAR are transmembrane proteins expressed primarily in the islets of Langerhans, and the central nervous system [Cui et al, 1996;Notkins et al, 1996Notkins et al, , 1998]. IA-2/IAR autoantibodies are considered reliable markers of ongoing autoimmune process in b cells [Ellis et al, 1998].…”

Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk

“…Moreover, half of the ZnT8A-NH 2 -positive children did not develop other islet autoantibodies, and none of those progressed to diabetes. The high diabetes risk associated with the development of ZnT8A-COOH is similar to that seen in children with antibodies to the IA-2 and in particular IA-2β autoantigens [5,[25][26][27][28]. All of these antibody targets are the COOH-terminal cytosolic portion of secretory granule transmembrane proteins, suggesting a relative importance of autoimmunity to such proteins compared with other beta cell proteins in the pathogenesis of type 1 diabetes.…”

Differential Gene Expression after Zinc Supplementation and Deprivation in Human Leukocyte Subsets

“…Hence, the change could also be a response to a disturbance of the cellular redox balance by zinc. The receptor type protein tyrosine phosphatase (PTP) RN, also known as IA-2, is an autoantigen in diabetes that is found in pancreatic islets and the brain (28). For KIAA1109 and HAX1, no functions have thus far been published.…”

Enterovirus infection can induce immune responses that cross‐react with β‐cell autoantigen tyrosine phosphatase IA‐2/IAR

“…Tyrosine phosphatases IA-2 and IAR are transmembrane proteins expressed primarily in the islets of Langerhans, and the central nervous system [Cui et al, 1996;Notkins et al, 1996Notkins et al, , 1998]. IA-2/IAR autoantibodies are considered reliable markers of ongoing autoimmune process in b cells [Ellis et al, 1998].…”

Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk

“…Moreover, half of the ZnT8A-NH 2 -positive children did not develop other islet autoantibodies, and none of those progressed to diabetes. The high diabetes risk associated with the development of ZnT8A-COOH is similar to that seen in children with antibodies to the IA-2 and in particular IA-2β autoantigens [5,[25][26][27][28]. All of these antibody targets are the COOH-terminal cytosolic portion of secretory granule transmembrane proteins, suggesting a relative importance of autoimmunity to such proteins compared with other beta cell proteins in the pathogenesis of type 1 diabetes.…”

Differential Gene Expression after Zinc Supplementation and Deprivation in Human Leukocyte Subsets

“…Hence, the change could also be a response to a disturbance of the cellular redox balance by zinc. The receptor type protein tyrosine phosphatase (PTP) RN, also known as IA-2, is an autoantigen in diabetes that is found in pancreatic islets and the brain (28). For KIAA1109 and HAX1, no functions have thus far been published.…”

Enterovirus infection can induce immune responses that cross‐react with β‐cell autoantigen tyrosine phosphatase IA‐2/IAR

“…Tyrosine phosphatases IA-2 and IAR are transmembrane proteins expressed primarily in the islets of Langerhans, and the central nervous system [Cui et al, 1996;Notkins et al, 1996Notkins et al, , 1998]. IA-2/IAR autoantibodies are considered reliable markers of ongoing autoimmune process in b cells [Ellis et al, 1998].…”