The goal of the Project 2 of the SLE SCOR is to investigate the mechanism whereby the lupus autoimmune response is initiated and propagated, leading to renal and salivary gland immunopathology. The study will use, as a model lupus autoantigen (Ag), mouse Ro60. The central hypothesis is: systemic autoimmune disease like SLE can result from the single pivotal event of a strong and persistent T cell response to a foreign or unrelated self peptide that mimics the target self T cell peptide. It is supported by the following observations. Through sharing of a critical residue motif with self peptide, a foreign T cell peptide induces autoimmune response and disease. Once triggered, the helper T cell response is rapidly followed by an autoantibody (autoAb) response that is diversified to distant epitopes. The diversified autoAb response, which depends on the presence of endogenous Ag, can be adoptively transferred by Ro60 specific T cell line, and cause SLE-like renal immunopathology. Moreover, the neonatal period is most susceptible to induction of autoAb response and epitope spreading. The project has three Specific Aims:
The first Aim will study the nature of T cell response that mediates autoAb production, resulting in renal and salivary gland pathology. Mouse Ro60 specific T cell clones will be made, their cognate Ro60 peptide, their phenotype and ability to adoptively transfer autoAb and disease defined. The genes encoding the Ro60 T cell receptor (TCR) will be cloned and used to generate TCR transgenic mice. The transgenic mice will be studied for spontaneous autoAb and pathology. To further enhance and dissect the autoimmune response, the mice will be manipulated, as follows: 1) non- transgenic T cell elimination by rendering the mice RAG or TCR-V alpha deficient, 2) to stimulate with adjuvant, 3) to be made B cell deficient, 4) infusion of recombinant mouse Ro60 or apoptotic cell nuclei, and 5) study the responses of normal mice given a finite number of transgenic T cells.
The second Aim will study the response of neonatal mice to the Ro60 T cell epitope. We will fully characterize the neonatal Th2-dominant T cell autoimmune response and memory to self Ag; and determine whether this will lead to Ro60 autoAb response through epitope spreading, and renal immunopathology.
The third Aim will study the mechanisms of molecular mimicry in SLE. To address whether self B cell activation is the initiating event, we will immunize mice with chimeric peptides containing native Ro60 B cell epitope and foreign T cell peptide, and study T cell response to Ro60, autoAb diversification and disease. Finally, mimicry at the Ro60 T cell epitope through sharing of critical residue motif will be investigated.

Project Start
2000-07-01
Project End
2001-06-30
Budget Start
Budget End
Support Year
3
Fiscal Year
2000
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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