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Blood, 15 July 2008, Vol. 112, No. 2, pp. 446.
CORRESPONDENCE T-cell homeostasis: the dark(ened) side of common variable immunodeficiencyTo the editor:We have read with interest the paper by Wehr et al,1 recently published in Blood, which defines subgroups in common variable immunodeficiency (CVID). CVID is a heterogeneous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections and a variety of immunologic abnormalities. The authors stated that the aims of their study "were to determine the clinical and immunologic phenotype of CVID patients in Europe and to test and possibly improve and unify the current classification schemes." In fact, the vast heterogeneity of this immunodeficiency has so far hindered the fulfillment of a commonly accepted approach to classify subgroups of patients. Therefore, any attempts to improve the classification of this disease are welcome news. The article by Wehr et al1 was no exception. A severe reduction of switched memory B cells, associated with splenomegaly and granulomatous disease, was shown in most of the patients, while an expansion of CD21low B cells marked the patients with splenomegaly. Finally, lymphadenopathy was significantly linked with transitional B-cell expansion. Based on these findings, Wehr et al suggested a classification separating CVID patients with nearly absent B cells (less than 1%), those with severely reduced switched memory B cells (less than 2%), and those with expansion of transitional (more than 9%) or CD21low B cells (more than 10%). However, it is disappointing to note that the T-cell compartment had hardly been investigated. A huge amount of data exist demonstrating that CVID is also, and probably for the most part, a T-cell disorder.2,3 Therefore the proposal of a strict B cell–based classification appears far from complete, especially now that clinical phenotypes have been thoroughly defined.4 We refer to the work of Chapel et al prepublished March 4, 2008, in Blood. In this study the authors used clinical features of an impressive number of European CVID patients to subdivide patients in 5 clinical phenotypes. Unfortunately, also in this work, the study of the T-cell compartment appears inadequate to the complexity and importance of the harvested clinical data, being solely restricted to the evaluation of the peripheral distribution of CD4+ and CD8+ T lymphocytes. We should hereby like to raise the issue of T-cell phenotyping in CVID patients, since in our opinion an efficient classification of the disease cannot exclude the evaluation of the T-cell homeostasis. This conviction results from an in-depth analysis of the T-cell compartment which we performed in a large cohort of CVID patients.5 In our study we demonstrated multiple T-cell abnormalities (eg increased T-cell activation, reduced thymic output, disrupted T-cell receptor B variable [TCRBV] repertoires, altered cytokine production, increased T-cell turnover and apoptosis) whose severity reflected in a parallel loss of CD4+-naive T cells. More importantly, a strong correlation between the number of CD4+-naive T cells and clinical features was demonstrated, supporting the subgrouping of patients according to their number of naive CD4+ T lymphocytes. Particularly, CD4+-naive T cells were strongly associated with clinical severity. This was quantified on the basis of several criteria evaluated within the last 5 years of the patients' history and included, among others, severe respiratory tract infections. A detailed comparison between the CD4+-naive T cell–based classification and the Freiburg classification allowed us to reveal the limits of a "pure" B cell–based classification. A similar comparison was not performed by Wehr et al, who nonetheless stated that their proposed classification "is superior to previous models in the differentiation of clinical phenomena." Therefore, while the data presented in the above mentioned papers are not disputed, we would like to remark here that both reports would have been more meaningful if the deep alteration of the T-cell compartment (firstly the loss of CD4+-naive T cells) had been considered somehow. Such information is not only of cursory interest but also may have therapeutic implications. In fact, current therapy for CVID includes regular infusions of intravenous immunoglobulin and antibiotics as needed, but significant morbidity and mortality remain.6 CVID patients might be likely to benefit from therapies which can enhance T-cell functions and reverse T-cell anergy.7 Authorship Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Antonello Giovannetti, Department of Clinical Medicine, Division of Clinical Immunology and Allergy, La Sapienza University, Viale dell'Università 37, 00185 Rome, Italy; e-mail: antonello.giovannetti{at}uniroma1.it.
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