Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci.
Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor-ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.
Carrington
Mary
M
Basic Research Program, Laboratory of Genomic Diversity, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21702, USA. carringt@ncifcrf.gov
Wang
Sophia
S
Martin
Maureen P
MP
Gao
Xiaojiang
X
Schiffman
Mark
M
Cheng
Jie
J
Herrero
Rolando
R
Rodriguez
Ana Cecilia
AC
Kurman
Robert
R
Mortel
Rodrigue
R
Schwartz
Peter
P
Glass
Andrew
A
Hildesheim
Allan
A
D016022:Case-Control Studies; D003364:Costa Rica; D005260:Female; D005805:Genes, MHC Class I / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology*; D005838:Genotype; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D054340:Receptors, KIR; D054349:Receptors, KIR3DS1; D014481:United States; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000276:immunology*
D008024:Ligands; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054349:Receptors, KIR3DS1