title: Lack of expression of inhibitory KIR3DL1 receptor in patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes.
abstract: BACKGROUND
  Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3(-)CD16(+) granular lymphocytes. By flow cytometry analysis, we previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes.
  
  
  METHODS
  We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population.
  
  
  RESULTS
  We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls.
  
  
  CONCLUSIONS
  In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Padova, via Giustiniani 2, Padua, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gattazzo
authors.forename: Antonella
authors.initials: A
authors.lastname: Teramo
authors.forename: Marta
authors.initials: M
authors.lastname: Miorin
authors.forename: Elisa
authors.initials: E
authors.lastname: Scquizzato
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Mirna
authors.initials: M
authors.lastname: Balsamo
authors.forename: Carlo
authors.initials: C
authors.lastname: Agostini
authors.forename: Elena
authors.initials: E
authors.lastname: Vendrame
authors.forename: Monica
authors.initials: M
authors.lastname: Facco
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Albergoni
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.forename: Massimo
authors.initials: M
authors.lastname: Vitale
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000473:pathology*; D054066:Leukemia, Large Granular Lymphocytic / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D054341:Receptors, KIR3DL1 / Q000172:deficiency* / Q000235:genetics; D054349:Receptors, KIR3DS1 / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1
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