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 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=0.001) and their first infection occurred earlier (3.6 vs. 5.0 months; p=0.005) than children with no islet autoimmunity. By May 2016, seven children (0.9%) had developed T1D (progressors). Compared to non-diabetic children, T1D progressors were younger at first infection (2.2 vs. 4.9 months; p=0.004) and had more infections during the first 2 years of life (during each year 6.0 vs. 3.0; p=0.001 and p=0.027, respectively). By 3 years of age, the T1D progressors had twice as many infections as the other children (17.5 vs. 9.0; p=0.006). 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