title: Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG).
abstract: BACKGROUND
  PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.
  
  
  OBJECTIVE
  To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors.
  
  
  METHODS
  We studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay.
  
  
  RESULTS
  We found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules.
  
  
  CONCLUSIONS
  Our results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves our understanding of the immunological functions in PMM2-CDG and possibly in other CDG-I types.
authors.affiliation: Departamento de Bioquímica, Biología Molecular B e Inmunología, Facultad de Medicina, IMIB-University of Murcia, Murcia, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: García-López
authors.affiliation: Centro Regional de Hemodonación, Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, IMIB-Arrixaca, Murcia, Spain.|CIBERER, Valencia, Spain.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: de la Morena-Barrio
authors.affiliation: Sección de Alergia e Inmunología Clínica, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Alsina
authors.affiliation: Departamento de Neurología Infantil, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez-Dueñas
authors.affiliation: Center for Metabolic Diseases, Universitair Ziekenhuis Gasthuisberg, KULeuven, Leuven, Belgium.
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.affiliation: Departamento de Neurología Infantil, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Departamento de Bioquímica Clínica y Neuropediatría, Hospital Sant Joan de Deu CIBERER-ISCIII, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Casado
authors.affiliation: Departamento de Bioquímica, Biología Molecular B e Inmunología, Facultad de Medicina, IMIB-University of Murcia, Murcia, Spain.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Hernández-Caselles
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000276:immunology / Q000378:metabolism*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation; D008297:Male; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D017875:Phosphotransferases (Phosphomutases) / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000378:metabolism*; D055815:Young Adult
chemical_list: C527085:KLRK1 protein, human; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055607:Receptors, Natural Killer Cell; D018799:Intercellular Adhesion Molecule-1; D017875:Phosphotransferases (Phosphomutases); C519582:phosphomannomutase 2, human