Type 1 Diabetes Discordant Monozygotic Twin Study (Microchimerism Twin Study)
Gene Environmental Interactions Group
Type 1 diabetes is one of several autoimmune diseases of unclear etiology in which the discordance rate between identical twins is between 30-40%, even after many years of follow-up. The intermediate discordance rate indicates that both genetic susceptibility and environmental factors are involved in type 1 etiology. While it has been established that much of the genetic contribution is from the HLA locus, no consensus exists on the nature of the putative environmental differences. These are all that more remarkable for occurring in twins that generally share the same intrauterine, family and school environment.
Recent evidence has suggested that the development of certain autoimmune diseases, particularly scleroderma, may be influenced by microchimerism. Both fetomaternal microchimerism (persistence of fetal cells in the maternal circulation after birth of the child) and maternofetal microchimerism (persistence of maternal cells in the child's circulation for years after birth) can create an abnormal environment that might stimulate the development of autoimmunity in genetically susceptible individuals. The reverse is also possible, i.e., that these abnormal cells may stimulate the immune system in such a way that autoimmunity does not develop.
The objective of this study is to determine, using monozygotic (MZ) twins discordant for type 1 diabetes, whether persistent maternofetal michrochimerism can influence the development of type 1 diabetes in genetically susceptible individuals.
To date, we have recruited about 30 MZ twin pairs discordant for type 1 diabetes from the British Diabetic Twins Study being conducted by Dr. David Leslie at St. Bartholomew's Hospital (London, UK). The twin pairs' mothers will be asked to participate by donating blood samples and if the twin pairs are female, their offspring must participate as well. Since trafficking of chimeric cells can be bi-directional, female twins who have had offspring can have chimeric cells of both fetal and maternal origin in their circulation. Therefore for the female twins, DNA samples are required from all 3 generations to determine the origin of chimeric cells.
HLA loci will be used to identify nonshared HLA alleles that will then be used to develop specific assays for the persistence of maternal DNA in the twins' circulation. Quantitative PCR of the mother's genotype in CD3+ cells isolated from the twins will be done to give us an estimate of the number of maternal cells present in the twins' circulation. Results of the study might provide evidence in support of microchimerism as an influential factor in the development of type 1 diabetes. This concept could lead to potential immunosuppression or other strategies in type 1 diabetes prevention.