Autoantibodies are a characteristic of most autoimmune diseases and appear in the serum many years before the onset of clinical disease, suggesting an early break in B cell tolerance. An important role for B cells in some autoimmune diseases has been supported by successful treatment of patients with anti-CD20 monoclonal antibodies that eliminate B cells. The underlying mechanisms that account for autoreactive B cell and autoantibody production in autoimmune diseases are poorly defined. We analyzed B cell tolerance in untreated active rheumatoid arthritis (RA) and type 1 diabetes (T1D) patients by testing the specificity of recombinant antibodies cloned from single new emigrant and mature naive B cells. RA and T1D patients exhibit defective central and peripheral B cell tolerance checkpoints that result in the accumulation of selfreactive mature naive B cells, likely contributing to pathogenesis. The long range goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy humans but may be defective in patients with autoimmune diseases. The working hypothesis is that developing autoreactive B cells in patients with autoimmune diseases surfer from intrinsic defects that impinge on their proper counterselection in the bone marrow. In addition, defects in regulatory T cell functions and elevated BAFF levels may alter peripheral B cell tolerance and result in the abnormal recruitment and activation of autoreactive B cell clones.
The first aim of the project will consist of determining whether B cell tolerance defects in T1D persist after B cell depletion and may therefore predict patients'relapse. The second part of the project will analyze the development and involvement of autoreactive B cells in primary Sjogren's syndrome. The third part of the project will characterize the molecular basis for early defects in B cell tolerance checkpoints by analyzing the impact of known polymorphism that are protective or associated to the development of autoimmune diseases.

Public Health Relevance

Understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease. In particular, anti-B cell therapies, that are effective at blocking disease progression and have already received FDA approval for use in RA, may be useful for delaying or preventing the development of other autoimmune diseases such as T1D, pSS, and IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082713-04
Application #
8375229
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$191,695
Indirect Cost
$69,752
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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