We analyzed whether there is an association between Tregs cells (CD4+CD25+CD127<sup>low</sup> and CD4+CD25+FoxP3+); memory T cells (CD4+CD45RO+); memory B cells (CD19+CD27-IgD-); and CD21<sup>low</sup> B cells (CD19+CD38<sup>low</sup>CD21<sup>low</sup>); as well as autoimmune manifestations in 36 patients with CVID (25 women and 11 men, mean age 24 years), all by flow cytometry.
The proportions of nCD4+ Treg (CD4+ CD127low CD25high FoxP3+), iCD4+ Treg (CD4+ CD127low CD25high FoxP3+), iCD8+ Treg (CD8+ CD25high CD183+ FoxP3+), and Breg (CD19+ CD24high CD38high) lymphocytes were significantly lower in patients with CVID than in controls.
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.
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.
Moreover, spontaneous apoptosis of CD19(+) B cells from patients with CVID or IgAD was prevented by a combination of IL-21, IL-4, and anti-CD40 stimulation.
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 recent discovery that some CVID patients show monogenic defects in the genes encoding ICOS, TACI or CD19 prompted us to investigate several functional candidate genes in individuals with CVID.
These findings extend the mutation spectrum of the CD19 deficiency to four, and confirm the homogeneity of the CD19 deficiency as a unique type of CVID.
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 mean +/- SD absolute count of CD19+ B cells among the 36 patients (65%) with CVID who had inherited HLA*B8 or HLA*B44 was 218 +/- 23 cells/mm3 compared with 119 +/- 27 cells/mm3 in those who had not inherited HLA*B8 or HLA*B44 (P = .008).
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).
In recent years the first three monogenetic defects in the inducible costimulator, transmembrane activator and CAML interactor (TACI), and CD19 were discovered in patients with common variable immunodeficiency revealing a multifaceted genetic background for this disease.
The patient was originally diagnosed as having common variable immunodeficiency disease because of the presence of circulating B cells (CD19+ B cells: 7%) at 11 years old.
Correspondingly, most CVID patients exhibit a severely decreased proportion of class switched memory B cells (CD19+CD27+IgD-IgM-IgG+ or IgA+) in their peripheral blood (CVID type I).