title: Defective NK cell activation in X-linked lymphoproliferative disease.
abstract: X-linked lymphoproliferative disease (XLP) is characterized by a selective immune deficiency to EBV. The molecular basis of XLP has been attributed to mutations of signaling lymphocytic activation molecule-associated protein, an intracellular molecule known to associate with the lymphocyte-activating surface receptors SLAM and 2B4. We have identified a single nucleotide mutation in SLAM-associated protein that affects the NK cell function of males carrying the mutated gene. In contrast to normal controls, both NK and lymphokine-activated killer cell cytotoxicity was significantly reduced in two XLP patients. In addition to decreased baseline cytotoxicity, ligation of 2B4 significantly augmented NK lytic function in normal controls but failed to enhance the cytotoxicity of NK cells from XLP patients. These findings suggest that association of SAP with 2B4 is necessary for optimal NK/lymphokine-activated killer cytotoxicity and imply that alterations in SAP/2B4 signaling contribute to the immune dysfunction observed in XLP.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver Hospital and Health Sciences Centre, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Benoit
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: H F
authors.initials: HF
authors.lastname: Pabst
authors.forename: J
authors.initials: J
authors.lastname: Dutz
authors.forename: R
authors.initials: R
authors.lastname: Tan
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D015703:Antigens, CD / Q000096:biosynthesis; D000071178:CD48 Antigen; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D008040:Genetic Linkage / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D011971:Receptors, Immunologic; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D014407:Tumor Cells, Cultured; D014960:X Chromosome / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; C084093:CD244 protein, human; D000071178:CD48 Antigen; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family