Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations

Romina Dieli-Crimi, Mónica Martínez-Gallo, Clara Franco-Jarava, Maria Antolin, Laura Blasco, Ida Paramonov, Maria E. Semidey, Antoni Álvarez Fernández, Xavier Molero, Julio Velásquez, Andrea Martín-Nalda, Ricardo Pujol-Borrell, Roger Colobran

Research output: Contribution to journalArticleResearch

10 Citations (Scopus)

Abstract

© 2018 Elsevier Inc. Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1β TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.
Original languageEnglish
Pages (from-to)49-58
JournalClinical Immunology
Volume195
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Autoinflammation
  • Common Variable Immunodeficiency
  • Enteropathy
  • Next Generation Sequencing
  • NF-κB pathway
  • NFKB1
  • NOD2
  • Primary Immunodeficiency
  • Th1 cells

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