This application is designed to test the """"""""receptor presentation"""""""" hypothesis as a mechanism for recruiting autoreactive B lymphocytes in systemic lupus erythematosus (SLE). There is a growing body of evidence, even from studies of Ig transgenic animal models, that spontaneous recruitment of autoreactive B cells in SLE is a rare clonal event. Novel data from this laboratory have associated recruitment with the acquisition of somatic mutations that produce class II MHC-restricted epitopes in Ig V regions. This finding is reinforced by evidence from others, indicating that peptides from autoreactive V regions are immunogenic and may influence disease in autoimmune-prone mice. Accordingly, we propose that autoreactive B cells in SLE are recruited by T helper cells that are specific for peptide epitopes, derived from somatically-altered segments of the B cell receptor that are self-presented by class II MHC on the B cell surface. To test the receptor presentation hypothesis, we will identify and determine the functional significance of somatic mutations that are shared by members of large autoreactive hybridoma lineages. A specialized mouse will be generated to permit identification and evaluation of all somatic mutations in autoreactive clones, and thus provide a firm test of the hypothesis and plausible alternatives. The premise that T cells from autoimmune-prone mice attain a state of tolerance to germline-encoded antibody V region peptides will be examined. And we will generate a novel transgenic animal in which a reproducible, clonally defined autoantibody response can occur, so that B cell recruitment can be systematically studied and experimentally manipulated, with all of the power historically applied to studies of anti-hapten immune responses. The information obtained from, and model systems generated by, this work will significantly advance our capabilities and comprehension of elusive events that initiate B cell clonal expansion in SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048108-03
Application #
6632439
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Esch, Thomas R
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$304,200
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
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Liu, Xiaohe; Wysocki, Lawrence J; Manser, Tim (2007) Autoantigen-B cell antigen receptor interactions that regulate expression of B cell antigen receptor Loci. J Immunol 178:5035-47
Guo, Wenzhong; Smith, Diana; Guth, Amanda et al. (2005) T cell tolerance to germline-encoded antibody sequences in a lupus-prone mouse. J Immunol 175:2184-90
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Guth, Amanda M; Zhang, Xianghua; Smith, Diana et al. (2003) Chromatin specificity of anti-double-stranded DNA antibodies and a role for Arg residues in the third complementarity-determining region of the heavy chain. J Immunol 171:6260-6