Abstract

The molecular interaction of class II molecule, antigen and T cell receptor is central to the immune response. The polymorphic residues of the class II molecule not only control the bindings of specific antigens but also select the repertoire of T cell receptors available to recognize the class II/antigen complex. Thus, class II diversity is important in the survival of a species which must coexist with diverse and versatile pathogens. The remarkable polymorphism within the HLA-DRw52 family of DRB1 alleles is characterized by subtle, stepwise changes outlining an evolutionary pathway. One hypothesis is that this family of DRB1 alleles and their associated HLA haplotypes, present at a high frequency in the American black population, have evolved to provide a selective advantage to these individuals who derive from a region plagued by multiple pathogens. The goal of this study is to define how these DRB1 microvariants affect immune recognition and to probe how selection may have influenced DR polymorphism. To do this, a panel of DR transfectants expressing naturally occurring and mutated DRB1 genes will be generated (AIM1). These transfectants will be used to examine the impact of variations in specific regions of the DR beta chain on function. The mutants will also provide a means of assessing the effect of point mutation/gene conversion on the DR molecule as it evolves. Existing alloproliferation T cell clones will be used to survey the effect of DR polymorphism on immune recognition (AIM2). T cell clones specific for an immunodominant T cell epitope of the malaria parasite will be generated (AIM3). This model system will not only allow us to analyze the effect of DR polymorphism on immune recognition in a defined antigen system (AIM4) but will also allow us to analyze the influence of DR polymorphism on peptide binding (AIM5). Finally, the interaction between DR polymorphism and pathogen diversity will be studied (AIM6). These studies will provide basic information about the effect of subtle amino acid substitutions in various regions of the DR molecule on immune recognition and will begin to examine the role that pathogens may have played in positive selection of DR polymorphism and, ultimately, in shaping the human immune response repertoire.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023371-07
Application #
3135388
Study Section
Immunobiology Study Section (IMB)
Project Start
1986-12-01
Project End
1995-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Georgetown University
Department
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057

  Publications

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
Johnson, A H; Araujo, H; Tang, T F et al. (1996) Cellular crossreactivity. Implications for solid organ transplantation matching. Transplantation 61:643-8
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
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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