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.

Keywords: B cell subsets; CVID; T cell subsets; common variable immunodeficiency disorder; inborn errors of immunity; monogenic disorders; primary immunodeficiency.

Figure 1

The development pathway of B cells and genes involved in each stage; mutation of these genes leads to monogenic CVID. RAC2 encodes a protein that is involved in the differentiation of stem cells to pro-B cells, as well as pro-B cells to pre-B cells. Differentiation of pro-B cells to pre-B cells is further regulated by proteins encoded by the IKZF1, PIK3R1, PIK3CD and TRNT1 genes. BAFFR and TWEAK encode proteins involved in differentiation of transitional B cells to naϊve mature B cells. Then, naϊve mature B cells undergo selection and enter peripheral lymphoid tissues that is regulated by proteins encoded by the CD19, CD21, CD81, SH3KBP1 and ATP6AP1 genes. TACI encodes a protein involved in conversion of naϊve mature B cells to germinal center B cells. CD20 encodes a protein involved in conversion of naϊve mature B cells to extra follicular B cells. Finally, plasma cell differentiation is regulated by proteins encoded by the APRIL, RAC2, IRF2BP2, SEC61A1, MOGS and CTNNBL1 genes.

Figure 2

The development pathway of T cells and genes involved in each stage; mutation of these genes leads to monogenic CVID. Conversion of early T cell progenitor to double negative 1 (DN1) cells is regulated by the protein encoded by IKAROS, a transcription factor encoded by the IKZF1 gene, which later is involved in conversion of stage double negative 4 (DN4) to stage double positive (DP). PTEN, NFKB1 and NFKB2 encode proteins involved in development of stage DN3 to stage DN4. Then, RAC2 regulates differentiation of DP cells to single positive (SP) cells. Furthermore, NF-κB1 and NF-κB2 regulate the conversion of CD4⁺ cells to naϊve CD4⁺ cells as well as CD8⁺ cells to naϊve CD8⁺ cells. The exact mechanism and location of action of proteins encoded by the PIK3R1, PIK3CD, TWEAK, BAFFR, TRNT1, CD81, PI3Kγ and CTNNBL1 genes are not understood and further studies are required to come to a definite conclusion.