Seven known genetic defects, including Bruton tyrosine kinase (Btk), CD4OL, and signaling lymphocyte activation molecule-associated protein (SAP) (all X-linked) and inducible costimulator molecule (ICOS), transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI), B-cell-activating factor of the tumor necrosis family receptor (BAFFR), and CD19 (all autosomal recessive), were found in patients with the phenotype of common variable immunodeficiency (CVID).
Three different classifications, B lymphocyte subpopulations, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) gene mutations, CTLA-4 and ICOS gene polymorphisms in Turkish patients with common variable immunodeficiency.
Recently, the authors discovered that the homozygous loss of the ICOS in humans presents as common variable immunodeficiency, the most prevalent treated primary immunodeficiency in man.
The discovery of human ICOS deficiency showed that a monogenic disorder could account for the full spectrum of manifestations seen in childhood and adulthood-onset CVID, including autoimmune, inflammatory, and malignant disease complications, as well as recurrent infections.
In addition, the flowcytometric analysis of the inducible costimulator on activated T cells, CD19 and BAFF-R on B cells are valid screening methods for three of the four known genetic defects associated with CVID.
The candidate gene approach has led to the detection of associations between common variable immunodeficiency (CVID) and mutations in the genes TACI, ICOS, BAFF-R, CD19, CD20, and CD81.
Subsequent whole exome sequencing studies have revealed germline heterozygous C-terminal mutations of NFKB2 as a cause of DAVID syndrome or of CVID without clinical hypopituitarism.
Using flow cytometry, we further demonstrated that there was a reduction in B cells (CD19+), switched memory B cells (CD27+IgD-) and T follicular helper (Tfh) cells (both CD4+CXCR5+ and CD4+CXCR5Hi) in a CVID patient with NFKB2/p100Δ19, compared to healthy controls.
In conclusion, pathogenic stop variants in the ARD of NFKB2 can cause 'infection-only' CVID with an abnormal B-cell phenotype and a variable clinical penetrance.
TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181ETNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development.
Remarkably, we did not find the TNFRSF13B mutation in the third index-child with CVID, despite his hypogammaglobulinaemia and decreased response to unconjugated pneumococcal vaccine.
In some patients with common variable immunodeficiency (CVID) and immunoglobulin (Ig) A deficiency (IgAD), tumor necrosis factor (TNF) family receptor transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) gene mutations have been reported.
Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes.
Of the 6 IgAD patients, 1 had a heterozygous TACI mutation (16.67%), while of the 3 unclassified patients, 1 had a monoallelic TACI mutation (33.3%), but his sibling who also had the same mutation had CVID.
To summarize the recent advancements in common variable immune deficiency (CVID), specifically CVID genetics, clinical discoveries and treatment implications.
We report the case of a man with CVID in association with a heterozygous TACI gene mutation (C104R) who had a highly unusual, invasive, polyclonal CD8+ T-cell lymphoproliferation resulting in massive hepatosplenomegaly and causing renal impairment because of infiltration.
The hypothesis that the CVID gene predisposes heterozygous female carriers to cancer may be evaluated more easily in the future when the genetic basis for CVID is better understood.