The overall objective of this project is to elucidate the mechanisms by which HLA class II genes are regulated.
The specific aims for this project period are: 1) to continue and complete development of a method of cloning transactive transcriptional factors, retroviral transactivation, which is not based on protein-DNA binding and is not dependent on mRNA abundance; 2) to identify and clone genes for transcription factors, particularly non-DNA binding transcription factors, which regulate expression of HLA class II genes and other genes important in the immune response; 3) to study transcriptional regulation of HLA class II genes using the cloned transactive factor genes; and 4) to continue investigation of post-translational mechanisms which effect HLA class II gene expression and function. Two general approaches will be used for cloning class II transcriptional factors, retroviral transactivation and complementation of class II transactive factor mutants. We expect that studies using cloned transactive regulatory genes will lead to a better understanding of the way that class II genes are regulated. Because the magnitude of T cell responses is dependent on levels of class II expression of antigen presenting cells, these studies in turn should help to elucidate an important determinant of T cell function. In addition we hope to elucidate the nature of the normal functioning of the genes mutated in the various forms of the Bare Lymphocyte Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI016689-18
Application #
2413507
Study Section
Special Emphasis Panel (NSS)
Project Start
1980-06-01
Project End
1998-09-30
Budget Start
1997-05-01
Budget End
1998-09-30
Support Year
18
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Muczynski, K A; Cotner, T; Anderson, S K (2001) Unusual expression of human lymphocyte antigen class II in normal renal microvascular endothelium. Kidney Int 59:488-97
Muczynski, K A; Anderson, S K; Pious, D (1998) Discoordinate surface expression of IFN-gamma-induced HLA class II proteins in nonprofessional antigen-presenting cells with absence of DM and class II colocalization. J Immunol 160:3207-16
Cotner, T; Pious, D (1995) HLA-DR beta chains enter into an aggregated complex containing GRP-78/BiP prior to their degradation by the pre-Golgi degradative pathway. J Biol Chem 270:2379-86
Cotner, T (1992) Unassembled HLA-DR beta monomers are degraded rapidly by a nonlysosomal mechanism. J Immunol 148:2163-8
Stimac, E; Urieli-Shoval, S; Kempin, S et al. (1991) Defective HLA DRA X box binding in the class II transactive transcription factor mutant 6.1.6 and in cell lines from class II immunodeficient patients. J Immunol 146:4398-405
Stimac, E; Lyons, S; Pious, D (1988) Transcription of HLA class II genes in the absence of B-cell-specific octamer-binding factor. Mol Cell Biol 8:3734-9
Pious, D; Dixon, L; Levine, F et al. (1985) HLA class II regulation and structure. Analysis with HLA-DR3 and HLA-DP point mutants. J Exp Med 162:1193-207
Levine, F; Erlich, H A; Mach, B et al. (1985) Transcriptional regulation of HLA class II and invariant chain genes. J Immunol 134:637-40
Levine, F; Erlich, H; Mach, B et al. (1985) Deletion mapping of HLA and chromosome 6p genes. Proc Natl Acad Sci U S A 82:3741-5
Levine, F; Pious, D (1985) Different roles for cytosine methylation in HLA class II gene expression. Immunogenetics 22:427-40