The objective of this project is to analyze the structural and regulatory features which control expression of HLA susceptibility genes contributing to Type I diabetes (IDDM). We will focus both on the genetic contributions of specific HLA class II genes on haplotypes associated with IDDM, and on the transcriptional regulation and tissue-specific expression of these genes.
Specific aims i nclude the use of allele- and locus-specific oligonucleotide probes to distinguish HLA DQ genetic variation differentially associated with IDDM; we will focus largely on the DQ3.2beta gene, a putative disease susceptibility allele previously implicated in diabetes susceptibility in order to clarify the contributions of the DQ3.2beta gene, and of other linked genes, as 'permissive' alleles in IDDM.
A second aim of these studies is to test the hypothesis that variation in DQ beta promoter elements accounts for altered transcriptional regulation and/or tissue-specific expression of putative susceptibility alleles; this will be tested by a series of promoter region gene amplification, sequencing, and expression studies involving the upstream regulatory elements associated with class II genes in IDDM. Third, we will use a series of in vitro mutagenized DQ genes, expressed in human B cell lines, to study the structure-function relationships of specific nucleotide substitutions on T-cell recognition. These three Aims present an inter-related set of objectives to identify and characterize genetic, structural, and regulatory components of IDDM susceptibility which are contributed by HLA class II genes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Benaroya Research Institute at Virginia Mason
United States
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Leech, N; Sorrentino, R; McCulloch, D K et al. (1995) Ultrastructural allelic variation in HLA-DQB1 promoter elements. Hum Immunol 43:251-8
Leech, N J; Kitabchi, A E; Gaur, L K et al. (1995) Genetic and immunological markers of insulin dependent diabetes in Black Americans. Autoimmunity 22:27-32
Kwok, W W; Kovats, S; Thurtle, P et al. (1993) HLA-DQ allelic polymorphisms constrain patterns of class II heterodimer formation. J Immunol 150:2263-72
Miller, G; Nepom, G T; Reich, M B et al. (1993) Autoreactive T cells from a type I diabetic recognize multiple class II products. Hum Immunol 36:219-26
Wassmuth, R; Eastman, S; Kockum, I et al. (1993) HLA DR and DQ RFLP analysis in Crohn's disease. Eur J Immunogenet 20:429-33
Gaur, L K; Heise, E R; Thurtle, P S et al. (1992) Conservation of the HLA-DQB2 locus in nonhuman primates. J Immunol 148:943-8
Andersen, L C; Beaty, J S; Nettles, J W et al. (1991) Allelic polymorphism in transcriptional regulatory regions of HLA-DQB genes. J Exp Med 173:181-92
Nepom, G T (1990) Mutagenesis and expression of putative class II susceptibility genes: a ""reverse immunogenetics"" approach to analysis of HLA and disease. Autoimmunity 7:189-99