We describe a nonradioactive microcytotoxicity assay for ICSA using a cloned rat insulinoma cell line. This assay system had good reproducibility (r = 0.93) and was suitable for the study of large numbers of samples. The following results were obtained by testing the sera of 111 patients with IDDM (type I diabetes) and all of their first-degree relatives. (1) Thirty-five percent of IDDM patients had ICSA, as compared with only 2% of healthy controls. (2) ICSA was found more frequently in patients within 2 yr of onset (45%) than in those with disease for longer than 2 yr (27%) (P < 0.05). (3) The prevalence of ICSA was associated with the presence of cytoplasmic islet cell antibodies (ICA) (P < 0.05). (4) No association was found between the prevalence of ICSA and specific HLA-DR aileles. Association with the HLA haplotypes in families with ICSA-positive probands, on the other hand, is suggested although not proven by these data. (5) Among the nondiabetic relatives of IDDM patients, 5% of the parents and 14% of the sibs had ICSA. Increased prevalence of ICSA occurred in the unaffected sibs of ICSA-positive probands (31%) but not in those of ICSA-negative probands (4%) (P < 0.001); in fact, therelatives of ICSA-negative probands had ICSA with a frequency not higher than in unrelated controls. (6) Female relatives of ICSA-positive probands were more often ICSA-positive than males, but no such difference was found among probands. (7) In multiplex sibships, ICSA were not associated with disease in the sibs. These results suggest that the persistent presence of ICSA in relativesof IDDM patients is determined by a combination of environmental and genetic factors, including sex.

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