title: Common variable immunodeficiency is associated with a functional deficiency of invariant natural killer T cells.
abstract: BACKGROUND
  Common variable immunodeficiency (CVID) is the commonest symptomatic primary antibody disorder, with monogenic causes identified in less than 10% of all cases. X-linked proliferative disease is a monogenic disorder that is associated with hypogammaglobulinemia and characterized by a deficiency of invariant NKT (iNKT) cells. We sought to evaluate whether a defect in iNKT cell number or function was associated with CVID.
  
  
  OBJECTIVE
  An evaluation of the function and number of iNKT cells in CVID.
  
  
  METHODS
  Six-color flow cytometry enumerated iNKT cells in 36 patients with CVID and 50 healthy controls. Their proliferative capacity and cytokine production (IFN-γ, IL-13, IL-17) was then investigated following activation with CD1d ligand alpha-galactosylceramide.
  
  
  RESULTS
  A reduction in the number of iNKT cells (31 iNKT cells/10(5) T cells) in patients with CVID compared with healthy controls (100 iNKT cells/10(5) T cells) was observed (P < .0001). Two cohorts could be discerned within the CVID group: group 1 with an abnormal number of iNKT cells (n = 28) and group 2 with a normal number of iNKT cells (n = 8). This segregation coassociated with the proliferative capacity of iNKT cells between the 2 groups. However, differences in the function of iNKT cells were noted in group 2, in which an increase in IFN-γ (P = .0016) and a decrease in IL-17 (P = .0002) production was observed between patients with CVID and controls. Finally, a significant association was seen between the number of iNKT cells and the percentage of class-switched memory B cells and propensity to lymphoproliferation (P = .002) in patients with CVID.
  
  
  CONCLUSIONS
  iNKT cells are deficient and/or functionally impaired in most of the patients with CVID.
authors.affiliation: Faculty of Medicine, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Clinical Immunology and Molecular Pathology, Royal Free Hospital, London, United Kingdom; University College London, London, United Kingdom.
authors.forename: Sarita
authors.initials: S
authors.lastname: Workman
authors.affiliation: Faculty of Medicine, Clinical and Experimental Sciences Division, University of Southampton, Southampton, United Kingdom.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gadola
authors.affiliation: Faculty of Medicine, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.affiliation: Department of Clinical Immunology and Molecular Pathology, Royal Free Hospital, London, United Kingdom; University College London, London, United Kingdom.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Faculty of Medicine, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom. Electronic address: apw2@soton.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Williams
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D008297:Male; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines
keywords: CVID; XLA; cytokine; iNKT; proliferation