Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

Abstract

Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by hypogammaglobulinaemia, impaired production of specific antibodies after immunisation and increased susceptibility to infections. CVID shows a considerable phenotypical and genetic heterogeneity. In contrast to many other primary immunodeficiencies, monogenic forms count for only 2-10% of patients with CVID. Genes that have been implicated in monogenic CVID include ICOS, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), IL21, IL21R, LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R1, VAV1, RAC2, BLK, IKZF1 (IKAROS) and IRF2BP2. With the increasing number of disease genes identified in CVID, it has become clear that CVID is an umbrella diagnosis and that many of these genetic defects cause distinct disease entities. Moreover, there is accumulating evidence that at least a subgroup of patients with CVID has a complex rather than a monogenic inheritance. This review aims to discuss current knowledge regarding the molecular genetic basis of CVID with an emphasis on the relationship with the clinical and immunological phenotype

The immunophenotypic fingerprint of patients with primary antibody deficiencies is partially present in their asymptomatic first-degree relatives

“…[20][21][22][23] A multifactorial basis in the majority of CVID, and in extension PAD, would explain the vast variations in the clinical and immunological landscape seen in these patients. 2,14 The immunophenotypic characteristics found in our CVID group are comparable to those reported previously in the literature: increased naïve and transitional B cells, CD21 37,38 and decreased CCR7 expression on T cells, especially on cTfh cells. 38,39 It should be noted that the observed reduction of BAFF-R in CVID might be an overestimation because BAFF-R expression levels are lower on CD27 -B cells, the predominant B-cell subset in these patients.…”

“…3,15,16 Monogenic defects have only been identified in a minority of cases with CVID. 14 Remarkably, some relatives with the same monogenic defect were found to be asymptomatic or suffer from a milder PAD phenotype such as IgGSD. [20][21][22][23] A multifactorial basis in the majority of CVID, and in extension PAD, would explain the vast variations in the clinical and immunological landscape seen in these patients.…”

Transcriptome analysis of bronchoalveolar lavage fluid from children with severe Mycoplasma pneumoniae pneumonia reveals novel gene expression and immunodeficiency

“…TNFRSF13C (tumor necrosis factor receptor superfamily member 13C) encodes a receptor for BAFF (B cell activating factor), which enhances B cell survival in vitro and regulates the peripheral B cell population. TNFRSF13C is a principal receptor required for BAFF-mediated mature B cell survival and it has been reported to be associated with common variable immunodeficiency [45]. In our study, significantly decreased expression levels of CD79A , AICDA , CD19 , and TNFRSF13C have been observed in the BALF of the severe MPP group comparing to the mild MPP group.…”

Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations

“…Although diagnosis is characterized by low levels of immunoglobulins, a significant fraction of patients suffer from complications, some of which are autoimmune in nature including enteropathy and cytopenias. 1,2 The use of exome and genome sequencing has identified an increasing number of genes that are associated with CVID, 3,4 however, this raises the issue of determining whether individual mutations in such genes are functionally significant. Accordingly, functional dissection is required in order to validate the impact of gene mutations.…”