How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?

ABSTRACT

Introduction

Genetic defects affect the manner of the immune system’s development, activation, and function. Nuclear factor-kappa B subunit 1 (NF-κB1) and NF-κB2 are involved in different biological processes, and deficiency in these transcription factors may reveal clinical and immunological difficulties.

Areas covered

This review article gathers the most frequent clinical and immunological remarkable characteristics of NF-κB1 and NF-κB2 deficiencies. Afterward, an effort is made to describe the biological mechanism, which is likely to be the cause of these clinical and immunological abnormalities.

Expert opinion

The present review article has explained the mechanism of contributions of the NF-κB1 and NF-κB2 deficiency in revealing immunodeficiency symptoms, specifically immunological and clinical manifestations. These mechanisms demonstrate the importance of NF-κB1 and NF-κB2 signaling pathways for B and T cell development, activation, antibody production, and immunotolerance. The manifestation of a mutation can range from no symptoms to severe complications in a family.

Plain Language Summary

• NF-κB1 and NF-κB2 are the transcription factors that have an essential role in the development and function of the immune system. Several mutations in the NF-κBs could lead to inborn errors of immune manifestations.

• There are different reports of NF-κB mutations with various clinical and immunological manifestations, whereas the mechanisms behind the appearance of these have been less discussed. We collected frequent clinical and immunological manifestations from the literature and discussed the likely biological cause of their occurrence. Here we clarify the potential mechanism that defects in NF-κB1 and NF-κB2 signaling lead to inadequate B and T cells function, specifically, insufficient switched memory B cells and class-switched antibodies and autoimmunity. We also focused on the straight correlation between deficiencies in immune system responses caused by defects in NF-κB and susceptibility to recurrent infections and other clinical problems.

Since our understanding of the mechanisms of signaling pathways such as NF-κB deficiencies from genetic mutations to clinical manifestations in PIDs is limited, further in vitro and animal model studies are necessary to assess these pathways’ comprehensive roles in immunodeficiency more accurately.

KEYWORDS:

• Antibody deficiency
• common variable immunodeficiency
• inborn errors of immunity
• NF-κB1
• NF-κB2
• nuclear factor kappa B
• primary immunodeficiency

Article highlights

• Inborn errors of immunity (IEI) are sometimes severe with potentially life-threatening immune diseases or, in some cases, completely no symptoms.

• The monogenic mutations in transcription factors, nuclear factor-kappa B subunit 1 (NF-κB1) and NF-κB2, can lead to several clinical manifestations such as recurrent infections, autoimmune or inflammatory, and endocrinopathies specifically in NF-κB2 deficiency.

• Decreased rates of class-switched memory B cells and decreased at least two types of antibodies that are frequently observed in affected patients.

• The development, activation, and function of B and T lymphocytes may be affected by NF-κB1 and NF-κB2 mutations, leading to antibody deficiency, low switched memory B cell, and T cell-mediated autoimmunity.

Acknowledgments

The authors would like to thank Babak Mahmoudpour for helping to draw the article’s scheme.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

Inborn errors of immunity (IEI), nuclear factor-kappa B subunit 1 (NF-κB1), nuclear factor-kappa B subunit 2 (NF-κB2), Common variable immunodeficiency (CVID), Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2), Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Delta (PIK3CD), Phosphatase and tensin homolog (PTEN), SEC61 Translocon Subunit Alpha 1 (SEC61A1), TNF Superfamily Member 12 (TNFSF12), Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), IKAROS Family Zinc Finger 1 (IKZF1), Tumor necrosis factor (TNF), Activation-induced cytidine deaminase (AICDA), Rel homology domain (RHD), Inhibitors of NF-kB protein (IkB), Pattern recognition receptors (PRRs), B-cell receptors (BCR), T-cell receptors (TCR), Bone morphogenetic protein (BMP), Epidermal growth factor (EGF), Human growth hormone (HGH), Insulin, Nerve growth factor (NGF), Transforming growth factor-alpha (TGF-alpha), Leukotriene (LT), B-cell activating factor receptor (BAFF-R), Phosphorylation of NF-κB-inducing kinase (NIK), Inducible T cell co-stimulator (ICOS), Interleukin (IL-), TNF receptor (TNFR), Inhibitory of NF-κB kinases (IKKs), Chronic obstructive pulmonary disease (COPD), Idiopathic thrombocytopenic purpura (ITP), Autoimmune hemolytic anemia (AIHA), Combined immunodeficiency (CID), Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome, Adrenocorticotropic hormone (ACTH), Loss-of-function (LOF), Natural killer (NK), Immunoglobulin (Ig), European Society for Immunodeficiencies (ESID), Mucosa-associated invariant T (MAIT), T regulatory cells (Tregs), medullary thymic epithelial cells (mTEC), Nonsense-mediated mRNA decay (NMD), Ankyrin repeat domain (ARD), Common lymphoid progenitor (CLP), Hematopoietic stem cells (HSC), follicular (FO) or marginal zone (MZ), T cell-dependent (TD), T cell-independent (TI), Toll-like receptor (TLR), Class-switch recombination (CSR), Activation-induced deaminase (AID), NF-kB essential modulator (NEMO), Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID), Variant of uncertain significance (VUS), Binarized Scale Invariant Feature Transform (B-SIFT), Polyphen-2, BLOcks SUbstitution Matrix (BLOSUM), Combined Annotation-Dependent Depletion (CADD), Protein Variation Effect Analyzer (PROVEAN), Deep neural network (DNN), Phylogenetic p-values (PhyliP), and QIAGEN Clinical Insights (QCI), Electrophoretic mobility shift assays (EMSA), Germinal center (GC), B cell maturation antigen (BCMA), Plasma cell (PC), Interferon-γ (IFN-γ), Transforming growth factor-β (TGF-β), circulating follicular helper T (cTFH), Autoimmune regulator (AIRE).

Additional information

Funding

This paper was not funded.