# The Role of TNF in Breaking B Cell Tolerance

> **NIH NIH K01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $127,710

## Abstract

Dr. Quach's central goal is to acquire new skills that will establish her as a systems immunologist. The proposed
research combines murine and human studies to identify mechanisms by which TNF deficiency breaks tolerance.
The gained knowledge will guide future efforts in designing personalized medicine for autoimmune patients.
Candidate: Dr. Quach is an instructor at the Feinstein Institute for Medical Research (FIMR). Through her Ph.D
and post-doctoral work, she focused on the development and regulation of B cells in humans. The proposed
career development plan will build upon her previous experience with four training goals to enhance her trajectory
toward becoming an independent investigator: 1) gain expertise in utilizing mouse models; 2) become proficient
in computational biology; 3) gain insights into conducting clinically oriented research projects, and 4) build a
foundation of data and methodologies to generate predictive models.
Mentors/Environment: Dr. Quach and her mentor, Dr. Anne Davidson, have assembled a strong team of
advisors and collaborators to guide her through the proposed training and research activities. The proposed
project utilizes the intellectual, research and clinical facilities available at the FIMR and the resources available
through her external advisors and collaborators, Dr. Steven Kleinstein and Dr. Inaki Sanz. FIMR is committed to
support junior faculty members through internal grants and opportunities for networking and education. Dr.
Quach will attend national seminars/workshops when optimal training is not available locally.
Research: 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 study proposes that TNF deficiency, together with a second inducing
stimulus, compromises GC B cell selection via reduction of negative GC B cell signaling and enhancement of T
effector cell activities. To test this hypothesis, the first aim utilizes TNF deficient mice of 2 different backgrounds,
autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, to
determine the mechanism for the signaling defect in GC B cells that alters B cell selection, and how T cells help
to enhance this process. The second aim will address similar questions in TNFi treated patients using a novel
fluorescent reagent to detect and isolate ANA reactive B cells combined with next generation sequencing
technology. A combination of phenotyping and functional studies is used to determine T ce...

## Key facts

- **NIH application ID:** 9977378
- **Project number:** 1K01AR075097-01A1
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Tam D Quach
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $127,710
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977378

## Citation

> US National Institutes of Health, RePORTER application 9977378, The Role of TNF in Breaking B Cell Tolerance (1K01AR075097-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977378. Licensed CC0.

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