Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM

Abstract

To determine the value of antibodies to the intracytoplasmic domain of the tyrosine phosphatase IA-2 (anti-IA-2ic) and glutamic acid decarboxylase (GADA) for identification of subjects at risk for insulin-dependent diabetes mellitus (IDDM) we investigated 1238 first degree relatives of patients with IDDM for the presence of anti-IA-2ic and GADA and compared the results with cytoplasmic islet cell antibodies (ICA). Anti-IA-2ic were observed in 54 (4.4%) first degree relatives, in 51 of 86 (59.3%) ICA positive relatives and in 3 of 4 individuals who developed overt IDDM within a follow-up period of 1 to 28 months. GADA were found in 78 of 1238 (6.3%) first degree relatives. They were detected in 22 of 35 (62.9%) sera with ICA alone and in 1 of 3 subjects with anti-IA-2ic in the absence of ICA. Of the 1238 subjects 37 (3.0%) sera were positive for all three antibodies. Both anti-IA-2ic and GADA were positively correlated with high levels of ICA. Anti-IA-2ic and GADA were detected in 39.1 and 47.8% of subjects with ICA of less than 20 Juvenile Diabetes Foundation units (JDF-U) but in 66.7 and 76.2% of individuals with ICA of 20 JDF-U or more, respectively (p < 0.05). The levels of ICA and GADA in first degree relatives with at least one additional marker were significantly higher than in subjects with ICA alone (p < 0.005) or GADA alone (p < 0.03). The combination of anti-IA-2ic and GADA identified 84.9% of all ICA positive subjects and 93.7% of individuals with high level ICA (> or = 20 IDF-U). All 4 individuals who progressed to IDDM had either IA-2ic or GADA. Our data indicate that primary screening for anti-IA-2ic and GADA provides a powerful approach with which to identify subjects at risk for IDDM in large-scale population studies which may represent the basis for the design of new intervention strategies.

Karlsburg Type I diabetes risk study of a general population: frequencies and interactions of the four major Type I diabetes-associated autoantibodies studied in 9419 schoolchildren

“…Our results suggest that the co-occurrence of Type I diabetes-associated AAbs detected in persons of a general population has a similar predictive value for developing diabetes as described for first-degree relatives [9,17,25]. In both cohorts, the diabetic subjects' and AAb-positive schoolchildren's levels of each AAb were significantly (p < 0.05) increased by AAb co-occurrence, which is consistent with data from first-degree relatives of Type I diabetic patients [7,8] (Table 1).…”

“…Recombinant IA2ic was a kind gift of N. Morgenthaler (BRAHMS Diagnostica, Berlin, Germany) and produced by coupled in vitro transcription and translation of human IA2ic cDNA [16,17]. The assay was done according the anti-IA2 test from BRAHMS Diagnostica.…”

Diabetes Antibody Standardization Program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2

“…Although used in fewer laboratories, the ELISA for IA-2A also improved and achieved AUC equivalent to those of in-house RIA, although results of the two assay formats correlated less well than for GADA. A small number of combined assays for GADA and IA-2A were included in DASP 2005 and, as expected, some achieved high sensitivity, confirming the value of this approach for initial screening [14][15][16], particularly since one of these assays used the ELISA format. In addition, the IA-2 clone used was a determinant of differences in assay performance; the relatively small numbers of RIA using the IA-2bdc giving significantly lower sensitivity and AUC than those using IA-2ic.…”

Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic beta-cells.

“…Recently, one member of the receptortype protein tyrosine phosphatase (PTP) family, designated as IA-2 or ICA512, has been identified as a major diabetes-specific autoantigen (1)(2)(3). Autoantibodies to IA-2 were observed in 50-70% of newly diagnosed patients with type 1 diabetes (4,5) and in 49-64% of prediabetic subjects at high risk for rapid development of the disease (6)(7)(8). In addition, a specific T-cell response has been described in 42-60% of diabetic patients, suggesting that IA-2 is a dominant target of humoral and cellular autoimmunity (8)(9)(10)(11).…”