Antibodies are generated during early B cell development by random joining of immunoglobulin (Ig) gene segments. Ig gene recombination can result in the assembly of self-reactive antibodies or B cell receptors (BCR). B cells that develop self-reactive receptors can be silenced by one of three mechanisms: deletion, anergy; and receptor editing. Whereas deletion and anergy ultimately eliminate self-reactive B cells, receptor editing rescues them by replacing autoreactive antibodies. We analyzed how B cell tolerance was established in humans by following the evolution of autoantibody-producing B cells during B cell development. We found that 55-75% of early B cell precursors expressed self-reactive antibodies and that autoantibodyproducing B cells in healthy donors were removed from the population at two discrete checkpoints. The mechanisms that prevail in silencing these autoreactive B cells remain to be characterized, and little is known about the effect of antibody specificity and BCR signaling in regulating the balance between deletion, anergy, and receptor editing. However, defects in BCR signaling have been reported in B cells from patients with systemic lupus erythematosus and common variable immunodeficiency (CVID) who frequently develop autoimmunity suggesting that BCR signaling may play a role in counterselecting self-reactive B cells. The long range goal of the proposed research is to elucidate the role of BCR in the regulation of B cell tolerance by analyzing primary immunodeficient patient B cells with altered BCR signaling. The working hypothesis is that BCR signaling is essential in establishing B cell tolerance and when it is affected, autoreactive B cells are not silenced and can migrate to the periphery.
The first aim of the project will consist of cloning antibodies from single B cells from the blood of X-linked agammaglobulinemia patients and determine whether modified threshold of BCR signaling in btk gene-deficient B cells impacts B cell tolerance mechanisms. The second part of the project will analyze how BCR co-receptors such as CD40 influence the establishment and the maintenance of B cell tolerance in hyper-IgM patients. The third part of the project will study B cell tolerance in CVID patients. These studies have significant implications for understanding how self-reactive B cells may be produced with or without maintaining self-tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI061093-02
Application #
7063477
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$414,348
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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