IA-2, A TRANSMEMBRANE PROTEIN OF THE PROTEIN-TYROSINE-PHOSPHATASE FAMILY, IS A MAJOR AUTOANTIGEN IN INSULIN-DEPENDENT DIABETES-MELLITUS

IA-2 is a 105,847 Da transmembrane protein that belongs to the protein tyrosine phosphatase family, Immunoperoxidase staining with antibody raised against IA-2 showed that this protein Is expressed in human pan creatic islet cells, In this study, we expressed the full-length cDNA clone of IA-2 in a rabbit reticulocyte transcription/translation syste m and used the recombinant radiolabeled IA-2 protein to detect autoant ibodies by immunoprecipitation, Coded sera (100) were tested: 50 from patients with newly diagnosed insulin-dependent diabetes mellitus (IDD M) and 50 from age-matched normal controls, Sixty-six percent of the s era from patients, but none of the sera from controls, reacted with IA -2, The same diabetic sera tested for autoantibodies to islet cells (I CA) by indirect immunofluorescence and glutamic acid decarboxylase (GA D(65)Ab) by depletion ELISA showed 68% and 52% positivity, respectivel y, Up to 86% of the IDDM patients had autoantibodies to IA-2 and/or GA D(65). Moreover, greater than 90% (14 of 15) of the ICA-positive but G AD(65) Ab-negative sera had autoantibodies to IA-2, Absorption experim ents showed that the immunofluorescence reactivity of ICA-positive ser a was greatly reduced by prior incubation with recombinant IA-2 or GAD (65) when the respective antibody was present, A little over one-half (9 of 16) of the IDDM sera that were negative for ICA were found to be positive for autoantibodies to IA-2 and/or GAD(65), arguing that the immunofluorescence test for ICA is less sensitive than the recombinant tests for autoantibodies to IA-2 and GAD(65) If is concluded that IA- 2 is a major islet cell autoantigen in IDDM, and, together with GAD(65 ), is responsible for much of the reactivity of ICA with pancreatic is lets, Tests for the detection of autoantibodies to recombinant IA-2 an d GAD(65) may eventually replace ICA immunofluorescence for IDDM popul ation screening.