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*
Department of Immunology, Mayo Clinic, Rochester, MN 55905; and
Department of Endocrinology, Yale University School of Medicine, New Haven, CT 06510
The genetic factors that contribute to the etiology of type 1
diabetes are still largely uncharacterized. However, the genes of the
MHC (HLA in humans) have been consistently associated with
susceptibility to disease. We have used several transgenic mice
generated in our laboratory, bearing susceptible or resistant HLA
alleles, in the absence of endogenous MHC class II (A
o), to study
immune responses to the autoantigen glutamic acid decarboxylase (GAD)
65 and its relevance in determining the association between
autoreactivity and disease pathogenesis. Mice bearing
diabetes-susceptible haplotypes, HLA DR3 (DRB1*0301) or DQ8
(DQB1*0302), singly or in combination showed spontaneous T cell
reactivity to rat GAD 65, which is highly homologous to the self Ag,
mouse GAD 65. The presence of diabetes-resistant or neutral alleles,
such as HLA DQ6 (DQB1*0602) and DR2 (DRB1*1502) prevented the
generation of any self-reactive responses to rat GAD. In addition,
unmanipulated Ao/DR3, Ao/DQ8, and Ao/DR3/DQ8 mice recognized
specific peptides, mainly from the N-terminal region of the GAD 65
molecule. Most of these regions are conserved between human, mouse, and
rat GAD 65. Further analysis revealed that the reactivity was mediated
primarily by CD4+ T cells. Stimulation of these T cells by
rat GAD 65 resulted in the generation of a mixed Th1/Th2 cytokine
profile in the Ao/DR3/DQ8, Ao/DR3, and Ao/DQ8 mice. Thus, the
presence of diabetes-associated genes determines whether immune
tolerance is maintained to islet autoantigens, but autoreactivity in
itself is not sufficient to induce diabetes.
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