title: Natural killer (NK) cell lytic dysfunction and putative NK cell receptor expression abnormality in members of a family with chromosome 3p-linked von Hippel-Lindau disease.
abstract: BACKGROUND. Using antibodies to a putative natural killer (NK) cell receptor (pNKR), we recently cloned a novel cDNA and localized this gene to the short arm of human chromosome 3, region 3p21-3p24. Individuals susceptible to or clinically manifesting von Hippel-Lindau disease (VHL) have a genetic defect telomeric to this region on chromosome 3. This defect, resulting in VHL, is manifested by a high incidence of certain tumors.
  
  
  OBJECTIVE
  Based on the location of this gene, we sought to determine if VHL patients have a defect in gene expression of pNKR.
  
  
  METHODS
  Because of the proximity of the VHL and pNKR genetic regions, the variable expression of VHL tumors, and the ability of NK cells to target tumor cells, we investigated NK cell activity and other aspects of the immunologic status in 40 members (four branches) of a family with a high incidence of VHL tumors.
  
  
  RESULTS
  Individuals affected with VHL and lacking in normal surface expression of pNKR had virtually no NK cell lytic activity. Analysis of genotypes and phenotypes of all subjects revealed that the greatest difference in NK cell lytic activity (P = .0002) was seen when family members exhibited both VHL and pNKR surface expression defects, compared with normal relatives who had neither defect. Furthermore, the lack of NK cell activity strongly correlated (P = .0005) with abnormal pNKR protein surface expression. Of particular interest, individuals who lacked NK cell activity had normal numbers of NK cells. In addition, analysis of leukocyte subsets indicated normal numbers of T and B cells, monocytes, and NK cells in both affected and normal individuals.
  
  
  CONCLUSIONS
  These data indicate that although all affected individuals have the cell population responsible for NK cell activity, many have cells low in expression of pNKR and lack functional NK cell activity. Overall, these results indicate that, in addition to a predisposition to the development of neoplasms, VHL patients have a defect in a specific mechanism of natural immunosurveillance that correlates with a defect in expression of a novel large granular lymphocyte pNKR protein.
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Md. 21702-1201.
authors.forename: J R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: G M
authors.initials: GM
authors.lastname: Glenn
authors.forename: H A
authors.initials: HA
authors.lastname: Young
authors.forename: J L
authors.initials: JL
authors.lastname: Frey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002893:Chromosomes, Human, Pair 3; D003602:Cytotoxicity, Immunologic; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000032:analysis* / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000276:immunology*
chemical_list: D011971:Receptors, Immunologic