Antibodies to DNA or nucleosomes possess numerous positively charged amino acids, such as arginines, in their heavy chain CDR3. These cationic residues are critical contact points with negatively charged sites on the DNA helix in chromatin. Atypical VH-D-J H rearrangements such as D-D fusions contribute to create these arginine codons. Based on our preliminary data, we propose that secondary immunoglobulin heavy gene rearrangements in lupus-prone mice are responsible for potentially selfreactive VH-D-J H junctions. An increased predisposition to generate such atypical VH-D-J H rearrangements can be an important contributor to the development of lupus. We propose to test our hypothesis by accomplishing the following objectives.
In Specific Aim 1, we will investigate whether lupus-prone MRL mice differ from control strains in their levels of RAG1 and RAG2 mRNA during B cell ontogeny. We will evaluate whether RAG expression is differentially affected in MRL B cells after engagement of the B cell receptor. We will also characterize, at the DNA level, VH-D-J H and D-J H rearrangements as well as other evidence of receptor revision in MRL and control B cells at various stages of development.
In Specific Aim 2, we will directly test this model in vivo by examining the presence of secondary heavy chain rearrangements and autoimmune manifestations in hemizygous MRL Jh +/- mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR050777-02
Application #
6804736
Study Section
Special Emphasis Panel (ZAR1-RJB-A (O1))
Program Officer
Gretz, Elizabeth
Project Start
2003-09-25
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$75,250
Indirect Cost
Name
Temple University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122