Although it is widely accepted that B cells with self-reactivity are deleted or rendered functionally inactive, self-reactive antibodies, referred to as """"""""natural autoantibodies,"""""""" can be found in the serum of healthy animals, in an apparent paradox to the clonal tolerance theory. An anti-thymocyte/T cell autoantibody (ATA) encoded by VH36O9/VK 21C germline genes is such a natural antibody, derived from CD5+ B cells (B-1) in mice, the population predominantly responsible for natural autoantibody secretion. ATA recognizes a developmentally regulated T cell specific carbohydrate epitope on the Thy-l/CD90 glycoprotein expressed on thymocytes and helper T cells. Our previous work with VH36O9mu transgenic mice (ATAmuTg) demonstrated that the generation of ATA B cells and the secretion of serum ATA required self-antigen, since both were absent from Thy-1 knockout mice. In contrast, forced expression of ATA specificity by the bone marrow B cells in VH36O9mu/VK29C double transgenic mice (ATAmuKTg) results in predominantly negative selection as our recent study suggests. Here we propose to investigate why this positive versus negative selection occurs. By characterizing VH36O9mu/VK29C double transgenic mice (ATAmuKTg), we will identify the developmental stage(s) of B cell positive/negative selection (Aim 1). To investigate if the antigen form is critical for positive/negative selection, we will establish Thy-1 transgenic mouse lines expressing either transmembrane or secreted Thy-1 (Aim 2) In Aim 3 we will test whether positive selection is a unique feature of fetal """"""""B-1"""""""" B cell development, selecting in favor of natural autoreactive specificities. The possibility of differences in selection threshold between """"""""B-1"""""""" versus """"""""B-2"""""""" B cell development will be tested (Aim 3). Accomplishing these aims will help to establish a more complete picture of antigen receptor repertoire selection in B cell development and will test our hypothesis that natural autoreactive B cell generation is a part of the innate immune system. """"""""B-1"""""""" may actively produce certain autoreactive B cells essential for immune protection, preserving important lymphocyte clones for the rest of life to serve in immunologic surveillance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049335-05
Application #
7033082
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Nasseri, M Faraz
Project Start
2002-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$448,073
Indirect Cost
Name
Institute for Cancer Research
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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