COMPARISON OF IA-2 WITH IA-2-BETA AND WITH 6 OTHER MEMBERS OF THE PROTEIN-TYROSINE-PHOSPHATASE FAMILY - RECOGNITION OF ANTIGENIC DETERMINANTS BY IDDM SERA

To study the expression of protein tyrosine phosphatases (PTPs) in pan creatic islets, a cDNA library from islet cells was constructed and an alysed. Twenty one different fYTPs were found to be expressed in islet cells, including three previously unknown PTPs. One of these, IA-2 be ta, was cloned, sequenced, and found to be related to IA-2, a major au toantigen in insulin-dependent diabetes mellitus (IDDM). The intracell ular and extracellular domains of IA-2 beta were 74 and 27% identical, respectively, to the intracellular and extracellular domains of IA-2. Approximately 70 and 45% of sera from patients with IDDM had autoanti bodies that immunoprecipitated recombinant IA-2 and IA-2 beta, respect ively. By use of deletion mutants; we were able to show that the autoa ntibodies reacted with the intracellular, and not the extracellular, d omains of IA-2 and IA-2 beta, and that the major antigenic determinant s resided within the COOH-terminus of the intracellular domains. Furth er studies revealed that approximately 97% of the IDDM sera that react ed with IA-2 beta also reacted with IA-2, whereas only 50% of IDDM ser a that reacted with IA-2 also reacted with IA-2 beta. In contrast to t he reactivity of IDDM sera with the IA-2 and IA-2 beta , IDDM sera did not react with six other members of the PTP family. It is concluded t hat many members of the PTP family are expressed in pancreatic islets, but thus far only IA-2 and IA-2 beta appear to be recognized as autoa ntigens by IDDM sera. (C) 1997 Academic Press Limited.