Immune deficiencies, infection, and systemic immune disorders
Influence of cytomegalovirus infection on immune cell phenotypes in patients with common variable immunodeficiency

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Background

A subset of patients with common variable immunodeficiency (CVID) have debilitating inflammatory complications strongly associated with cytomegalovirus (CMV) infection and a hyperproliferative CMV-specific T-cell response.

Objectives

We studied the T-cell response to CMV and the global effect of this virus on immune effector cell populations in patients with CVID.

Methods

Antibody staining, peptide stimulation, and proliferation assays were used to profile CMV-specific T-cell function.

Results

CMV infection drives the CD4/CD8 ratio inversion that is characteristic of CVID. The late effector CD8+ T-cell subset is expanded in CMV-infected patients with CVID. This expansion is largely attributable to CMV-specific cells and correlates with inflammatory disease; within the CMV-specific population, the frequency of late effector cells correlates inversely with the frequency of cells expressing programmed death 1. Supernatants from proliferating CMV-specific CD8+ cells from patients with inflammatory disease can confer proliferative potential on cells from patients with noninflammatory CVID and healthy subjects. Blocking experiments showed that this proliferation is mediated in part by IFN-γ and TNF-α.

Conclusions

These data strengthen the association of CMV with inflammatory pathology in patients with CVID, explain some of the well-known T-cell abnormalities associated with this condition, and provide a plausible mechanism for the documented therapeutic activity of anti–TNF-α and antiviral chemotherapy in managing CVID-associated inflammatory disease.

Section snippets

Study populations

Seventy-one patients with CVID (35 male patients; age, 24-86 years; median, 52 years) attending the Royal Free Hospital and 19 healthy subjects (7 male subjects; age, 25-71 years; median, 45 years; P > .05 vs patients with CVID) were analyzed. CVID was defined according to the International Union of Immunological Societies criteria.9, 10 All patients with CVID received standard immunoglobulin therapy, and blood samples for T-cell studies were collected before immunoglobulin treatment. CMV

CMV infection is associated with inversion of the CD4/CD8 T-cell ratio in patients with CVID

The cellular immunologic profiles of the patients with CVID and healthy control subjects are shown in Table I. Differences between patients with CVID and healthy subjects are well documented12, 13, 14, 15; here we separate them according to CMV status. Frequencies of switched memory and transitional B cells and plasmablasts were marginally reduced in CMV-positive patients compared with CMV-negative patients, but these changes were not statistically significant.

CD4 T-cell numbers in patients

Discussion

CVID is the most common clinically relevant primary immune deficiency. A subset of patients experience debilitating inflammatory complications that are strongly associated with CMV infection. We previously described a distinct hyperproliferative CD8+ T-cell phenotype in these patients. In this study we have extended our previous observations to profile the global effect of CMV on immune effector cell populations in patients with CVID, refine our description of the functional phenotype of the CD8

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The UCL MRC Centre for Medical Molecular Virology is funded by Centre Grant from the Medical Research Council. Part of this work was funded by a Wellcome Trust Grant (to V.C.E. and colleagues) and a grant from the Primary Immunodeficiency Association (to A.D.W.). S.M.M. received a scholarship from Tehran University of Medical Sciences and was supported by a PhD studentship from the Iranian Ministry of Health.

Disclosure of potential conflict of interest: S. Workman has received honoraria from Octapharma UK. V. C. Emery is on the advisory board and is a speaker for Roche and has received research support from the Wellcome Trust. The rest of the authors declare that they have no relevant conflicts of interest.

Mohammed Raeiszadeh, MPhil, is currently affiliated with the School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.

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