ABSTRACT
Introduction
Inborn errors of immunity (IEIs) refer to a heterogeneous category of diseases with defects in the number and/or function of components of the immune system. Immunoglobulin A (IgA) deficiency is the most prevalent IEI characterized by low serum level of IgA and normal serum levels of IgG and/or IgM. Most of the individuals with IgA deficiency are asymptomatic and are only identified through routine laboratory tests. Others may experience a wide range of clinical features including mucosal infections, allergies, and malignancies as the most important features. IgA deficiency is a multi-complex disease, and the exact pathogenesis of it is still unknown.
Areas covered
This review compiles recent research on genetic and epigenetic factors that may contribute to the development of IgA deficiency. These factors include defects in B-cell development, IgA class switch recombination, synthesis, secretion, and the long-term survival of IgA switched memory B cells and plasma cells.
Expert opinion
A better and more comprehensive understanding of the cellular pathways involved in IgA deficiency could lead to personalized surveillance and potentially curative strategies for affected patients, especially those with severe symptoms.
Article highlights
Immunoglobulin A deficiency is the most frequent type of inborn errors of immunity (IEIs) characterized by a low serum level of IgA along with normal serum levels of IgG and/or IgM.
Although the majority of these patients are asymptomatic, the remaining patients present a wide range of clinical features. A better understanding of the underlying mechanisms of IgA deficiency could help physicians in earlier diagnosis and management of this high percentage of IEI patients, thus improving quality of life and survival.
To date, the exact pathogenesis of IgA deficiency has not been clearly understood, however several human leukocyte antigen (HLA) haplotypes and genes are found to be involved in the development of IgA deficiency.
The most commonly found HLA haplotypes among IgA-deficient individuals include HLA-B * 08- DRB1 × 0301-DQB1 × 02, HLA-B * 14-DRB1 × 0102-DQB1 × 05 and HLA-B * 44-DRB1 × 0701.
Defects in genes encoding factors involved in various steps of B-cell development, IgA class switch recombination (CSR), synthesis and secretion along with long-term survival of IgA switched memory B cells and plasma cells are associated with the development of IgA deficiency. Therefore, considering these genes as candidates for targeted sequencing could help in the timely diagnosis of monogenic individuals with suspected IgA deficiency, improving patient diagnosis, management, quality of life and survival.
Of interest, epigenetic modifications are shown to have pivotal roles in gene expression, B cell development, and the regulation of B cell CSR, somatic hypermutation, plasma cell differentiation, and memory B cells’ generation. Several IEIs with defects in genes responsible for the epigenetic control of cellular identity and function are reported to correlate with IgA deficiency in a number of patients.
Author contributions statement
S Fekrvand contributed through the acquisition and interpretation of the literature and wrote the first draft. H Abolhassani contributed to the article design and the revision of the article. N Rezaei contributed to the conception of the article, revised the article and supervised the whole project. All the authors approved of the version to be published and agreed to be accountable for all aspects of the work.
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.