We will determine the sites, developmental stages and mechanisms of B cell tolerance, concentrating on tolerance to those self-antigens that are the targets of disease-associated autoantibodies. The autoantibodies of interest are those that arise spontaneously in systemic autoimmune disease and include anti-dsDNA, anti-ssDNA, anti-Sm and RF. To enhance our ability to study the regulation of B cells expressing these autoantibodies, we will determine whether regulation is manifested by deletion, anergy or receptor editing; the stage B cell development or differentiation at which regulation takes place; and the mechanism by which regulation is carried out. These objectives can be achieved with a new mouse model, site directed transgenics. Here variable region genes coding for autoantibodies are introduced into their normal genomic context. These variable region genes are subject to the normal processes and regulatory elements of antibody genes, and they lead to highly enriched populations of autoreactive B-cells. How normal mice recognize and regulate these populations can be readily studied. Our ultimate goal is to know why normal mechanisms of B-cell tolerance fail in autoimmune disease. Comparison of transgene regulation in autoimmune and non-autoimmune strains of mice will identify what forms of regulation are defective and the stage(s) at which the defect is manifested. Knowing why these prominent autoantibodies are deregulated will provide a comprehensive understanding of loss of self-tolerance in systemic autoimmunity. The detailed understanding of how self-antigens interact with each of these autoantibodies will direct approaches for restoring regulation in autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM020964-24
Application #
2021725
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1977-01-01
Project End
2001-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
24
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Kalinina, Olga; Wang, Yue; Sia, Kevin et al. (2014) Light chain editors of anti-DNA receptors in human B cells. J Exp Med 211:357-64
Schoettler, Nathan; Ni, Dongyao; Weigert, Martin (2012) B cell receptor light chain repertoires show signs of selection with differences between groups of healthy individuals and SLE patients. Mol Immunol 51:273-82
Meng, Wenzhao; Yunk, Lenka; Wang, Li-San et al. (2011) Selection of individual VH genes occurs at the pro-B to pre-B cell transition. J Immunol 187:1835-44
Kalinina, Olga; Doyle-Cooper, Colleen M; Miksanek, Jennifer et al. (2011) Alternative mechanisms of receptor editing in autoreactive B cells. Proc Natl Acad Sci U S A 108:7125-30
Louzoun, Yoram; Vider, Tal; Weigert, Martin (2006) T-cell epitope repertoire as predicted from human and viral genomes. Mol Immunol 43:559-69
Witsch, Esther J; Cao, Hong; Fukuyama, Hidehiro et al. (2006) Light chain editing generates polyreactive antibodies in chronic graft-versus-host reaction. J Exp Med 203:1761-72
Chen, Ching; Li, Hui; Tian, Qi et al. (2006) Selection of anti-double-stranded DNA B cells in autoimmune MRL-lpr/lpr mice. J Immunol 176:5183-90
Li, Yijin; Louzoun, Yoram; Weigert, Martin (2004) Editing anti-DNA B cells by Vlambdax. J Exp Med 199:337-46
Li, Yijin; Li, Hui; Ni, Dongyao et al. (2002) Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern. J Exp Med 196:1543-52
Detours, V; Mehr, R; Perelson, A S (2000) Deriving quantitative constraints on T cell selection from data on the mature T cell repertoire. J Immunol 164:121-8

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