Molecules controlled by the human histocompatibility gene complex (MHC) play a central role in immune responsiveness. The HLA-D region of the MHC encodes several subsets of highly polymorphic molecules which function in antigen presentation and alloreactivity. The nature and extent of HLA-D region heterogeneity observed in a reference Caucasian population can be further expanded by the analysis of HLA-D region molecules in other population groups. American Blacks represent a valuable resource for study of HLA-D region molecules because of unique characteristics which are different from populations presently studied: 1) Presence of an unidentified HLA-D specificity associated with DR3; 2) Alteration of genes in linkage disequilibrium resulting in the unusual antigen combination DR3,DQ blank; and 3) high frequency of DRw6-related alleles. These unique characteristics provide a probe to investigate and expand our knowledge of the molecular basis of HLA-D region diversity. Specific topics which will be addressed are the following: 1) Variability of HLA-D region gene number and gene expression; 2) Identification of new and/or null HLA-D region alleles (D,DR,DQ); 3) Polymorphism of expressed DR and DQ molecules; and 4) Relationship of defined serologic, molecular, and functional heterogeneity to the biology of the immune response and to the evolution of polymorphism. HLAL-D region molecules will be characterized from this population using functional studies to generate T cell clones against T cell recognition determinants; DNA studies using Southern and Northern blotting to identify variability in restriction fragment polymorphism, gene number and expression; and protein chemistry to characterize new and/or variant HLA-D region molecules by gel electrophoresis, amino acid sequence analysis and peptide mapping. While current studies of HLA-D region molecules have outlined a wide range of diversity, expansion of these studies into another population will aid in understanding the intricate way in which the diversity of the immune response is generated and controlled.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023371-02
Application #
3135384
Study Section
Immunobiology Study Section (IMB)
Project Start
1986-12-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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Hastings, A E; Hurley, C K; Robinson, E D et al. (1996) Molecular interactions between transfected human TCR, immunodominant myelin basic protein peptide 152-165, and HLA-DR13. J Immunol 157:3460-71
Posch, P E; Hurley, C K; Geluk, A et al. (1996) The impact of DR3 microvariation on peptide binding: the combinations of specific DR beta residues critical to binding differ for different peptides. Hum Immunol 49:96-105
Hurley, C K; Steiner, N (1995) Differences in peptide binding of DR11 and DR13 microvariants demonstrate the power of minor variation in generating DR functional diversity. Hum Immunol 43:101-12
Posch, P E; Araujo, H A; Creswell, K et al. (1995) Microvariation creates significant functional differences in the DR3 molecules. Hum Immunol 42:61-71
Hurley, C K (1993) HLA diversity in African Americans. Transplant Proc 25:2399
Lee, K W; Johnson, A H; Hurley, C K (1991) New DQw1 diversity identified within DRw12 and DRw14 haplotypes. Tissue Antigens 38:231-4
Johnson, A H; Lee, K W; Tang, T F et al. (1991) DRw11/w13: a structurally and functionally related family of alleles. Transplant Proc 23:451-2
Lee, K W; Johnson, A H; Tang, T et al. (1991) DRw11 haplotypes: continuum of DRB1 diversity augmented by unique DQ/DRw52 associations. Hum Immunol 32:150-5
Johnson, A H; Tang, T F; Cowell, V et al. (1991) The impact of naturally occurring DR3 microvariants, DRw17 and DRw18, on T-cell allorecognition. Hum Immunol 32:46-55

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