This program project is concerned with several areas that affect blood service care: immunity to hepatitis B virus, natural killer and T cell function, and selective deficiency of IgA. The three projects involve the major histocompatibility complex (MHC) and use conserved extended MHC haplotypes to help define the role of MHC genes in each of the areas of study. The projects are supported by an Administrative Core and a Tissue Culture and MHC Typing Core. The First Project seeks to define the genetic bases for response or nonresponse to HBsAg, the hepatitis B surface antigen, in both MHC and T cell antigen receptor (TCR) genes and the interactions between them. The portions of the HBsAg molecule involved in the induction and target of an immune response, binding of antigenic peptides to specific antigen-presenting cells and class II molecules, and the utilization of specific TCR V gene segments and junctional sequences will all be studied . The next project will determine whether antigen- presenting or T cells are defective in nonresponders to HBsAg and will provide T cell liens for study in Project 1. This Project will also explore the nature of MHC-encoded targets for natural killer cells, related then to genes we have identified that control natural killer cell number and activity, and determine if there are non-MHC-encoded targets as well. The specific MHC genes that serve as natural killer cell targets will be localized an possibly identified using B lymphoblastoid cell lines and activated B cells from individuals homozygous and heterozygous for MHC extended haplotypes, extended haplotype fragments and alleles. The relationship of the genes that control NK cell numbers and cytolytic activity to those that determine NK targets will be explored. Finally, the last project will attempt to identify and localize MHC susceptibility genes for IgA and other immunoglobulin deficiencies through the intensive MHC marker study of patients and their families. This project will attempt to define subsets of IgA deficiency in relation to specific clinical features and extended haplotype markers. In a second set of studies, incompletely penetrant genes that determine immunoglobulin defects will be identified in subjects with IgA deficiency susceptibility haplotypes. The modes of genetic determination and the penetrance of such genes will be determined in a novel approach. This project will also seek to define the nature of the defect in IgA deficiency in terms of the switch to IgA and from surface to secreted IgA in response to several different cytokines. A model for the study of IgA deficiency and for control of IgA synthesis will be established in vitro using the CD40 B cell culture system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL029583-15
Application #
2883216
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
1983-07-01
Project End
2000-11-30
Budget Start
1999-03-01
Budget End
2000-11-30
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
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Husain, Zaheed; Kelly, M Ann; Eisenbarth, George S et al. (2008) The MHC type 1 diabetes susceptibility gene is centromeric to HLA-DQB1. J Autoimmun 30:266-72
Romero, Viviana; Zuniga, Joaquin; Azocar, Jose et al. (2008) Genetic interactions of KIR and G1M immunoglobulin allotypes differ in obese from non-obese individuals with type 2 diabetes. Mol Immunol 45:3857-62
Romero, Viviana; Azocar, Jose; Zuniga, Joaquin et al. (2008) Interaction of NK inhibitory receptor genes with HLA-C and MHC class II alleles in Hepatitis C virus infection outcome. Mol Immunol 45:2429-36

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