Exploring Monogenic, Polygenic, and Epigenetic Models of Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is the most frequent symptomatic inborn error of immunity (IEI). CVID is genetically heterogeneous and occurs in sporadic or familial forms with different inheritance patterns. Monogenic mutations have been found in a low percentage of patients, and multifactorial or polygenic inheritance may be involved in unsolved patients. In the complex disease model, the epistatic effect of multiple variants in several genes and environmental factors such as infections may contribute. Epigenetic modifications, such as DNA methylation changes, are also proposed to be involved in CVID pathogenesis. In general, the pathogenic mechanism and molecular basis of CVID disease are still unknown, and identifying patterns of association across the genome in polygenic models and epigenetic modification profiles in CVID requires more studies. Here, we describe the current knowledge of the molecular genetic basis of CVID from monogenic, polygenic, and epigenetic aspects.

Keywords: common variable immunodeficiency; etiology; inborn errors of immunity; primary immunodeficiency.

Figure 1

Proposed potential models as the origin of CVID disease. Monogenic: A condition that arises from a pathogenic mutation in a single gene, which can be either dominant or recessive. A monogenic mutation with classical Mendelian inheritance has been detected in a low percentage of CVID patients. Digenic: A genetic condition where mutations in two different genes are necessary to produce a specific phenotype. Oligogenic: A genetic condition that is influenced by minor defects in a limited number of genes. Polygenic: A hypothesized model for unsolved CVID patients is a polygenic model in which a genetic condition is influenced by multiple genes, each contributing a small and cumulative effect. Epigenetic: Another theory for unsolved cases of CVID is epigenetic dysfunction, such as modification in the DNA methylation pattern. Multifactorial: CVID may also be caused by multifactorial inheritance, and the effect of nonhereditary factors (such as gut microbiota) in developing CVID has been identified. Skewed X-inactivation (XCI): Skewed XCI involves the preferential inactivation of one of the two X chromosomes in females. In some women with CVID, the disease results from skewed XCI and highly penetrant gene variants on the X chromosome. Somatic variants: Somatic variants are mutations that occur in somatic cells and can play a significant role in the development of various diseases. A significantly greater prevalence of somatic mutations in the immune cells of CVID patients has been observed than in healthy individuals, potentially contributing to the development of this disorder. Figures were generated with BioRender (https://biorender.com/).

Figure 2

Development pathway of B cell and the role of CVID-related genes in each stage of development. RAC2 is a crucial Rho-GTPase for the process of differentiation of hematopoietic stem cells (HSC) to progenitor B cells (pro-B cells) and then pro-B cells to B-cell precursors (pre-B cells) [79]. Other essential genes during the process of differentiating pro-B cells into pre-B cells are TRNT1, IKZF1, PIK3CD, and PIK3R1 [3]. TNFRSF13C and TNFRSF12 participate in transitional to naive mature B-cell differentiation [80]. Afterward, CD19 complex (CD19, CD81, and CD21), ATP6AP1, and SH3KBP regulate selection and differentiation of naive B cells in peripheral lymphatic tissues [81]. Differentiation of naive mature B cells to germinal center (GCs) B cells and extrafollicular B cells is controlled by TNFRSF13B and MS4A1 gene, respectively [3]. Then, clonal expansion of B cells, CSR, and SHM occurs in the pathway of differentiation of B cells in the GCs, which proteins encoded by PTEN, PIK3CD, PIK3R1, NFKB1, NFKB2, and ARHGEF1 genes make a critical contribution in this pathway [3]. Eventually, the plasma cell differentiation from B cells is controlled by RAC2, APRIL, MOGS, SEC61A1, CTNNBL1, and IRF2BP2 genes [3]. Figures were generated with BioRender (https://biorender.com/).

Figure 3

Epigenetic defects in CVID. (a) DNA methylation defect: DNA methylation defect manifest as CpG hypermethylation and impaired demethylation majorly in memory B-cell subsets in CVID. It has been shown that a large number of the nearest genes to these CVID.no-demeth DMRs are upregulated in germinal center (GC) B cells or plasma cells (PCs) from healthy individuals and CVID.no-demeth DMRs are more highly enriched in active enhancer histone marks (H3K4me1 and H3K27ac) in GC B cells. This suggests that the CVID.no-demeth DMRs may contain functional genes relevant to B-cell activity [15, 83]. (b) Chromatin accessibility defect: In CVID, the dysregulation of chromatin accessibility occurs within a specific subset of memory B cells, resulting in some CVID-depleted and CVID-enriched regions. Motif enrichment of several TFs involved in enhancer regulation, such as BATF, IRF4, and CTCF has been described in CVID-depleted topics. Also, the association of CVID-depleted topics with active enhancers has been observed in GC B cells and PCs. These findings suggest that chromatin accessibility defects in CVID affect the regulatory elements essential for B-cell function [83]. (c) Differently expressed miRNA: Recent studies on the expression profiles of miRNAs have revealed that their expression is dysregulated in CVID. Additionally, the upregulation and downregulation of certain genes involved in the immune response have been observed to be associated with the dysregulation of miRNAs [–87]. The upward arrow indicates an increase in expression, while the downward arrow signifies a decrease. The dotted arrows illustrate the association of some dysregulated genes with miRNAs examined in the study. (d) DNA methylation in differentiation: During the normal differentiation of memory B cells, progressive demethylation takes place. But, in individuals with CVID, memory B cells show impaired DNA demethylation across the entire genome, leading to an increase in DNA methylation levels in these cells [83]. DMRs: differentially methylated regions, DARs: differentially accessible regions, CVID.no-demeth: no demethylated in CVID, CVID-depleted: less accessible DARs in CVID, CVID-enriched: more accessible DARs in CVID. Figures were generated with BioRender (https://biorender.com/).