The induction of autoantibody and autoimmunity in patients treated with TNF inhibitors is well-known; however, the mechanism by which these drugs breach B cell tolerance is yet to be determined. TNF inhibitors paradoxically cause loss of germinal centers, sites where autoantibodies are often generated. Germinal centers are pivotal for high affinity antigen-specific antibody production and negative selection of autoreactive B cells. In mice and humans, TNF and TNFR1 deficiencies disrupt germinal center formation but they also induce TFH cell expansion, and alter autoantibody profiles. This study proposes that TNF inhibition will compromise B cell extrafollicular selection and induce germline-encoded anti-nuclear autoantibodies in a large proportion of treated patients making them susceptible to autoimmune complications. Secondary insults, including genetic polymorphisms, T cell dysfunction and innate stimuli occur less frequently and may induce class switched and mutated lupus-related autoantibodies; this progresses to secondary clinical disease in only a small subset of treated patients. To test this hypothesis, we will, in collaboration with other ACE members, study the effects TNF inhibitors on autoreactivity in patients with inflammatory arthritis that develop either non-specific anti-nuclear antibodies or lupus-related autoantibodies.
Our first aim will determine how the phenotype of ANA specific B cells and activated T cells is altered by TNF inhibitors and will ask whether the development of lupus-related autoantibodies is associated with a particular B or T cell phenotype either before or after treatment. B cell phenotyping will be performed in collaboration with the Principal Project using a novel fluorescent reagent developed by the Diamond lab that can highly enrich for ANA positive B cells. T cell phenotyping will be performed in collaboration with the Pilot Project.
Our second aim will determine the mechanism of induction of lupus-related autoantibodies by TNF inhibition by examining the immunoglobulin repertoire of plasma cells (both ANA+ and ANA- obtained before and after treatment) sorted from subjects that develop non-specific ANAs and subjects that develop lupus-related specificities. Read outs that may be associated with loss of tolerance include clonal expansion, clonal restriction, enhanced somatic mutation, class switching to the IgG isotype, evidence of antigen driven selection pressure, and altered selection either of the V regions or of the CDR region of the heavy chain. Overall, this study should enhance our understanding of how a commonly used drug that inhibits germinal center formation paradoxically induces autoimmunity. The feasibility of our study will be greatly enhanced by the ACE mechanism that will allow us to screen large numbers of patients starting TNF inhibitors and to collaborate with other groups that have extensive expertise in analyzing the B cell repertoire.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI144306-01
Application #
9730913
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2019-05-01
Project End
2024-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030