# TNF deficiency induces breach of B cell tolerance via altering B cell regulatory signals

> **NIH NIH R03** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2022 · $83,750

## Abstract

PROJECT SUMMARY
The induction of autoantibody and autoimmunity in patients treated with TNF inhibitors (TNFi) is well-known;
however, the mechanism by which TNFi induce breach of B cell tolerance is yet to be determined. In humans,
TNFi affect B and T cell homeostasis via disruption of germinal center (GC) formation which is pivotal for high
affinity antigen-specific antibody production and negative selection of autoreactive B cells. Similarly, in mice,
TNF signaling deficiency prevents GC formation, induces TFH and CD4+IL-17 producing cell expansion, and
alters autoantibody profiles. This small focused study proposes that TNF deficiency, together with a second
inducing stimulus, compromises B cell selection via reduction of negative B cell signaling and enhancement of
T effector cell activities. To test this hypothesis, the first aim utilizes: 1) TNF deficient mice of 2 different
backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double
deficient mice, and 2) Sle1.TNF-/-.Yaa, in which male mice over express TLR7, to determine the mechanism for
the signaling defect of activated B cells that alters B cell selection via either GC and/or extrafollicular pathway.
The second aim will address similar questions in TNFi treated patients by identifying changes in CD22 binding
dynamics which thereby affect BCR signaling in autoreactive B cells. This aim is made possible due to the
development of the novel ANA reagent that identify enriched autoreactive B cells in both humans and mice. The
results from this study will elucidate the effects of TNFi on regulating B cell tolerance and improve our
understanding of how the immune system regulates B cell tolerance in GC and extrafollicular pathways.

## Key facts

- **NIH application ID:** 10432124
- **Project number:** 5R03AI156516-02
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Tam D Quach
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $83,750
- **Award type:** 5
- **Project period:** 2021-06-16 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432124

## Citation

> US National Institutes of Health, RePORTER application 10432124, TNF deficiency induces breach of B cell tolerance via altering B cell regulatory signals (5R03AI156516-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10432124. Licensed CC0.

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