The Heterogeneous Pathogenesis of Selective Immunoglobulin A Deficiency

Abstract

Selective immunoglobulin A deficiency (SIgAD) is the most prevalent type of primary immunodeficiency disorder. The phenotypic feature of SIgAD is related to a defect in B lymphocyte differentiation into plasma cell-producing immunoglobulin A (IgA). In this review, we summarize the recent advances in this regard. Genetic (including major histocompatibility complex [MHC] and non-MHC genes), immunologic (including B and T lymphocyte subsets abnormality), cytokines/chemokines and their related receptors, apoptosis and microbiota defects are reviewed. The mechanisms leading to SIgAD are most likely multifactorial and it can be speculated that several pathways controlling B cells functions or regulating epigenetic of the IGHA gene encoding constant region of IgA heavy chain and long-term survival of IgA switched memory B cells and plasma cells may be defective in different SIgAD patients.

Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults

“…However, a fundamental defect in SIgAD seems to be impaired maturation of IgA-bearing B-cells into IgA-secreting plasma cells [ 29 ]. Moreover, studies have proven that IgA-deficient patients have defects in the process of IgA class switching recombination (CSR), production, as well as secretion of IgA, and long-term survival of IgA-switched memory B-cells and plasma cells, possibly due to an increased rate of apoptosis [ 30 , 31 , 32 ]. The latter leads to a paucity of B-cells secreting IgA both in the plasma and GI tract mucosa, in contrary to a healthy population [ 33 , 34 ].…”

“…Many authors suggested a role of impaired T-cell function in the development of SIgAD, as possibly defective antibody production or secretion may be due to dysfunction or decreased activity of different subpopulations of T-cells [ 30 , 36 ]. However, most of the studies concerning the role of T-cells in the pathogenesis of SIgAD are inconclusive.…”

“…Other important elements that likely account for the development of SIgAD are cytokines and their receptor milieu, as B-cell stimulation via this network is responsible for B-cell differentiation and CSR. Therefore, a combination of abnormalities in the cytokine pattern releasing at local sites of B-cell proliferation, or cytokine kinetics, can contribute to the failure of IgA production in SIgAD patients [ 30 ]. This involves transforming growth factor-beta (TGB-β) and downstream transcription factors, which indicates a key role in this process [ 39 ].…”

“…Another receptor participating in the process is CD40, which stimulates CSR by the T-cell-mediated pathway. T-cell-independent IgA CSR engages other receptors, cytokines, and transcription factors, which includes inter alia toll-like receptor, B-cell receptor (BCR), nitric oxide, retinoic acid, IL−6, TACI (transmembrane activator and CAML interactor), BAFF (B-cell activating factor), A proliferation-inducing ligand (APRIL), and thymic stromal lymphopoietin [ 30 ]. Defects in all the aforementioned particles can account for SIgAD.…”

“…Furthermore, abnormalities in several cytokines, including IL−4, IL−6, IL−7, IL−10, and most newly IL−21, has been found in SIgAD [ 29 , 40 , 41 ]. This cytokine profile may be changed due to the abnormalities of B-, T-, and dendritic cells (DCs) [ 30 ].…”