Jie Yin MD , Kevin M. Hayes BS , Mei-Sing Ong PhD , Joseph P. Mizgerd ScD , Charlotte Cunningham-Rundles MD, PhD , Isabel Dominguez PhD , Sara Barmettler MD , Jocelyn R. Farmer MD, PhD , Paul J. Maglione MD, PhD
{"title":"常见的可变免疫缺陷临床表现是由杂合子NFKB1变异的存在和类型决定的。","authors":"Jie Yin MD , Kevin M. Hayes BS , Mei-Sing Ong PhD , Joseph P. Mizgerd ScD , Charlotte Cunningham-Rundles MD, PhD , Isabel Dominguez PhD , Sara Barmettler MD , Jocelyn R. Farmer MD, PhD , Paul J. Maglione MD, PhD","doi":"10.1016/j.jaip.2024.12.002","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div><em>NFKB1</em> encodes p105, which is processed to p50 to mediate canonical nuclear factor-κB (NF-κB) signaling. Although NF-κB is a central driver of inflammation and heterozygous <em>NFKB1</em> variants are considered the most common monogenic etiologies of common variable immunodeficiency (CVID), few studies have explored how <em>NFKB1</em> variants shape clinical course or inflammation in CVID.</div></div><div><h3>Objective</h3><div>We leveraged a regional cohort of patients with CVID with and without heterozygous <em>NFKB1</em> variants to assess how clinical and inflammatory features of CVID are shaped by the presence of these variants.</div></div><div><h3>Methods</h3><div>We compared clinical complications, immunologic features, and plasma cytokine levels of 15 patients with CVID with heterozygous <em>NFKB1</em> variants and 77 genetically undefined patients with CVID from the same referral base. We also assessed differences between patients with CVID with frameshift or nonsense <em>NFKB1</em> variants compared with those with missense <em>NFKB1</em> variants.</div></div><div><h3>Results</h3><div>We found patients with CVID with heterozygous <em>NFKB1</em> variants to have increased autoimmune disease, bronchiectasis, gastrointestinal infections, inflammatory bowel disease, and plasma cytokines. These findings were more pronounced and included elevation of monocytes in patients with CVID with frameshift or nonsense <em>NFKB1</em> variants relative to those with missense <em>NFKB1</em> variants.</div></div><div><h3>Conclusions</h3><div>In a regional cohort, heterozygous <em>NFKB1</em> variants were associated with worsened CVID clinical course and increased evidence of inflammation in the blood. Patients with CVID with frameshift or nonsense <em>NFKB1</em> variants had more significant increases in noninfectious complications and peripheral monocytes than those with missense <em>NFKB1</em> variants. Presence of pathogenic <em>NFKB1</em> variants in patients with CVID may worsen the disease course and warrant closer monitoring.</div></div>","PeriodicalId":51323,"journal":{"name":"Journal of Allergy and Clinical Immunology-In Practice","volume":"13 3","pages":"Pages 639-646"},"PeriodicalIF":8.2000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Common Variable Immunodeficiency Clinical Manifestations Are Shaped by Presence and Type of Heterozygous NFKB1 Variants\",\"authors\":\"Jie Yin MD , Kevin M. Hayes BS , Mei-Sing Ong PhD , Joseph P. Mizgerd ScD , Charlotte Cunningham-Rundles MD, PhD , Isabel Dominguez PhD , Sara Barmettler MD , Jocelyn R. Farmer MD, PhD , Paul J. Maglione MD, PhD\",\"doi\":\"10.1016/j.jaip.2024.12.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div><em>NFKB1</em> encodes p105, which is processed to p50 to mediate canonical nuclear factor-κB (NF-κB) signaling. Although NF-κB is a central driver of inflammation and heterozygous <em>NFKB1</em> variants are considered the most common monogenic etiologies of common variable immunodeficiency (CVID), few studies have explored how <em>NFKB1</em> variants shape clinical course or inflammation in CVID.</div></div><div><h3>Objective</h3><div>We leveraged a regional cohort of patients with CVID with and without heterozygous <em>NFKB1</em> variants to assess how clinical and inflammatory features of CVID are shaped by the presence of these variants.</div></div><div><h3>Methods</h3><div>We compared clinical complications, immunologic features, and plasma cytokine levels of 15 patients with CVID with heterozygous <em>NFKB1</em> variants and 77 genetically undefined patients with CVID from the same referral base. We also assessed differences between patients with CVID with frameshift or nonsense <em>NFKB1</em> variants compared with those with missense <em>NFKB1</em> variants.</div></div><div><h3>Results</h3><div>We found patients with CVID with heterozygous <em>NFKB1</em> variants to have increased autoimmune disease, bronchiectasis, gastrointestinal infections, inflammatory bowel disease, and plasma cytokines. These findings were more pronounced and included elevation of monocytes in patients with CVID with frameshift or nonsense <em>NFKB1</em> variants relative to those with missense <em>NFKB1</em> variants.