The First Signs of -Cell Autoimmunity Appear in Infancy in Genetically Susceptible Children from the General Population: The Finnish Type 1 Diabetes Prediction and Prevention Study
Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this popula- tion-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of -cell au- toimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 ge- netically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant se- roconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and anti- bodies to the protein tyrosine phosphatase-related IA-2 mol- ecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate- risk genotype (1.2%; P 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibod- ies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ- defined genetic risk of type 1 diabetes show signs of -cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specific- ity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of -cell autoimmunity sug- gests that infectious agents may play a role in the induction of such autoimmunity. (J Clin Endocrinol Metab 86: 4782- 4788, 2001)