Problem: The function of the immune system is to distinguish self from non-self. When self-tolerance is lost, auto-immunity ensues. Systemic lupus erythematosus is a prototypic auto-immune disease, where loss of tolerance to nuclear antigens leads to a plethora of autoimmune pathology. Yet, little is known about which tolerance check points or mechanisms are actually breached in this disease. Parallel advances in the fields of B- cell tolerances, and genetics of autoimmunity, now allow us to investigate this in a systematic manner. Research Design: The use of immunoglobulin transgenics allows us to assess the integrity of B-cell tolerance at successive check points: deletion, receptor-edition, follicular exclusion, and anergy. Also, the availability of B6 congenic strains bearing individual lupus susceptibility intervals, allows us to evaluate the impact of each of these loci on B-cell tolerance, in a systematic way. This proposal will focus on two such potent loci, originally derived from the NZM2410 lupus strain: Sle1, which is responsible for triggering a strong anti-nuclear humoral response, and Sl32, which leads to spontaneous B-cell hyperactivity. By crossing DNA-specific, or lysozyme-specific immunoglobulin transgenes into these congenic backgrounds, we plan to study how Sle1 and Sle2 impact B-cell tolerance, to these two antigens. Significance: These experiments will tell us if the different lupus susceptibility loci breach B-cell tolerance in a global, or (nuclear) antigen-specific manner. Appreciating how the lupus genes tip the delicate balance from tolerance, towards flagrant auto-aggression, together with their actual identification, will enrich our understanding of lupus and humor autoimmunity, and pave the way towards more rational and effective therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044894-04
Application #
6341785
Study Section
Special Emphasis Panel (ZRG2-ALY (02))
Program Officer
Gretz, Elizabeth
Project Start
1998-01-15
Project End
2002-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
4
Fiscal Year
2001
Total Cost
$109,200
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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