Early childhood infections precede development of beta-cell autoimmunity and type 1 diabetes in children with HLA-conferred disease risk.

BACKGROUND: The etiology of type 1 diabetes (T1D) is largely unknown. Infections and microbial exposures are believed to play a role in the pathogenesis and in the development of islet autoimmunity in genetically susceptible individuals. OBJECTIVE: To assess the relationships between early childhood infections, islet autoimmunity, and progression to T1D in genetically predisposed children. METHODS: Children with human leukocyte antigen (HLA)-conferred disease susceptibility (N=790; 51.5% males) from Finland (n = 386), Estonia (n = 322), and Russian Karelia (n = 82) were observed from birth up to the age of 3 years. Children attended clinical visits at the age of 3, 6, 12, 18, 24, and 36 months. Serum samples for analyzing T1D-associated autoimmune markers were collected and health data recorded during the visits. RESULTS: Children developing islet autoimmunity (n = 46, 5.8%) had more infections during the first year of life (3.0 vs 3.0, mean rank 439.1 vs 336.2; P = .001) and their first infection occurred earlier (3.6 vs 5.0 months; P = .005) than children with no islet autoimmunity. By May 2016, 7 children (0.9%) had developed T1D (progressors). Compared with non-diabetic children, T1D progressors were younger at first infection (2.2 vs 4.9 months; P = .004) and had more infections during the first 2 years of life (during each year 6.0 vs 3.0; P = .001 and P = .027, respectively). By 3 years of age, the T1D progressors had twice as many infections as the other children (17.5 vs 9.0; P = .006). CONCLUSIONS: Early childhood infections may play an important role in the pathogenesis of T1D. Current findings may reflect either differences in microbial exposures or early immunological aberrations making diabetes-prone children more susceptible to infections.

Prediction of type 1 diabetes among siblings of affected children and in the general population.

AIMS/HYPOTHESIS: To compare the predictive characteristics of autoantibodies to GAD (GADA) and islet antigen 2 (IA-2A) for type 1 diabetes between siblings of affected children and children from the general population. METHODS: Seven-hundred and fifty-five siblings and 3,475 population-derived children were screened for GADA and IA-2A and observed for type 1 diabetes for 15 years. Sensitivity and cumulative disease risks from GADA, IA-2A and double positivity were compared between the cohorts. RESULTS: Fifty-six siblings (7.4%) tested positive for GADA, 39 (5.2%) for IA-2A and 29 (3.8%) for both autoantibodies. Thirty-four population derived participants (1.0%) had GADA, 22 (0.6%) had IA-2A and 7 (0.2%) had double positivity. Fifty-one siblings (6.8%) and 15 participants in the population cohort (0.4%) progressed to type 1 diabetes. The predictive sensitivity of GADA was 68% (95% CI 53-81%) among siblings and 50% (95% CI 23-77%) in the general population, while the corresponding values were 58 (95% CI 43-72%) and 43% (95% CI 18-71%) for IA-2A. Double-autoantibody positivity had a sensitivity of 48% (95% CI 34-63%) among siblings and 36% (95% CI 13-65%) in the population cohort. Cumulative disease risks from GADA, IA-2A and double positivity were, respectively, 61% (95% CI 48-74%), 74% (95% CI 61-88%) and 83% (95% CI 69-97%) among siblings compared with those of 24% (95% CI 9-38%), 32% (95% CI 12-51%) and 86% (95% CI 60-100%) in the general population. CONCLUSIONS/INTERPRETATION: There were no significant differences in the disease-predictive sensitivity of GADA and IA-2A positivity or their combination between siblings and the population cohort, whereas, for each antibody, positivity was associated with a higher cumulative disease risk among siblings. Double-antibody positivity conferred similar cumulative disease risk both among siblings and in the general population.