title: Possible KIR-driven genetic pressure on the genesis and maintenance of specific HLA-A,B haplotypes as functional genetic blocks.
abstract: The HLA genomic structure underlines the permanence of fixed haplotypes transmitted in blocks as allelic combinations. One of the most discussed concerns is how and why such a strong linkage between HLA alleles has been maintained for so long. We hypothesized a possible KIR-driven pressure in the genesis of specific HLA-A,B haplotypes. Certain HLA-A and -B molecules are ligands for the same KIR receptors through the Bw4 binding motif spanning residues 77-83 in the α1 domain. We analyzed the HLA-A and -B genomic types of 9897 Caucasian people (3533 newborns and 6364 adults) subdividing them according to the presence/absence of the HLA-B Bw4 serological epitope. For each HLA-B Bw4- and Bw6-cross-reactive group, we evaluated the presence/absence of HLA-A ligands for KIR3DL1 (HLA-A*23, HLA-A*24, HLA-A*32) and KIR3DL2 (HLA-A*03, HLA-A*11). The frequency of HLA-A KIR ligands significantly increased moving from the HLA-B Bw4/Bw4 to the HLA-B Bw4/Bw6 and the HLA-B Bw6/Bw6 groups among both newborns and adults (P<0.0001). Here, we suggest that, when the HLA-B KIR-ligand motif is lacking, the HLA-A KIR-ligand might have a vicarious role in controlling the natural killer cell-mediated innate immune response. Basing upon this compensatory function in the engagement of KIR receptors, we hypothesize that specific HLA-A,B ancestral haplotypes were generated.
authors.affiliation: Laboratorio di Immunogenetica, Servizio di Immunoematologia e Medicina Trasfusionale, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. cristina.capittini@libero.it
authors.forename: C
authors.initials: C
authors.lastname: Capittini
authors.forename: C
authors.initials: C
authors.lastname: Tinelli
authors.forename: M
authors.initials: M
authors.lastname: Guarene
authors.forename: A
authors.initials: A
authors.lastname: Pasi
authors.forename: C
authors.initials: C
authors.lastname: Badulli
authors.forename: I
authors.initials: I
authors.lastname: Sbarsi
authors.forename: F
authors.initials: F
authors.lastname: Garlaschelli
authors.forename: A L
authors.initials: AL
authors.lastname: Cremaschi
authors.forename: C
authors.initials: C
authors.lastname: Pizzochero
authors.forename: C
authors.initials: C
authors.lastname: Monti
authors.forename: L
authors.initials: L
authors.lastname: Salvaneschi
authors.forename: M
authors.initials: M
authors.lastname: Martinetti
mesh_terms: D000328:Adult; D005787:Gene Frequency; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007231:Infant, Newborn; D007558:Italy; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008957:Models, Genetic; D018448:Models, Immunological; D054340:Receptors, KIR / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D008024:Ligands; D054340:Receptors, KIR