title: Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus.
abstract: OBJECTIVE
  A putative regulatory intronic polymorphism (PD1.3) in the programmed death 1 (PD-1) gene, a negative regulator of T cells involved in peripheral tolerance, is associated with increased risk for systemic lupus erythematosus (SLE). We undertook this study to determine the expression and function of PD-1 in SLE patients.
  
  
  METHODS
  We genotyped 289 SLE patients and 256 matched healthy controls for PD1.3 by polymerase chain reaction-restriction fragment length polymorphism analysis. Expression of PD-1 and its ligand, PDL-1, was determined in peripheral blood lymphocytes and in renal biopsy samples by flow cytometry and immunohistochemistry. A crosslinker of PD-1 was used to assess its effects on anti-CD3/anti-CD28-induced T cell proliferation and cytokine production.
  
  
  RESULTS
  SLE patients had an increased frequency of the PD1.3 polymorphism (30.1%, versus 18.4% in controls; P=0.006), with the risk A allele conferring decreased transcriptional activity in transfected Jurkat cells. Patients homozygous for PD1.3-but not patients heterozygous for PD1.3-had reduced basal and induced PD-1 expression on activated CD4+ T cells. In autologous mixed lymphocyte reactions (AMLRs), SLE patients had defective PD-1 induction on activated CD4+ cells; abnormalities were more pronounced among homozygotes. PD-1 was detected within the glomeruli and renal tubules of lupus nephritis patients, while PDL-1 was expressed by the renal tubules of both patients and controls. PD-1 crosslinking suppressed proliferation and cytokine production in both normal and lupus T cells; addition of serum from patients with active SLE significantly ameliorated this effect on proliferation.
  
  
  CONCLUSIONS
  SLE patients display aberrant expression and function of PD-1 attributed to both direct and indirect effects. The expression of PD-1/PDL-1 in renal tissue and during AMLRs suggests an important role in regulating peripheral T cell tolerance.
authors.affiliation: University of Crete Medical School, Heraklion, Crete, Greece.
authors.forename: George K
authors.initials: GK
authors.lastname: Bertsias
authors.forename: Magda
authors.initials: M
authors.lastname: Nakou
authors.forename: Christianna
authors.initials: C
authors.lastname: Choulaki
authors.forename: Amalia
authors.initials: A
authors.lastname: Raptopoulou
authors.forename: Eva
authors.initials: E
authors.lastname: Papadimitraki
authors.forename: George
authors.initials: G
authors.lastname: Goulielmos
authors.forename: Herakles
authors.initials: H
authors.lastname: Kritikos
authors.forename: Prodromos
authors.initials: P
authors.lastname: Sidiropoulos
authors.forename: Maria
authors.initials: M
authors.lastname: Tzardi
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kardassis
authors.forename: Clio
authors.initials: C
authors.lastname: Mamalaki
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Boumpas
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D061026:Programmed Cell Death 1 Receptor
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor