IA-2 and IA-2β are Major Autoantigens in IDDM and the Precursors of the 40 kDa and 37 kDa Tryptic Fragments

By subtraction strategy and polymerase chain reaction amplification, two novel cDNAs, designated IA-2 and IA-2β, were cloned, sequenced and expressed. Both are transmembrane proteins belonging to the protein tyrosine phosphatase family and are expressed in pancreatic islets. Serological studies revealed that a high percentage of patients with IDDM have autoantibodies to IA-2/IA-2β and that the presence of these autoantibodies in otherwise normal individuals is highly predictive in identifying those at risk of ultimately developing clinical diabetes. Moreover, many patients who are ICA positive, but who do not have Abs to GAD65, have Abs to IA-2/IA-2β. Enzymatic cleavage of IA-2/IA-2β and serological analysis showed that IA-2 is the precursor of the 40 kDa tryptic fragment and IA-2β is the precursor of the 37 kDa tryptic fragment, both previously shown to be autoantigens. It is concluded that IA-2/IA-2β are major autoantigens in IDDM and together with GAD65are responsible for much of the reactivity of ICA with pancreatic islets. Tests for the detection of autoantibodies to recombinant IA-2/IA-2β and recombinant GAD65are likely to replace the ICA immunofluorescence test for population screening.