Systemic lupus erythematosis (SLE) is an autoimmune disease characterized by loss of tolerance to nuclear antigens. Mice deficient in Lyn, a negative regulator of B and myeloid cell function, develop SLE-like disease. Reduced dosage of Btk in B cells and lack of Btk expression in myeloid cells prevents plasma cell accumulation and autoantibodies in lyn-/- mice while maintaining B cell hypersensitivity to BCR crosslinking. This suggeststhat 1) control of plasma cell numbers by the balance of Lyn and Btk signals is a checkpoint that normally prevents autoimmunity and 2) myeloid defects may contribute to autoimmunity in lyn-/- mice. The mechanism for the Btk-dependent increase in splenic plasma cells in lyn-/- mice will be defined in Specific Aim 1. Plasma cell lifespan will be measured in vivo to determine whether increased production or increased survival of plasma cells occurs in lyn-/- mice. In vitro culture systems will be used to compare the ability of wild type, lyn-/-, and Iyn-/-Btklo plasma cells to differentiate and survive alone, in response to various stimuli, and in the presence of wild type, lyn-/-, and Iyn-/-Btklo myeloid lineage cells.
In Specific Aim 2, mixed bone marrow chimeras and mice with conditional deletion of lyn in either the B or myeloid lineage will be used to determine whether autoimmunity requires Lyn deficiency in B cells, myeloid cells, or both.
Specific Aim 3 will determine whether reduced Btk dosage and the Slesl suppressor allele (characterized in detail in Project 1) suppress autoimmunity via similar or different mechanisms. Iyn-/-Sles1 mice will be generated and compared to lyn-/- and Iyn-/-Btklo mice in terms of autoimmune phenotypes, splenic cell populations, sensitivity of B and myeloid lineage cells to activation, and gene expression profiles. In addition, the effect of Btk and Slesl on tolerance checkpoints in immature B cells will be compared. These studies will identify potential new therapeutic targets for SLE at the level of cell populations, pathways,and individual molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI039824-14
Application #
8079566
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
14
Fiscal Year
2010
Total Cost
$258,277
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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