We propose to comprehensively analyze the genetic polymorphisms of class II genes in a collection of mouse strains which are homozygous for H-2 haplotypes derived from 5 separate sub-species of Mus. The class II genes and gene-products of these wild mouse-derived H-2 haplotypes will be compared and they will be gouped into allelic families on the basis of structural similarities. The functional, structural, and genetic properties of these families of class II gene alleles will then be studied in detail. The purpose of this study is to assess the evolutionary mechanisms responsible for the production and maintenance of class II gene polymorphisms. The genetic mechanisms which generate class II gene diversity will be studied by comparing the DNA sequences of structural gene exons which have recently diverged. This analysis will determine whether copy mechanisms or gene conversion is involved in the generation of class II gene diversity. The presence of mutational """"""""hot spots"""""""" in the I region will be tested by the analysis of I region restriction site polymorphisms with class II gene DNA probes. Finally, the evolutionary stability of specific class II alleles and class II gene haplotypes will be assessed by comparisons of class II gene alleles prevalent in separate sub-species of Mus. The analysis of class II gene polymorphism in wild mice is a useful model system for the analysis of class II genes in human populations. Our studies of wild mice suggest that a limited number of distally-related allelic families of class II genes may predominate in natural populations. Class II alleles in the same family encode A molecules with very similar antigenic phenotypes and structural properties. However, our functional analysis of these closely-related alleles indicate that the minor structural variations which distinguish their products are often capable of stimulating strong mixed lymphocyte reactions and acute skin graft rejections. These observations in wild mice may be relevant to the poor success rate of allograft survival between DR-identical, genetically unrelated donor-recipient pairs in human transplantation studies. We are in the process of searching for minor structural variations in the class II molecules of DR-identical individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017966-07
Application #
3127573
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1981-06-01
Project End
1989-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Myrick, C; DiGuisto, R; DeWolfe, J et al. (2002) Linkage analysis of variations in CD4:CD8 T cell subsets between C57BL/6 and DBA/2. Genes Immun 3:144-50
Lu, C C; Ye, Y; She, J X et al. (1996) Evolutionary origins of retroposon lineages of Mhc class II Ab alleles. Immunogenetics 43:115-24
Wu, J; Longmate, J A; Adamus, G et al. (1996) Interval mapping of quantitative trait loci controlling humoral immunity to exogenous antigens: evidence that non-MHC immune response genes may also influence susceptibility to autoimmunity. J Immunol 157:2498-505
Morel, L; Rudofsky, U H; Longmate, J A et al. (1994) Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1:219-29
She, J X; Boehme, S A; Wang, T W et al. (1991) Amplification of major histocompatibility complex class II gene diversity by intraexonic recombination. Proc Natl Acad Sci U S A 88:453-7
Wakeland, E K; Boehme, S; She, J X et al. (1990) Ancestral polymorphisms of MHC class II genes: divergent allele advantage. Immunol Res 9:115-22
Tine, J A; Walsh, A; Rathbun, D et al. (1990) Genetic polymorphisms of Q region genes from wild-derived mice: implications for Q region evolution. Immunogenetics 31:315-25
Wakeland, E K; Boehme, S; She, J X (1990) The generation and maintenance of MHC class II gene polymorphism in rodents. Immunol Rev 113:207-26
Siegelman, M H; Cheng, I C; Weissman, I L et al. (1990) The mouse lymph node homing receptor is identical with the lymphocyte cell surface marker Ly-22: role of the EGF domain in endothelial binding. Cell 61:611-22
Pullen, A M; Potts, W; Wakeland, E K et al. (1990) Surprisingly uneven distribution of the T cell receptor V beta repertoire in wild mice. J Exp Med 171:49-62

Showing the most recent 10 out of 14 publications