OBJECTIVE -To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of ␤-cell autoimmunity among three geographical regions in Finland.RESEARCH DESIGN AND METHODS -The series comprised 4,642 children with increased HLA-DQB1-defined genetic risk of type 1 diabetes from the Diabetes Prediction and Prevention (DIPP) study: 1,793 (38.6%) born in Turku, 1,646 (35.5%) in Oulu, and 1,203 (25.9%) in Tampere. These children were examined frequently for the emergence of signs of ␤-cell autoimmunity, for the primary screening of which islet cell antibodies (ICA) were used. If the child developed ICA, all samples were also analyzed for insulin autoantibodies (IAA), GAD65 antibodies (GADA), and antibodies to the IA-2 molecule (IA-2A).RESULTS -The high-and moderate-risk genotypes were unevenly distributed among the three areas (P Ͻ 0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) than in the Turku (28.4%; P Ͻ 0.001) or Tampere regions (27.2%; P Ͻ 0.001). This genotype was associated with an increased frequency of ICA seroconversion relative to the moderate risk genotypes (hazard ratio 1.89, 95% CI 1.36 -2.62). Seroconversions to ICA positivity occurred less commonly in Tampere than in Turku (0.47, 0.28 -0.75), whereas the seroconversion rate in Oulu did not differ from that in Turku (0.72, 0.51-1.03). The Tampere-Turku difference persisted after adjustment for risk genotypes, sex, and time of birth (before January 1998 versus later). Seroconversion for at least one additional autoantibody was also less frequent in Tampere than in Turku (0.39,.CONCLUSIONS -These data show that in Finland, the country with the highest incidence of type 1 diabetes in the world, both the frequency of the high-risk HLA-DQB1 genotype and the risk of seroconversion to autoantibody positivity show geographical variation. The difference in seroconversion rate could not be explained by the difference in HLA-DQB1-defined disease susceptibility, implying that the impact of environmental triggers of diabetes-associated autoimmunity may differ between the three regions studied. Diabetes Care 27:676 -681, 2004T he epidemiological map of type 1 diabetes that has been drawn over the last few decades shows marked differences in the incidence of the disease among countries and various racial groups (1,2). The reasons behind these differences have remained poorly defined, but both genetic and environmental factors may contribute to them. Type 1 diabetes is a polygenic disorder, but it has been estimated that the genes of the HLA complex explain 30 -60% of its familial clustering (3). The main genes contributing to disease susceptibility are located in the HLA-DQ locus on the short arm of chromosome 6, 6p21 (4), and alleles at this locus also provide resistance to diabetes. There are some differences within Europe in the distribution of the HLA risk alleles among patients affected by type 1 diabetes. The proportion of DQB1*02-positive subjects is higher among patients from southern Europe, wh...

We measured the concentrations of the soluble forms of the intercellular adhesion molecule-1 (sICAM-1) and L-selectin in 95 autoantibody-positive siblings of children with type 1 diabetes and 95 sex-and age-matched siblings testing negative for diabetes-associated autoantibodies to assess the possible role of soluble adhesion molecules as markers of progressive ␤-cell destruction in preclinical diabetes and their ability to discriminate between those siblings who progress to clinical disease and those who remain nondiabetic. We observed an inverse correlation between age and the levels of both sICAM-1 (r ϭ Ϫ0.31, p Ͻ 0.001) and sL-selectin (r ϭ Ϫ0.27, p Ͻ 0.001) in the control siblings but no association with HLA-DR phenotypes. There was no difference in the circulating levels of soluble adhesion molecules between the antibody-positive and negative siblings. Among the antibody-positive siblings, those with at least three autoantibodies had higher sICAM-1 levels (p Ͻ 0.01) than those testing positive for only one, and siblings with three autoantibodies or more had higher concentrations of sL-selectin (p Ͻ 0.01) than those with two autoantibodies. Siblings with an islet cell antibody level of 20 Juvenile Diabetes Foundation units or more had higher sICAM-1 concentrations than those with a level below 20 (p Ͻ 0.001), and those testing positive for antibodies to the protein tyrosine phosphatase-related IA-2 antigen had increased levels of both sICAM-1 (p ϭ 0.03) and sL-selectin (p ϭ 0.02) compared with siblings who tested negative. The antibodypositive siblings who progressed to clinical type 1 diabetes were significantly younger than the nonprogressors (p Ͻ 0.001) and had higher levels of sICAM-1 initially (p Ͻ 0.001). The difference in sICAM-1 concentrations remained significant (p ϭ 0.03) after age adjustment. Our results indicate that concentrations of soluble adhesion molecules are increased in the autoantibodypositive siblings who have the highest risk of developing clinical diabetes, suggesting that ␤-cell destruction is reflected in increased circulating levels of these molecules. This is supported by the observation of elevated sICAM-1 concentrations in the 29 siblings who actually progressed to clinical type 1 diabetes. Peripheral levels of soluble adhesion molecules are not able to discriminate between progressors and nonprogressors, however, due to substantial overlapping between these two groups. Type 1 diabetes is an organ-specific autoimmune disease with a subclinical prodrome characterized by destruction of the insulin-producing ␤ cells in the pancreatic islets of Langerhans. During the pathogenetic process, the islets become infiltrated by inflammatory mononuclear cells, mainly lymphocytes (1) but also macrophages (2), giving the histopathologic lesion characteristic of insulitis. The migration of autoreactive lymphocytes and other leukocytes from the bloodstream into the target organ is a key feature in the etiology of many organspecific autoimmune/inflammatory disorders such as type 1 diabetes. Th...

SummaryThe natural history of preclinical diabetes is partly characterized, but there is still limited information on the dynamics of the immune response to β β β β -cell autoantigens during the course of preclinical disease. The aim of this work was to assess the maturation of the humoral immune response to the protein tyrosine phosphatase(PTP)-related proteins (IA-2 and IA-2β β β β ) in preclinical type I diabetes (TID). Forty-five children participating in the Finnish Type I Diabetes Prediction and Prevention (DIPP) Study who had seroconverted to IA-2 antibody positivity were analysed. Specific radiobinding assays were used to determine IA-2/IA-2β β β β epitope-specific antibodies (the juxtamembrane (JM) region of IA-2, PTP-like domain and β β β β PTP-like domain) and isotype-specific IA-2 antibodies. Individual areas under the curve (AUC) over the observation period were calculated for total IA-2 antibodies, each isotype and specific epitope responses. The children who progressed to TID tended to have an initial IA-2 JM epitope response more frequently ( P = = = = 0·06), and this response was more often dominant during the observation period ( P < < < < 0·05). The children who did not progress to TID had IgE-IA-2 more frequently (70%; versus progressors 27%; P < < < < 0·05), and had higher integrated titres of IgE-IA-2 antibodies ( P < < < < 0·05). The occurrence of IgE-IA-2 antibodies was protective even when combined with positivity for IA-2 JM antibodies ( P = = = = 0·002). IgE-IA-2 antibody reactivity may be a marker of a regulatory immune response providing protection against or delaying progression to TID among IA-2 antibody-positive young children with HLA-conferred disease susceptibility.