Possible KIR-driven genetic pressure on the genesis and maintenance of specific HLA-A,B haplotypes as functional genetic blocks.

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.