This application refers to continuing studies on the HLA-linked genetic component of the susceptibility to Type 1 diabetes (T1D) and on the pathogenetic mechanisms that result in decompensation in those at genetic risk. Previous data indicate that the DR alleles positively associated with T1D (DR3 and DR4) and those negatively associated (DR2 and DR5) are parts of haplotypes that are different in """"""""affected"""""""" and """"""""unaffected"""""""" conditions (""""""""affected"""""""" designates those haplotypes present in the patient and """"""""unaffected"""""""" refers to the other HLA haplotypes of the pedigree). We propose to establish whether these different haplotypes involve structurally different though serologically identical DR and DQ genes. Southern blotting of genomic DNA restriction fragments (RF) with cDNA probes corresponding to the alpha and beta chain genes of DR and DQ will be performed on all members of selected pedigrees and the RF patterns associated with the different haplotypes will be thereby identified. The patterns of """"""""affected"""""""" and """"""""unaffected"""""""" haplotypes will be compared to determine whether systematic differences exist. Additional prospective studies will be conducted to determine the metabolic and immunological changes that precede the decompensation of individuals at risk among the relatives of T1D patients and also among Congenital Rubella (CR) and Gestational Diabetic (GD) patients. The latter groups of patients exhibit HLA associations identical to those of classical T1D. Islet cell-specific Cellular immune functions will be investigated as well as the presence and concentrations of islet-cell specific antibodies. These data will improve our ability to estimate the true risks of decompensation for individual carriers of the different HLA alleles among relatives of probands and to study whether the same genetic variants present in """"""""affected"""""""" T1D haplotypes are found in CR patients with diabetes and in decompensated former GD women. Further studies of polymorphic RF linked to the Gm genes will be performed in multiplex sibships in order to determine whether these genes influence the liability to T1D.
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