Thesis (Ph.D.)--Murdoch University, 2009. / Thesis submitted to the Faculty of Health Sciences. Includes bibliographical references (leaves 204-226)

Abstract There is evidence that the process leading to type 1 diabetes may start in early infancy or even in utero, with a prodrome of variable duration preceding clinical manifestation. The purpose of the present work was to learn more about the occurrence and significance of humoral beta-cell autoimmunity during pregnancy and in infancy, to search for possible signs of prenatal or early postnatal induction of beta-cell autoimmunity and to explore the role of enterovirus infections as potential triggers of such autoimmunity. The population comprised mothers and their newborn infants from families with type 1 diabetes who had entered the first (n=20) or the second pilot study (n=208) of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Almost 40% of the mothers with type 1 diabetes had antibodies to islet cells (ICA), 55% to glutamic acid decarboxylase (GADA) and 54% to the IA-2 protein (IA-2A) in the two samples taken during pregnancy, where the frequencies for the unaffected mothers were 5%, 5% and 3%, respectively. All autoantibody specificities were detected in the cord blood largely at the same frequencies as in the maternal circulation. In addition, ICA was found in 2.7%, GADA in 0.6%, IA-2A in 0.3% and insulin autoantibodies (IAA) in 0.1% out of a series of 1002 cord blood samples from infants representing the normal population. None of the infants of the autoantibody-negative mothers in these series had autoantibodies detectable in their cord blood. The rate of decline of transplacentally transferred autoantibodies during the first months of life was observed to be similar to that reported for the disappearance of maternally acquired IgG antibodies, the estimated mean elimination time ranging from 3.1-4.5 months. The higher the initial autoantibody level, the longer was the elimination time, and transplacentally transferred autoantibodies were occasionally detected up to the age of 9-12 months, and even at 15 months in a very few cases. The peak incidence of enterovirus RNA in serum was observed at the age of 6-12 months, while that of infections, based on changes in antibody titres, was seen at the age of 18 months. The frequency of enterovirus infections in the autoantibody-positive infants during the 6 months before the appearance of the first autoantibodies was almost three times higher than in age-matched infants testing negative for autoantibodies. These observations suggest that pregnancy does not have any strong modulating effect on the prevalence and titres of diabetes-associated autoantibodies. If such autoantibodies are present in the mother, most of them are transferred to the foetal circulation and are detectable in the cord blood. No signs of foetal induction of beta-cell autoimmunity were observed, indicating that such a phenomenon is extremely rare. Most of the transplacentally transferred autoantibodies disappear within the first 3-6 months of postnatal life, but they may persist even up to the age of 15 months in exceptional cases, suggesting that the optimal age for the initiation of large-scale screening in the general population is 18-24 months. The temporal association between enterovirus infections and the first signs of beta-cell autoimmunity supports the hypothesis that enteroviruses may induce a primary beta-cell insult.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2008. / Härtill 4 uppsatser.