# Induction of lupus-related autoantibodies by TNF inhibitors

> **NIH NIH U19** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $125,625

## Abstract

Project Summary/Abstract
 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.

## Key facts

- **NIH application ID:** 9903210
- **Project number:** 5U19AI144306-02
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Anne Davidson
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $125,625
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903210

## Citation

> US National Institutes of Health, RePORTER application 9903210, Induction of lupus-related autoantibodies by TNF inhibitors (5U19AI144306-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9903210. Licensed CC0.

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