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.
Study Design
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.