B- and T-Cell Subset Abnormalities in Monogenic Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is a heterogeneous group of inborn errors of immunity characterized by reduced serum concentrations of different immunoglobulin isotypes. CVID is the most prevalent symptomatic antibody deficiency with a broad range of infectious and non-infectious clinical manifestations. Various genetic and immunological defects are known to be involved in the pathogenesis of CVID. Monogenic defects account for the pathogenesis of about 20-50% of CVID patients, while a variety of cases do not have a defined genetic background. Deficiencies in molecules of B cell receptor signaling or other pathways involving B-cell development, activation, and proliferation could be associated with monogenetic defects of CVID. Genetic defects damping different B cell developmental stages can alter B- and even other lymphocytes’ differentiation and might be involved in the clinical and immunologic presentations of the disorder. Reports concerning T and B cell abnormalities have been published in CVID patients, but such comprehensive data on monogenic CVID patients is few and no review article exists to describe the abrogation of lymphocyte subsets in these disorders. Hence, we aimed to review the role of altered B- and T-cell differentiation in the pathogenesis of CVID patients with monogenic defects.

Incidence, Management Experience and Characteristics of Patients with Giardiasis and Common Variable Immunodeficiency

“…Different genetic variants have been involved in the pathogenesis of CVID, but most patients do not have a specific genetic defect background [ 41 ]. The NGS analysis detected possible CVID-associated variants in two of our patients.…”

Common Variable Immunodeficiency and Selective IgA Deficiency: Focus on Autoimmune Manifestations and Their Pathogenesis

“…These monogenic defects result in abnormal B cell development at different stages, both in the lymph nodes and in the bone marrow, abnormal B cell activation, proliferation, and survival. Other genetic defects that have been identified affect T cells [30].…”

The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review

“…Historically, only 2–10% of CVID cases have had a recognised monogenic aetiology, with the rest either undiscovered or driven by oligogenic/polygenic mechanisms [ 15 , 16 , 17 ]. However, the advent and increased availability of more sophisticated genetic analysis has accelerated the discovery of new rare genetic variants, with recent papers identifying a monogenic cause in approximately 20–50% of CVID cases [ 18 , 19 , 20 ]. Genes that have been associated with monogenic CVID include ICOS , NFKB1 , NFKB2 , IKZF1 ( IKAROS ), TNFSF12 (TWEAK), TNFRSF13B (TACI), TNFRSF13C (BAFF-R), CTLA4 , CD19 , CD81 , CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), IL21 , IL21R , LRBA , PRKCD , PLCG2 , PIK3CD , PIK3R1 , VAV1 , RAC2 , BLK , and IRF2BP2 though diseases related to these are now considered distinct clinical entities, as in the case of activated Phosphoinositide 3-kinase δ syndrome (APDS) [ 17 , 21 ].…”

“…Indeed, monogenic causes of ‘CVID-like’ disorders are now excluded from the established CVID classification [ 7 ]. Nonetheless, the term ‘monogenic CVID’ is still used contemporaneously to denote CVID-like phenotypes driven by recognised deleterious monogenic variants, and retains validity as most CVID and CVID-like patients are indistinguishable in the clinical setting [ 20 ]. As this article is intended for a general immunological audience, ‘monogenic CVID’ remains a helpful way of characterising an important cohort in need of targeted genetic studies, and thus, will be used throughout this article.…”

“…More recent studies have removed monogenic CVID from their analyses and demonstrated signature B and T lymphocyte subset profiles, associated with different phenotypes, including infections only, autoimmune and a gastrointestinal/chronic enteropathy [ 24 ]. Various forms of monogenic CVID have also been investigated for lymphocyte subset profiles, and, if signature patterns are established, these could provide excellent indicators for further genetic testing in patients presenting with a CVID-like disorder [ 20 , 41 , 42 ].…”