IA-2 and IA-2b belong to family of protein tyrosine phosphatase-like (PTP) molecules. IA-2 is a transmembrane protein with 979 amino acids encoded by a gene on human chromosome 2q35. Similarly, IA-2b has 986 amino acids, and it is located on human chromosome 7q36. The IA-2 is synthesised as a pro-protein of 110 kDa which is then converted by post-translational modifications into a 130 kDa protein.
The IA-2 and IA-2b shares 74% identity within the intracellular domains, but only 27% in the extracellular domains.
The IA-2 protein is expressed mainly in cells of neuroendocrine origin, such as pancreatic islets and brain. The IA-2 protein is localised in the membrane of secretory granules of pancreatic β-cells.[7][8]
Even though the IA-2/b has a similar structure to other PTPs, there is a critical amino acid replacement at position 911 (Asp for Ala),[9] which is required for enzymatic activity. These proteins thus fail to show enzymatic activity and their function remains unclear.[7] They could play role in insulin secretory pathways, sorting out proteins or regulates other PTPs.[10]
The IA-2 is a second major autoantigeninType 1 Diabetes. IA-2 autoantibodies are found in 78% type 1 diabetics at the time of diagnosis.[11] It has been shown that the autoantibodies exclusively react with the intracellular domain, also called juxtamembrane, but not with the extracellular domain of IA-2/b.[7]
It is suggested that IA-2 and not the IA-2b is the primary PTP-like autoantigen in Type 1 Diabetes. The juxtamembrane region in IA-2 is probably the early antibody target. Followed by multiple epitope spreading which is believed to take place in the early development of the disease.[12]
Autoantibodies targeting pancreatic islet cell can occur years before a hyperglycaemia is established, therefore these autoantibodies are used in prediction of Type 1 Diabetes.
Islet cell autoantibodies are detected in serum, including ICA (islet cell cytoplasma autoantibodies), IAA (autoantibodies to insulin), GAD (glutamic acid decarboxylase), IA-2 (insulinoma-associated protein 2), and ZnT8 (zinc transporter of islet beta cells).[13]
However, it is not clear if a primary autoantigen exists and immune reaction against other molecules results from secondary antigen spreading, or multiple molecules represent a primary target.[14]
The first autoimmune targets are usually aimed against insulin or GAD, and it is unique to observe IA-2 or ZnT8 as the first autoantibodies. What set off the appearance of a first β-cell targeting autoantibody is unclear.[15]
The IAA antibody usually appears early in life, median age is 1.49. Presence of GAD as the first autoantibody is more widespread with median age 4.04. It is relatively rare to see IA-2 as the primary autoantibody, median age 3.03. Interestingly, secondary autoantibodies follow different patterns to mask the primary autoantibodies, if both are combined. If the primary autoantibody is IAA then GAD briskly appears with peak of 2 years age. Secondary IAA usually occurs after GAD, where the age distribution is over wide range.[14]
It is unknown whether the appearance of autoantibodies corresponds with insulitis process in the pancreas and if so, what is the combination of the autoantibodies.[13]
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Ort T, Maksimova E, Dirkx R, Kachinsky AM, Berghs S, Froehner SC, Solimena M (September 2000). "The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of beta2-syntrophin and nNOS in pancreatic beta-cells". European Journal of Cell Biology. 79 (9): 621–630. doi:10.1078/0171-9335-00095. PMID11043403.
Mikulecký M, Michalková D (2002). "Secular and seasonal cycling of IA2-ab autoantibody in Slovak diabetic children". Biomedicine & Pharmacotherapy. 55 (Suppl 1): 106s–109s. doi:10.1016/s0753-3322(01)90014-9. PMID11774856.
Miao D, Yu L, Tiberti C, Cuthbertson DD, Rewers M, di Mario U, et al. (March 2002). "ICA512(IA-2) epitope specific assays distinguish transient from diabetes associated autoantibodies". Journal of Autoimmunity. 18 (2): 191–196. doi:10.1006/jaut.2001.0577. PMID11908951.
Kawasaki E, Yamaguchi H, Hattori H, Egashira T, Eguchi K (April 2002). "Autoantibodies to IA-2 in type 1 diabetes: measurements with a new enzyme-linked immunosorbent assay". Annals of the New York Academy of Sciences. 958: 241–246. doi:10.1111/j.1749-6632.2002.tb02978.x. PMID12021115. S2CID45659598.
Bearzatto M, Lampasona V, Belloni C, Bonifacio E (December 2003). "Fine mapping of diabetes-associated IA-2 specific autoantibodies". Journal of Autoimmunity. 21 (4): 377–382. doi:10.1016/j.jaut.2003.08.002. PMID14624760.
Ota T, Takamura T, Nagai Y, Bando Y, Usuda R (January 2005). "Significance of IA-2 antibody in Japanese type 1 diabetes: its association with GAD antibody". Diabetes Research and Clinical Practice. 67 (1): 63–69. doi:10.1016/j.diabres.2004.05.004. PMID15620435.
