Inflammation in common variable immunodeficiency is associated with a distinct CD8+ response to cytomegalovirus

• Published in: Journal of allergy and clinical immunology Vol. 127; no. 6; pp. 1385 - 1393.e4
• Main Authors: Marashi, Sayed Mahdi, PhD, Raeiszadeh, Mohammad, MSc, Workman, Sarita, MSc, Rahbar, Afsar, PhD, Soderberg-Naucler, Cecilia, PhD, Klenerman, Paul, PhD, Chee, Ronnie, MBBS, Webster, A. David, MD, Milne, Richard S.B., PhD, Emery, Vincent C., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.06.2011; Elsevier; Elsevier Limited
• Subjects: Adult; Aged; Allergy and Immunology; Antigens; Antigens, Viral - genetics; Biological and medical sciences; Biopsy; Bowel disease; Case-Control Studies; CD8 + T cells; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Proliferation; common variable immunodeficiency; Common Variable Immunodeficiency - complications; Common Variable Immunodeficiency - immunology; Cytokines; Cytomegalovirus; Cytomegalovirus - genetics; Cytomegalovirus - immunology; Cytomegalovirus - isolation & purification; Cytomegalovirus Infections - complications; Cytomegalovirus Infections - immunology; Cytomegalovirus Infections - virology; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genotype & phenotype; Histology; Humans; Hypertension; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infections; Infectious diseases; inflammation; Inflammation - etiology; Inflammation - immunology; Inflammation - virology; Liver; Liver diseases; Lung diseases; Lymphocytes; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Patients; Phosphatase; Phosphoproteins - genetics; Phosphoproteins - immunology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Spleen; T cell receptors; Tumors; Viral diseases; Viral infections; Viral Matrix Proteins - genetics; Viral Matrix Proteins - immunology; United Kingdom > UK; Fluorescein isothiocyanate; Cytomegalovirus; Carboxyfluorescein diacetate succinimidyl ester; Late antigen; IEA; CFSE; Epstein Barr virus; common variable immunodeficiency; CMV; CVID; FITC; inflammation; LA; EBV; CD8 + T cells; Immediate-early antigen; Immunopathology; Common variable immunodeficiency; Herpesviridae; Inflammation; T cells; Betaherpesvirinae; Human cytomegalovirus; Infection; Virus; Association; Immunology; Immunoglobulinopathy; Viral disease; CD8; T-Lymphocyte; CD8 T lymphocyte
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2011.04.001

Background Common variable immunodeficiency is the most common primary immunodeficiency. A subset of patients has debilitating inflammatory complications. Objectives We investigated the role of cytomegalovirus (CMV), and the T-cell response targeted at this virus, in this inflammatory disease. Methods Phenotypic and functional assays were used to profile CMV-specific T cells in patients with common variable immunodeficiency with and without inflammatory complications. Highly sensitive immunohistochemistry was used to detect CMV antigens at sites of inflammation. Results Cytomegalovirus was significantly associated with inflammatory disease, which occurred in 31 of 43 (72%) virus-exposed patients and 8 of 31 (26%) naive patients ( P  = .0001). CMV pp65-NLVPMVATV epitope–specific CD8+ T-cell frequencies were significantly elevated in inflammatory patients, but these cells did not show evidence of exhaustion, with low levels of programmed death-1 and high T-cell receptor avidity. Rather, they showed features consistent with high in vivo functionality and proliferative activity including reduced levels of the anti-inflammatory marker CD73 (1.67% of NLV+ cells were CD73+ vs 42.01% in noninflammatory patients; P  = .004) and increased Ki-67 expression (37% vs 2% in noninflammatory patients; P  < .0001). In vitro , the CMV-specific T cells showed high antigen-specific proliferative potential compared with cells from noninflammatory patients. By using sensitive immunohistochemistry, we detected for the first time viral antigen at the sites of inflammation, indicative of active viral replication. Conclusion Our data strongly support a direct role for CMV and a hyperreactive CMV-specific immune response in the debilitating chronic inflammatory complications of common variable immunodeficiency.