The molecular basis of autoimmunity remains largely unknown. One hypothesis is that molecular abnormalities in the means by which the B cell immunoglobulin receptor is assembled or subsequently selected play a role in the tendency to develop autoantibodies. To examine this possibility, a technique has been developed to analyze the B cell receptor expressed by individual B cells without bias. Using this technique, the B cell repertoire expressed by normal individuals has been analyzed in detail. This normal data base has been employed for comparison to determine abnormalities in patients with autoimmune disease. The objective of the current study is to use single cell analysis to delineate the nature of abnormalities in the B cell immunoglobulin repertoire that might underlie autoimmune disease. The B cell repertoire of patients with systemic lupus erythematosus and Sjogrens's syndrome have been analyzed. The lupus repertoire shows distinct abnormalities, including evidence of enhanced mutational activity, increased receptor editing/revision and clonal expansion, consistent with intense T cell dependent stimulation. By contrast, the B cell repertoire of Sjogren's syndrome patients showed different abnormalities, including restriction of the repertoire, no enhanced mutational activity and limited receptor editing, as well as a pattern of mutations consistent with intense T cell independent stimulation. In neither disease was evidence of molecular abnormalities in receptor assembly obtained. Rather, the data are most consistent with distinct abnormalities in peripheral B cell stimulation, resulting in autoimmunity in these two autoimmune diseases. The capacity to analyze the B cell repertoire without bias has provided new insights into the nature of the abnormalities that predispose to autoimmunity. In systemic lupus erythematosus, intense T cell dependent stimulation appears to overwhelm normal mechanisms preventing autoimmunity, leading to the escape of B cells producing pathogenic autoantibodies. In Sjogren's syndrome, T cell independent B cell activation with ineffective receptor editing appears to result in the emergence of autoantibody formation.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
Department
Type
DUNS #
City
State
Country
United States
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