Humoral beta‐cell autoimmunity in relation to HLA‐defined disease susceptibility in preclinical and clinical type 1 diabetes

We have studied the relationship between diabetes-associated autoantibodies and various HLA genotypes and alleles in patients with newly diagnosed type 1 diabetes, in non-diabetic siblings and in children representing the general population to test the hypothesis that specific HLA genes regulate the humoral immune response to various autoantigens. Among the newly diagnosed patients we observed that those carrying the DR4-DQB1*0302 haplotype had increased levels of insulin autoantibodies (IAA) and IA-2 antibodies (IA-2A), but low levels of GAD antibodies (GADA). In contrast, those with the DR3-DQB1*02 haplotype had increased GADA titers but low IAA and IA-2 levels. DQB1*02-homozygous patients had a conspicuously low frequency and low levels of IA-2A. Among the siblings there was an apparent association between genetic risk and the prevalence of islet cell antibodies (ICA), IAA, GADA, IA-2A and multiple autoantibodies, the latter being detectable at a frequency of 24.1% in high risk siblings and at a frequency of only 0.9% in those with genotypes conferring disease protection. Among 7-16-year-old Finnish schoolchildren there was an association between GADA and the DQB1*02/*0302 genotype and the DQB1*0302 allele. Among young children identified from the general population based on high (DQB1*02/0302 heterozygosity) or moderate (DQB1*0302/x; x not equal *02, *0301, *0602, *0603) genetic risk for type 1 diabetes the high risk children seroconverted more often to positivity for ICA, GADA and IA-2A over their first 2 years of life. Among older sibs of these children we observed an obvious relationship between the degree of genetic risk and the frequency of ICA, IAA, GADA, IA-2A, and multiple antibodies. Taken together these observations suggest that HLA genes have a strong impact on the appearance of diabetes-associated autoantibodies both in first-degree relatives of affected children and in the general population. In patients with newly diagnosed disease IA-2A may be a more specific marker of beta-cell damage, whereas GADA might reflect a propensity to autoimmunity in general.