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

T Cells in Common Variable Immunodeficiency

Several monocentric and one multicenter trial[55•] described the reduction of regulatory T cells in a subgroup of CVID patients.[56–58,59•] In most of the examined cohorts of CVID patients there is a significant association between low numbers of regulatory T cells and an autoimmune manifestation,[55•,56,57,59•] but also granulomatous disease[55•] and splenomegaly.[56] In addition, the reduction of regulatory T cells correlated significantly with the expansion of CD21low B cells and therefore with the Freiburg class Ia.[55•,56] The majority of these reports rely on phenotypic analysis of Tregs in peripheral blood. Only Yu et al.[59•] show that sorted Treg from CVID patients with autoimmune disease are compromised in their suppressive activity, when compared with CVID patients without autoimmunity or healthy controls.[60] Furthermore several Treg marker proteins, including FoxP3, were expressed at lower levels, and the downregulation of FoxP3, Granzyme A and pStat5 was significantly correlated with the degree of regulatory T-cell dysfunction in CVID.[59•]

In addition, unlike XLA patients, CVID patients of the Freiburg group I characterized by their low number of switched memory B cells had a significant reduction in iNKT cells[60] as had been previously described for patients with X-linked lymphoproliferative disease (XLP). It remains to be determined which of these T-cell abnormalities are primary or secondary, possibly only relative due to emigration out of the bloodstream into inflammatory sites.

Functional evaluation of the T–B cooperation in vitro revealed only minor differences in few patients when analyzing CD86 up-regulation on B cells after 'bystander activation' of T cells.[61] The further development of in-vitro assays as a surrogate test for in-vivo T–B interaction is urgently needed in order to better characterize the disturbed germinal center response found in the majority of CVID patients.

Malphettes et al. [62•] were the first to label a subgroup of CVID patients within the DEFI cohort as late onset combined immunodeficiency (LOCID). The inclusion criteria for LOCID consisted either of a CD4 T-cell count below 200/μl [11 (3.5%) of 313] or the manifestation of an opportunistic infection [17 (5.4%) of 313]. Interestingly, only about 10% of LOCID patients fulfilled both inclusion criteria suggesting two independent subgroups within the LOCID group. LOCID patients presented more often with consanguinity of the parents, granulomatous and gastrointestinal tract disease, splenomegaly, and lymphoma. Some of these secondary complications are most likely an expression of a combined immunodeficiency. Thus especially autoimmunity and inflammatory involvement of the lung or gut are likely to present a dysregulated cellular immune system. An evaluation of all LOCID patients combined showed a significant reduction in CD4, CD8 T-cell, natural killer (NK) cell and B-cell counts. Unfortunately, a separate analysis of the different lymphocyte populations for the subgroup of LOCID patients with opportunistic infections was not supplied. It is a major task for the coming years to define the underlying immune pathology in these patients, a set of biomarkers which will allow prediction of the risk for opportunistic infection especially in the absence of low CD4 T-cell counts and to determine new therapeutic strategies for these patients.

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