Innate Mechanisms in Selective IgA Deficiency

Abstract

Selective IgA deficiency (SIgAD), characterized by a serum IgA level below 0.07 mg/ml, while displaying normal serum levels of IgM and IgG antibodies, is the most frequently occurring primary immunodeficiency that reveals itself after the first four years after birth. These individuals with SIgAD are for the majority healthy and even when they are identified they are usually not investigated further or followed up. However, recent studies show that newborns and young infants already display clinical manifestations of this condition due to aberrancies in their immune defense. Interestingly, there is a huge heterogeneity in the clinical symptoms of the affected individuals. More than 50% of the affected individuals do not have clinical symptoms, while the individuals that do show clinical symptoms can suffer from mild to severe infections, allergies and autoimmune diseases. However, the reason for this heterogeneity in the manifestation of clinical symptoms of the individuals with SIgAD is unknown. Therefore, this review focusses on the characteristics of innate immune system driving T-cell independent IgA production and providing a mechanism underlying the development of SIgAD. Thereby, we focus on some important genes, including TNFRSF13B (encoding TACI), associated with SIgAD and the involvement of epigenetics, which will cover the methylation degree of TNFRSF13B, and environmental factors, including the gut microbiota, in the development of SIgAD. Currently, no specific treatment for SIgAD exists and novel therapeutic strategies could be developed based on the discussed information.

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

“…The TNFRSF13B and TNFRSF13C genes also provided variants illustrating the often complicated and unclear genotype-phenotype correlations. Indeed, mutations of the former gene, also known as TACI, though rare, have already shown to vary between disease susceptibility and pathogenesis, with clinical presentation ranging from unaffected to severe immunodeficiency and also occurring in healthy controls [49,52,53]. Nonetheless, asymptomatic family members have been reported with detectable in vitro B cell defects, thus suggesting that the penetrance of some mutations could be higher in cells than for the clinical phenotype [54].…”

IgA Vasculitis: Etiology, Treatment, Biomarkers and Epigenetic Changes

“…These two different actions of IgA against pathogens are important for host defense against pathogens. Indeed, IgA deficiency is known to result in insufficient host defense action against pathogens, leading to the frequent onset of infectious diseases, suggesting that the characteristics of high affinity but no high specific reaction of IgA play a crucial role in the host defense [ 21 ].…”

The Epidemiology and Clinical Presentations of Atopic Diseases in Selective IgA Deficiency

“…T reg cells colonize the intestinal mucosa where they produce TGF-beta and IL-10, which are essential in the production of IgA. Reduced amount of T reg negatively affects the amount of IgA + B lymphocytes, and restoration of the correct amount of T reg , consequently, restores normal IgA production in the intestines [50][51][52] Interestingly, according to the meta-analysis by Bronson et al there is a multiple gene linkage between the "Intestinal Immune Network for IgA production" and "T reg " [53]. Besides, the highest levels of APRIL (a proliferation-inducing ligand), which is connected with IgA-synthesis as a compensatory mechanism, are observed in patients with sIgAD [20,54].…”