# Loss of B Cell Tolerance in Primary Immune Deficiency

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $448,939

## Abstract

Patients with primary immunodeficiency diseases (PID) often develop autoimmune complications and therefore
provide rare opportunities to study the impact of specific gene mutations on the regulation of B-cell tolerance
defective in patients with autoimmune diseases. The C104R and A181E mutations in the TNFRSF13B gene
encoding TACI are associated with the development of common variable immunodeficiency disease (CVID)
with autoimmune complications. We previously reported that mutations in TNFRSF13B gene impact B cell
tolerance at 2 distinct steps during B cell development; they interfere with the removal of developing
autoreactive B cells in the bone marrow and TACI mutations also induce the secretion of anti-nuclear
antibodies (ANAs). Our latest investigation revealed that TNFRSF13B hemizygosity does not affect B cell
tolerance, suggesting that the common C104R and A181 TACI mutations may encode dominant negative
products. However, it remains unclear why TACI is required for B cell tolerance and how this molecule may
contribute to self-antigen sensing during the central counterselection of developing autoreactive B cells or to
ANA secretion in the periphery.
The goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy
subjects but may be defective in patients with autoimmune diseases. The working hypothesis is that TACI is
required for B cell tolerance because it mediates in B cells the tolerogenic function of Toll-like receptors
(TLRs), which control the removal of developing autoreactive B cells in the marrow and the periphery when co-
triggered with B-cell receptors (BCRs). We will also further characterize the pathways integrating BCR and
TLR/TACI signaling required for B cell tolerance by analyzing additional PID patients with novel gene
mutations.

## Key facts

- **NIH application ID:** 9984943
- **Project number:** 5P01AI061093-16
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Eric Meffre
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,939
- **Award type:** 5
- **Project period:** 2004-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984943

## Citation

> US National Institutes of Health, RePORTER application 9984943, Loss of B Cell Tolerance in Primary Immune Deficiency (5P01AI061093-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984943. Licensed CC0.

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