1. Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations
- Author
-
Maria Antolin, Antoni Álvarez Fernández, Romina Dieli-Crimi, Clara Franco-Jarava, Roger Colobran, Ricardo Pujol-Borrell, Julio Velásquez, Laura Blasco, Mónica Martínez-Gallo, Xavier Molero, Ida Paramonov, Andrea Martín-Nalda, and Maria E. Semidey
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,Gastrointestinal Diseases ,Immunology ,Nod2 Signaling Adaptor Protein ,Disease ,Asymptomatic ,Proinflammatory cytokine ,Young Adult ,03 medical and health sciences ,Agammaglobulinemia ,NOD2 ,medicine ,Humans ,Immunology and Allergy ,Respiratory Tract Infections ,Cells, Cultured ,Immunodeficiency ,Sequence Deletion ,B-Lymphocytes ,business.industry ,Common variable immunodeficiency ,NF-kappa B ,Th1 Cells ,medicine.disease ,Phenotype ,Common Variable Immunodeficiency ,030104 developmental biology ,Primary immunodeficiency ,Cytokines ,Female ,Inflammation Mediators ,medicine.symptom ,business - Abstract
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 naive. 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.
- Published
- 2018