# Heterozygous NFKB1 variant causes inflammatory dysregulation shaped by broader genetic context in common variable immunodeficiency

## TL;DR

A genetic variant in NFKB1 contributes to severe inflammation in a type of immune deficiency, and targeting TNF can help reduce symptoms.

## Contribution

A novel approach using gene-edited stem cells reveals how a specific NFKB1 variant worsens inflammation in CVID patients.

## Key findings

- Heterozygous NFKB1 variant reduces NFKB1 protein and increases inflammatory gene expression in CVID patient monocytes.
- TNF antagonism reduced GI disease and neutrophilic markers in the patient with CVID.
- Inflammatory changes in CVID monocytes correlate with clinical response to treatment.

## Abstract

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary antibody deficiency. For unclear reasons, inflammatory complications, like gastrointestinal (GI) disease, occur in ~50% of CVID cases, worsening morbidity and mortality. NFKB1 variants are among the most frequent genetic variants in CVID. While effect of NFKB1 variants is not well understood, we previously found frameshift heterozygous NFKB1 variants to increase cytokines, monocytes, and inflammatory complications in CVID. In this report, we used induced pluripotent stem cell–derived (iPSC-derived) monocytes (iMONOs) with CRISPR/Cas9-mediated gene editing to study a heterozygous NFKB1 frameshift found in a patient with CVID with severe GI disease. The heterozygous NFKB1 variant similarly reduced NFKB1 protein in CVID patient– and healthy donor–derived iMONOs, but elevated LPS-induced IL-1β release and expression of inflammatory genes, including IL1B, IL6, TNF, and neutrophil chemoattractants, only in CVID patient iMONOs. CVID patient iMONOs also had elevations of IL-12, CCL4, and CCL12 unaffected by presence or absence of the NFKB1 variant. TNF antagonism improved the patient’s GI disease, diminishing neutrophilic gastritis, circulating neutrophils, and the neutrophil chemoattractant CXCL1 in the blood. While the biology remains complex, our approach found heterozygous NFKB1 variant–induced inflammatory changes intensified in CVID iMONOs, corresponding with clinical response to TNF antagonism.

This study uses induced pluripotent stem cells and targeted gene editing to understand how a frameshift NFKB1 variant promotes severe disease in common variable immunodeficiency.