Type 1A diabetes induced by infection and immunization.

Type 1A diabetes is an immune mediated disorder that results from progressive destruction of the islet beta-cells in the setting of genetic susceptibility. Both MHC and non-MHC genes contribute to disease with class II HLA molecules major determinants of susceptibility or protection. The presence of multiple anti-islet autoantibodies is associated with a high risk of disease progression, and the first anti-islet autoantibodies may appear as early as the first year of life. Congenital rubella is the only infection clearly associated with the development of type 1A diabetes. With the ability to detect children in the first year of life activating autoimmunity, prospective studies may in the future document additional environmental factors either increasing or decreasing diabetes risk.

Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes.

With the development of an insulin autoantibody (IAA) assay performed in 96-well filtration plates, we have evaluated prospectively the development of IAA in NOD mice (from 4 weeks of age) and children (from 7 to 10 months of age) at genetic risk for the development of type 1 diabetes. NOD mice had heterogeneous expression of IAA despite being inbred. IAA reached a peak between 8 and 16 weeks and then declined. IAA expression by NOD mice at 8 weeks of age was strongly associated with early development of diabetes, which occurred at 16-18 weeks of age (NOD mice IAA(+) at 8 weeks: 83% (5/6) diabetic by 18 weeks versus 11% (1/9) of IAA negative at 8 weeks; P <.01). In man, IAA was frequently present as early as 9 months of age, the first sampling time. Of five children found to have persistent IAA before 1 year of age, four have progressed to diabetes (all before 3.5 years of age) and the fifth is currently less than age 2. Of the 929 children not expressing persistent IAA before age 1, only one has progressed to diabetes to date (age onset 3), and this child expressed IAA at his second visit (age 1.1). In new onset patients, the highest levels of IAA correlated with an earlier age of diabetes onset. Our data suggest that the program for developing diabetes of NOD mice and humans is relatively "fixed" early in life and, for NOD mice, a high risk of early development of diabetes is often determined by 8 weeks of age. With such early determination of high risk of progression to diabetes, immunologic therapies in humans may need to be tested in children before the development of IAA for maximal efficacy.