Global Epidemiology of IDDM—Host Susceptibility
Our previous research has demonstrated that there are extraordinary geographic and racial variations in the annual incidence of IDDM. More than a 30-fold difference in IDDM risk has been found, where the rates are highest in Finland and lowest in Japan. Identification of the factors associated with these variations in incidence would prove invaluable for understanding the etiology of IDDM, and ultimately contribute to its prevention. Our molecular studies have revealed that the presence of an amino acid other than aspartate in position 57 (non-Asp-57) of the DQ beta-chain is a stronger marker of IDDM susceptibility than the serologically defined HLA-DR3 and DR4 antigens. The estimated relative risk (RR) of developing the disease was 107 for non-Asp-57 homozygotes among Caucasians in Allegheny County. Also, an arginine in position 52 of the DQ alpha-chain contributes to increase RR to more than 200 in patients found to be islet cell antibody (ICA)-positive. We have predicted that not only is this DNA polymorphism a very strong marker of IDDM within populations, but that the global patterns of IDDM incidence can be explained by variation in the distribution of these alleles across racial groups and countries. The study was unique in that this association was evaluated using an epidemiologic model in high, medium and low risk areas with Caucasians, Blacks and Orientals. These populations were chosen because they are heterogeneous and representative of the global patterns of IDDM incidence.
The proposed epidemiologic research is also based on our prior achievements in the development of unique populations, both locally and globally, and stored blood sample libraries. These resources will be used to search for acute environmental triggers that precipitate clinical IDDM and identify factors that will differentiate those individuals who progress from autoimmune beta-cell disease to total destruction of the insulin-producing islet cells, from those who have an indolent autoimmune course without the development of diabetes or slow progression to insulin requirement.
The hypotheses to be tested are:
- IDDM on a population basis is triggered by acute precipitating agents;
- These triggering agents are associated with evidence of an infection and immune reactions with characteristics typical of those which are virally (i.e., superantigen) mediated; and
- There is a variable rate of progression of the autoimmune process as identified by the presence of circulating ICA.
Independent determinants, including genetic predisposition, characterize rapid progressors or latent autoimmune diabetes in adults and non-progressors.
Data derived from this research will give clues as to the pathogenesis of IDDM, the time course, and characteristics of the prodrome and risk factors for progression to clinical disease. These will assist in the design of intervention strategies and populations to be tested in future studies.
The immunocompetent cells involved in IDDM pathogenesis
The etiology and pathogenesis of IDDM still challenges our complete comprehension. Today, we better understand the genetic susceptibility to the disease, and the immunological mechanisms and endocrine structures possibly involved in the disease pathogenesis. Furthermore, fluctuations in the incidence of IDDM between particular years within both the same population (i.e., mini-epidemics) and among different populations has been examined epidemiologically and have yielded clues to possible environmental factors involved in diabetogenesis. Finally, theoretical approaches that are more effective in preventing the tragic complications of the disease have been developed. Although we now have more pieces of this intriguing clinical puzzle, a unifying picture that explains the results obtained from these diverse disciplines of molecular biology, endocrinology, immunology, and epidemiology is difficult to assemble.
We have, however, already brought together scientists in the disciplines of molecular biology, endocrinology, immunology, and epidemiology who constitute a working team. These scientists have a proven track record of individually funded diabetes research and will be brought together in order to create a diabetes interdisciplinary research program, focused on the immunocompetent cells involved in the pathogenesis of IDDM.
Particular attention is currently and will be further dedicated to better understand the role played by:
- The T cells as the most important immunologic elements involved in the attack against the insulin secreting cells in the pancreas;
- The antibodies secreted by mature B cells against new autoantigens, as well as those already well-characterized;
- The natural killer (NK) cells that appear to act in the first phase of the autoimmune attack against the pancreatic islets; and
- The cell-determined “footprints” present in new onset diabetic children.
These footprints will be studied to see if the conclusions from the laboratory work may help to interpret the results gathered at the population level through epidemiological means.
