(Taken from the application): Juvenile rheumatoid arthritis (JRA) is a pleomorphic, immune-mediated disease with a complex association with immunogenetic markers. In order to understand the pathogenetic role of HLA gene products in this disease, better cause- effect relationships between immunogenetic markers and functional aberrations in the immune system must be established. Prior studies by the Principle Investigator on subsets of JRA patients have uncovered an association between known HLA disease-susceptibility genes and a functional aberration of the intracellular signaling process. In normal individuals, the integrity of this pathway is essential for repairing DNA damage, and for physiologic elimination of unnecessary lymphocytes, a process known as apoptosis. The underlying hypothesis of the proposed research is that certain HLA gene products confer susceptibility to JRA through interference with the physiologic signaling process in immune cells. This may result in defective DNA damage repair with an increased risk of somatic mutations, and may also interfere with the ability of the immune system to rid itself of excessive immune cells through apoptosis. To examine this hypothesis, the proposed research will have five specific aims: 1. To further define the clinical and immunogenetic associations with these functional aberrations. 2. To determine whether susceptibility-conferring HLA gene products transduce an aberrant intracellular signal. 3. To determine whether such signals can interfere with other intracellular signals and the ability to eliminate immune cells through apoptosis. 4. To examine whether nitric oxide, a ubiquitous mediator of intracellular events, plays a role in these functional aberrations. 5. To examine whether repair of DNA damage is defective in individuals carrying HLA susceptibility conferring genes. These studies introduce a novel concept in the pathogenesis of JRA. The results of the proposed research may provide an important insight into the pathogenesis of this and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043999-03
Application #
2517521
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1995-09-30
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109