Translational mini-review series on immunodeficiency: molecular defects in common variable immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is a primary immunodeficiency that typically affects adults and is characterized by abnormalities of quantative and qualitative humoral function that are heterogeneous in their immunological profile and clinical manifestations. The recent identification of four monogenic defects that result in the CVID phenotype also demonstrates that the genetic basis of CVID is highly variable. Mutations in the genes encoding the tumour necrosis factor (TNF) superfamily receptors transmembrane activator and calcium-modulating ligand interactor (TACI) and B cell activation factor of the TNF family receptor (BAFF-R), CD19 and the co-stimulatory molecule inducible co-stimulator molecule (ICOS) all lead to CVID and illustrate the complex interplay required to co-ordinate an effective humoral immune response. The molecular mechanisms leading to the immune defect are still not understood clearly and particularly in the case of TACI, where a number of heterozygous mutations have been found in affected individuals, the molecular pathogenesis of disease requires further elucidation. Together these defects account for perhaps 10-15% of all cases of CVID and it is highly likely that further genetic defects will be identified.

Fig. 1

Inducible co-stimulator molecule (ICOS):ICOS-L signalling can results in multiple pathways. Like CD28, ICOS can bind to the p85 subunit of phosphatidylinositol 3-kinase (PI3K) resulting in activation of lipid kinase (PDK1, PKB/Akt). ICOS can activate mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) resulting in increased transcription of interleukin (IL)-10, IL-4 and interferon (IFN)-γ, prevention of cell death and up-regulation of cell metabolism. ICOS can also up-regulate CD40-L.

Fig. 2

(a) Genomic organization and protein structure of transmembrane activator and calcium-modulating ligand (CAML) interactor (TACI). The gene encoding TACI, TNFRSF13B, consists of five exons (represented by boxes and not in scale) and codes for a 293 amino acids protein. TACI contains cysteine-rich domains 1 and 2 (CRD1 and CRD2) in the extracellular domain of TACI and binding sites for tumour necrosis factor (TNF)-associated factors (TRAFs -2, -5 and -6) and calcium modulator and cyclophilin ligand (CAML) in its intracellular domain. The highly conserved DXL motif is located in the CRD2 domain. An alternative splicing can occur, giving rise to a short TACI protein lacking the CRD1. (b) B cell activation factor of the TNF family receptor (BAFF) and a proliferation-inducing ligand (APRIL) bind to the CRD2 of TACI trimers. Intracellular signalling though CAML and TRAFs results in activation of nuclear factor of activated T cells transcription factor (NF-AT) and nuclear factor-kappa B (NF-κB).

Fig. 3

Interactions of B cell activation factor of the TNF family receptor (BAFF) and a proliferation-inducing ligand (APRIL) with their receptors BAFF-R, transmembrane activator and calcium-modulating ligand (CAML) interactor (TACI) and B cell maturation antigen (BCMA) control B cell development and homeostasis. BAFF binds to BAFF-R, TACI and BCMA, while APRIL binds only to TACI and BCMA. The functional outcomes of BAFF and APRIL interactions with their receptors are listed. Simultaneous binding of APRIL to TACI and heparan sulphate proteoglycans mediates IgA production.