# Mechanisms of immune dysregulation due to NFKB1 mutation in common variable immunodeficiency

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $206,250

## Abstract

Project Summary
Common variable immunodeficiency (CVID) is defined by severe antibody deficiency and is the most common
symptomatic primary immunodeficiency. While immunoglobulin (Ig) replacement therapy limits frequency and
severity of infections, chronic inflammation involving gastrointestinal (GI) tract, lungs, and other sites still occurs
in half of CVID patients. The mechanisms and optimal therapies for CVID with these complications (CVIDc)
remain elusive. Until we fill this gap in our knowledge, CVID morbidity and mortality persist at excessive levels.
The genetic cause of CVID is typically unknown, but heterozygous mutations of NFKB1 are most common (~4%).
NFKB1 encodes p105 which is processed into p50 to form NF-κB heterodimers that drive inflammatory gene
expression. Alternatively, unprocessed p105 inhibits NF-κB-mediated transcription. Elevation of type 1 (Th1)
cytokines and altered NF-κB signaling are defining, but unexplained, features of CVIDc. The most common
mutations in CVIDc involve NFKB1, but little is known about their effects. Beyond CVID, NFKB1 polymorphisms
associate with gastric cancer and NFKB1 knockout mice also develop gastritis. Along these lines, we found
NFKB1 mutation in a CVIDc patient with severe gastritis that improved, for unclear reasons, with TNF blockade.
Determining if NFKB1 mutation outside the p50 coding region increases type 1 cytokines and promotes gastritis
will close key knowledge gaps in CVIDc and deepen understanding of a pathway implicated in many diseases.
Our long-term goal is to devise therapy to precisely modulate NF-κB signaling to treat inflammatory disease. Our
short-term goal is to understand how NFKB1 variant location and nature of NF-κB dysfunction promotes CVIDc.
The central hypothesis is that mutation of NFKB1 sparing p50 increases type 1 cytokines and promotes gastritis
by impairing p105-mediated regulation. We will test our hypothesis with two specific aims (1) Test the hypothesis
that CVID NFKB1 variant location determines its effect upon NF-κB signaling and (2) Determine if p105
deficiency promotes TNF-driven neutrophilic gastritis using iPSC organoids. Results will identify pivotal features
of NF-κB dysfunction underlying CVIDc and thereby provide insights into a broadly relevant pathway of
inflammation. Our expertise in primary immunodeficiency and iPSC biology uniquely positions us to carry out
this proposal. Novelty of our project includes the ability to study rare NFBK1 variants alongside samples from a
biobank of 100+ CVID patients connected with clinical data, allowing us to elucidate aspects of NF-κB
dysfunction pivotal to NFKB1 variants and the larger population of genetically undefined CVIDc with a similar
cytokine and/or RNA sequencing profile. Thus, we will show how rare variants can empower research into
complex CVID etiologies. Also, as the first application of iPSCs to CVID, this R21 research project will provide a
foundational precedent that positions us to use this ap...

## Key facts

- **NIH application ID:** 10114969
- **Project number:** 5R21AI151486-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Paul Joseph Maglione
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $206,250
- **Award type:** 5
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114969

## Citation

> US National Institutes of Health, RePORTER application 10114969, Mechanisms of immune dysregulation due to NFKB1 mutation in common variable immunodeficiency (5R21AI151486-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114969. Licensed CC0.

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