This is a proposal to define the immunoregulatory capabilities of anergic B cells. Anergy in B cells is a state of nonresponsiveness resulting from chronic stimulation through the B cell receptor (BCR), occurring in the absence of T cell help and/or innate stimulation. It is a major form of tolerance among self-reactive B cells. Anergic B cells are widely viewed as nothing more than slowly dying casualties of immunological self-tolerance, and as liabilities to the physiological immune system under circumstances where anergy might be reversed by costimulation or inflammation. To the contrary, we recently found that anergic B cells are potent regulators of immunity. Our initial observation was made upon a routine adoptive transfer involving anergic Ars/A1 B cells. Ars/A1 B cells express a dual-reactive transgenic BCR that binds the hapten p-azophenylarsonate (Ars) and single-stranded DNA, which stably maintains their anergic state upon adoptive transfer. We found that when wildtype adoptive recipients of Ars/A1 B cells were immunized with foreign proteins conjugated with Ars, not only did the Ars/A1 cells fail to mount an antibody response, they also profoundly inhibited the anti-Ars antibody response by the host immune system. This inhibition was systemic, potent (10-30 fold), antigen-specific, applied to the protein carrier, applied to the secondary immune response and required relatively few Ars/A1 B cells. On the basis of this discovery, we hypothesize that anergic B cells play a natural role in maintaining self-tolerance among CD4+ T cells. In this application, we propose to use the Ars/A1 model to define the regulatory capabilities of anergic B cells. The results of this project will almost certainly open new avenues of investigation that could lead to a paradigm shift, and to novel strategies to control autoimmunity and possibly transplant rejection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073945-05
Application #
8189786
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2007-12-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$382,239
Indirect Cost
$137,214
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
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