Common Variable Immunodeficiency at the End of a Prospering Decade: Towards Novel Gene Defects and Beyond

Hermann Eibel; Ulrich Salzer; Klaus Warnatz

Disclosures

Curr Opin Allergy Clin Immunol. 2010;10(6):526-533. 

In This Article

Phenotypic Analysis of Circulating Lymphocyte Subsets

Several abnormalities of circulating lymphocytes have been described and used for classification of CVID.[1,38] Mouillot et al. [39•] combined T-cell and B-cell phenotyping of 313 CVID patients within the French DEFI cohort. The analysis of the immunological parameters was performed separately for patients with infections only or patients with other secondary complications. While the reduction of switched memory B cells and plasmablasts was observed in all groups, in CVID patients with secondary complications this reduction was even more pronounced and only these patients presented with a significant expansion of CD21low B cells, independent of the type of complication. Similarly, all clinical subgroups had decreased numbers of naïve CD4 T cells, but again this was most severe in patients with secondary complications. Thus a combined B-cell and T-cell phenotyping reveals a stronger immune dysregulation in CVID patients with secondary complications.

Three studies[40,41•,42] have analyzed the abnormalities of circulating B cells in children with CVID. Van de Ven et al.[41•] compared circulating B and T cells of 36 pediatric CVID, 30 patients with other forms of hypogammaglobulinemia with 65 healthy controls. Like their adult counterparts most children presented with reduced numbers of switched memory B cells. In contrast, in most pediatric patients transitional IgD+CD10+CD38hi B cells were expanded and the decrease in IgM memory B cells and in CD4+ T cells was more prominent than reported for adult patients. It needs to be addressed whether these additional changes are an expression of a subgroup of CVID patients with early childhood onset or of the greater regenerative capacity in children producing a higher output of precursor B cells from the bone marrow. Unfortunately, none of these changes nor the classifications according to EUROclass,[1] Giovannetti et al.[38] or Chapel et al.[43] allowed the differentiation between CVID and other forms of hypogammaglobulinemia in this pediatric cohort. Additional prospective studies however need to confirm this lack of association. Stratifying pediatric CVID patients according to switched memory B cells below (group I) or above 5 cells/μl (group II), only patients in group I had secondary complications like splenomegaly, autoimmune cytopenia, lymphoma or chronic lung disease suggesting increased surveillance for this group.[42] Thus, children with hypogammaglobulinemia show similar alterations of their B-cell subpopulations as adults, but the ideal definition of abnormal numbers of switched memory B cells (percentage vs. absolute counts, flexible cut-offs according to age matched controls) remains to be determined for pediatric cohorts.

In order to define hierarchical clusters of B-cell phenotypes by computational algorithms, 48 CVID patients and 49 controls were analyzed by six-color flow cytometry.[44] As a proof of principle this approach was used to compare clusters defined by bins derived from six color gates with known phenotypic definitions of B-cell subsets. On a second level, clusters of B-cell phenotypes of patients were defined according to the composition of the circulating B-cell pool. A longitudinal analysis of patients could confirm the highly stable abnormal B-cell phenotype in 15 CVID patients.[44] Follow-up studies combining phenotypic, functional, and lineage-specific characteristics will have to prove the usefulness of computational methods for defining B-cell subsets and their relation to clinical presentations.

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