We propose to define more rigorously the genetics of predisposition to Type 1 Diabetes (T1D), and to investigate immunological aspects of the expression of this genetic susceptibility. T1D in second degree relatives of patients will provide information on the likelihood of sharing identical-by-descent (IBD) HLA haplotypes and on the gene frequencies of the T1D associated HLA alleles in the non-shared haplotypes (NSH) as a means of directly distinguishing between recessive and intermediate modes of inheritance. If the T1D-associated HLA alleles have equal frequencies in the IBD and NSH haplotypes, the intermediate inheritance would be inconsistent; if NSH had the population HLA frequencies, the resessive model would be excluded. We will also investigate whether the association with SB- is even closer than with DR-alleles and whether typing for SB allows a more precise definition of the mapping location of T1D. We will also determine whether HLA-unlinked genes participate in the inheritance of T1D or at least in its penetrance, particularly the Kidd and Gm systems. T1D inheritance patterns in families of Black, Hispanic and Jewish may help in differentiating the effects of association and linkage between HLA and T1D. Studies of conditions other than T1D but which may lead to insulin dependence will be extended since suggestive data has been obtained in patients with Congenital Rubella Syndrome (CR) and Gestational Diabetes (GD). Prospective and retrospective studies in these conditions and in Cystic Fibrosis are proposed in order to establish whether the chance of developing insulin dependent diabetes is under the control of HLA-linked genes with associations identical to those in T1D. Studies of immunological alterations as possible means of expression of the susceptibility to T1D will include functional assays of suppressor cells, precise enumeration of B-lymphocytes, monocytes and T-lymphocytes (including T-cell subsets) on patients and families and the development of a system for measuring cell mediated cytotoxicity to beta cells. We expect that the mechanism whereby beta cells are destroyed and T1D thus becomes expressed may emerge and that together with results on virological and epidemiological aspects, our results may lead to strategies for the protection of those at genetic risk.