title: Inflammation in common variable immunodeficiency is associated with a distinct CD8(+) response to cytomegalovirus.
abstract: BACKGROUND
  Common variable immunodeficiency is the most common primary immunodeficiency. A subset of patients has debilitating inflammatory complications.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, Royal Free Campus, University College London Medical School, London, United Kingdom.
authors.forename: Sayed Mahdi
authors.initials: SM
authors.lastname: Marashi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Raeiszadeh
authors.forename: Sarita
authors.initials: S
authors.lastname: Workman
authors.forename: Afsar
authors.initials: A
authors.lastname: Rahbar
authors.forename: Cecilia
authors.initials: C
authors.lastname: Soderberg-Naucler
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Ronnie
authors.initials: R
authors.lastname: Chee
authors.forename: A David
authors.initials: AD
authors.lastname: Webster
authors.forename: Richard S B
authors.initials: RS
authors.lastname: Milne
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Emery
mesh_terms: D000328:Adult; D000368:Aged; D000956:Antigens, Viral / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D017074:Common Variable Immunodeficiency / Q000150:complications* / Q000276:immunology*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology / Q000821:virology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000276:immunology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa