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For unclear reasons, inflammatory complications, like gastrointestinal (GI) disease, occur in ~50% of CVID cases, worsening morbidity and mortality.\n                    <jats:italic>NFKB1<\/jats:italic>\n                    variants are among the most frequent genetic variants in CVID. While effect of\n                    <jats:italic>NFKB1<\/jats:italic>\n                    variants is not well understood, we previously found frameshift heterozygous\n                    <jats:italic>NFKB1<\/jats:italic>\n                    variants to increase cytokines, monocytes, and inflammatory complications in CVID. In this report, we used induced pluripotent stem cell\u2013derived (iPSC-derived) monocytes (iMONOs) with CRISPR\/Cas9-mediated gene editing to study a heterozygous\n                    <jats:italic>NFKB1<\/jats:italic>\n                    frameshift found in a patient with CVID with severe GI disease. The heterozygous\n                    <jats:italic>NFKB1<\/jats:italic>\n                    variant similarly reduced NFKB1 protein in CVID patient\u2013 and healthy donor\u2013derived iMONOs, but elevated LPS-induced IL-1\u03b2 release and expression of inflammatory genes, including\n                    <jats:italic>IL1B<\/jats:italic>\n                    ,\n                    <jats:italic>IL6<\/jats:italic>\n                    ,\n                    <jats:italic>TNF<\/jats:italic>\n                    , 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\n                    <jats:italic>NFKB1<\/jats:italic>\n                    variant. TNF antagonism improved the patient\u2019s GI disease, diminishing neutrophilic gastritis, circulating neutrophils, and the neutrophil chemoattractant CXCL1 in the blood. While the biology remains complex, our approach found heterozygous\n                    <jats:italic>NFKB1<\/jats:italic>\n                    variant\u2013induced inflammatory changes intensified in CVID iMONOs, corresponding with clinical response to TNF antagonism.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.198703","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T19:27:46Z","timestamp":1774726066000},"source":"Crossref","is-referenced-by-count":2,"title":["Heterozygous NFKB1 variant causes inflammatory dysregulation shaped by broader genetic context in common variable immunodeficiency"],"prefix":"10.1172","volume":"11","author":[{"given":"Kevin M.","family":"Hayes","sequence":"first","affiliation":[{"name":"Pulmonary Center and Section of Pulmonary, Allergy, Sleep and Critical Care, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, 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