</div></div><div><h3>Conclusions</h3><div>In a regional cohort, heterozygous <em>NFKB1</em> variants were associated with worsened CVID clinical course and increased evidence of inflammation in the blood. Patients with CVID with frameshift or nonsense <em>NFKB1</em> variants had more significant increases in noninfectious complications and peripheral monocytes than those with missense <em>NFKB1</em> variants. Presence of pathogenic <em>NFKB1</em> variants in patients with CVID may worsen the disease course and warrant closer monitoring.</div></div>\",\"PeriodicalId\":51323,\"journal\":{\"name\":\"Journal of Allergy and Clinical Immunology-In Practice\",\"volume\":\"13 3\",\"pages\":\"Pages 639-646\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2025-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Allergy and Clinical Immunology-In Practice\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S221321982401242X\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology-In Practice","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S221321982401242X","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
Common Variable Immunodeficiency Clinical Manifestations Are Shaped by Presence and Type of Heterozygous NFKB1 Variants
Background
NFKB1 encodes p105, which is processed to p50 to mediate canonical nuclear factor-κB (NF-κB) signaling. Although NF-κB is a central driver of inflammation and heterozygous NFKB1 variants are considered the most common monogenic etiologies of common variable immunodeficiency (CVID), few studies have explored how NFKB1 variants shape clinical course or inflammation in CVID.
Objective
We leveraged a regional cohort of patients with CVID with and without heterozygous NFKB1 variants to assess how clinical and inflammatory features of CVID are shaped by the presence of these variants.
Methods
We compared clinical complications, immunologic features, and plasma cytokine levels of 15 patients with CVID with heterozygous NFKB1 variants and 77 genetically undefined patients with CVID from the same referral base. We also assessed differences between patients with CVID with frameshift or nonsense NFKB1 variants compared with those with missense NFKB1 variants.
Results
We found patients with CVID with heterozygous NFKB1 variants to have increased autoimmune disease, bronchiectasis, gastrointestinal infections, inflammatory bowel disease, and plasma cytokines. These findings were more pronounced and included elevation of monocytes in patients with CVID with frameshift or nonsense NFKB1 variants relative to those with missense NFKB1 variants.
Conclusions
In a regional cohort, heterozygous NFKB1 variants were associated with worsened CVID clinical course and increased evidence of inflammation in the blood. Patients with CVID with frameshift or nonsense NFKB1 variants had more significant increases in noninfectious complications and peripheral monocytes than those with missense NFKB1 variants. Presence of pathogenic NFKB1 variants in patients with CVID may worsen the disease course and warrant closer monitoring.
期刊介绍:
JACI: In Practice is an official publication of the American Academy of Allergy, Asthma & Immunology (AAAAI). It is a companion title to The Journal of Allergy and Clinical Immunology, and it aims to provide timely clinical papers, case reports, and management recommendations to clinical allergists and other physicians dealing with allergic and immunologic diseases in their practice. The mission of JACI: In Practice is to offer valid and impactful information that supports evidence-based clinical decisions in the diagnosis and management of asthma, allergies, immunologic conditions, and related diseases.
This journal publishes articles on various conditions treated by allergist-immunologists, including food allergy, respiratory disorders (such as asthma, rhinitis, nasal polyps, sinusitis, cough, ABPA, and hypersensitivity pneumonitis), drug allergy, insect sting allergy, anaphylaxis, dermatologic disorders (such as atopic dermatitis, contact dermatitis, urticaria, angioedema, and HAE), immunodeficiency, autoinflammatory syndromes, eosinophilic disorders, and mast cell disorders.
The focus of the journal is on providing cutting-edge clinical information that practitioners can use in their everyday practice or to acquire new knowledge and skills for the benefit of their patients. However, mechanistic or translational studies without immediate or near future clinical relevance, as well as animal studies, are not within the scope of the journal.