title: Conjunctival scarring in trachoma is associated with the HLA-C ligand of KIR and is exacerbated by heterozygosity at KIR2DL2/KIR2DL3.
abstract: BACKGROUND
  Chlamydia trachomatis is globally the predominant infectious cause of blindness and one of the most common bacterial causes of sexually transmitted infection. Infections of the conjunctiva cause the blinding disease trachoma, an immuno-pathological disease that is characterised by chronic conjunctival inflammation and fibrosis. The polymorphic Killer-cell Immunoglobulin-like Receptors (KIR) are found on Natural Killer cells and have co-evolved with the Human Leucocyte Antigen (HLA) class I system. Certain genetic constellations of KIR and HLA class I polymorphisms are associated with a number of diseases in which modulation of the innate responses to viral and intracellular bacterial pathogens is central.
  
  
  METHODS
  A sample of 134 Gambian pedigrees selected to contain at least one individual with conjunctival scarring in the F1 generation was used. Individuals (n = 830) were genotyped for HLA class I and KIR gene families. Family Based Association Tests and Case Pseudo-control tests were used to extend tests for transmission disequilibrium to take full advantage of the family design, genetic model and phenotype.
  
  
  RESULTS
  We found that the odds of trachomatous scarring increased with the number of genome copies of HLA-C2 (C1/C2 OR = 2.29 BHP-value = 0.006; C2/C2 OR = 3.97 BHP-value = 0.0004) and further increased when both KIR2DL2 and KIR2DL3 (C2/C2 OR = 5.95 BHP-value = 0.006) were present.
  
  
  CONCLUSIONS
  To explain the observations in the context of chlamydial infection and trachoma we propose a two-stage model of response and disease that balances the cytolytic response of KIR expressing NK cells with the ability to secrete interferon gamma, a combination that may cause pathology. The data presented indicate that HLA-C genotypes are important determinants of conjunctival scarring in trachoma and that KIR2DL2/KIR2DL3 heterozygosity further increases risk of conjunctival scarring in individuals carrying HLA-C2.
authors.affiliation: Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Chrissy H
authors.initials: CH
authors.lastname: Roberts
authors.affiliation: Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Molina
authors.affiliation: Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Pateh
authors.initials: P
authors.lastname: Makalo
authors.affiliation: Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Hassan
authors.initials: H
authors.lastname: Joof
authors.affiliation: Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Harding-Esch
authors.affiliation: Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom; Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Burr
authors.affiliation: Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: David C W
authors.initials: DC
authors.lastname: Mabey
authors.affiliation: Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Bailey
authors.affiliation: International Centre for Eye Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Burton
authors.affiliation: Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom; Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Holland
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002692:Chlamydia trachomatis / Q000276:immunology; D002921:Cicatrix / Q000276:immunology / Q000473:pathology*; D003228:Conjunctiva / Q000276:immunology / Q000473:pathology*; D005260:Female; D005714:Gambia; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015236:HLA-C Antigens / Q000276:immunology*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D054343:Receptors, KIR2DL2 / Q000235:genetics*; D054344:Receptors, KIR2DL3 / Q000235:genetics*; D014141:Trachoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D055815:Young Adult
chemical_list: D015236:HLA-C Antigens; C515077:KIR2DL2 protein, human; C515078:KIR2DL3 protein, human; D008024:Ligands; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3