A striking feature of KIR genes is their lack of conservation among species and their rapid evolution, which cannot be accounted for solely by divergence in HLA class I molecules (15
). If KIR gene evolution were pathogen driven, some of the diversity would be expected to correlate with resistance or sensitivity to certain infectious diseases. Indeed, several genetic studies of viral infection have revealed an influence of HLA–KIR gene interactions on disease outcome (). An interaction between KIR3DS1
and a subset of HLA-Bw4
alleles—those with Ile at position 80—is associated with delayed progression to AIDS in HIV-infected individuals (2
). In the case of hepatitis C virus (HCV) infection, homozygosity of both HLA-C1
is associated with resolution of infection (4
). A hypothesis proposed to explain the latter finding is that KIR2DL3 binds HLA-C with lower affinity than KIR2DL1 and KIR2DL2 receptors, thus reducing NK cell inhibition and favoring resolution of the infection. However, direct affinity measurements have not revealed a difference between KIR2DL binding to their respective HLA-C ligands (). The report in this issue (1
) reveals a predisposition to human papilloma virus (HPV)–induced cervical cancer with HLA–KIR gene combinations that seem to favor NK cell activation. In contrast to correlations seen with HIV and HCV infections, disease progression toward cervical neoplasia seems enhanced by an increase in activation signals.
Combinations of certain HLA–KIR genotypes have also been linked with susceptibility to autoimmune diseases. Thus, a combination of KIR2DS1
coupled with homozygosity of an HLA-C group favors susceptibility to psoriatic arthritis (5
). Susceptibility could be due to reduced NK cell inhibition, as individuals homozygous for HLA-C1
lack a ligand for KIR2DL2 and KIR2DL3, and those homozygous for HLA-C2
lack a ligand for KIR2DL1. Similarly, KIR2DS2
combined with HLA-C1
in the absence of HLA-C2
is associated with increased susceptibility to type I diabetes (3
). Likewise, KIR2DS1
in combination with HLA-Cw
is a risk factor for psoriasis vulgaris (7
). HLA–KIR combinations that favor NK cell or T cell activation may have been selected to improve resistance to viruses and to malignancy (8
), despite an associated risk of developing autoimmunity ().
HLA–KIR gene combinations that seem to favor NK cell inhibition have also been associated with preeclampsia (6
), a potentially fatal condition caused by incomplete remodeling of spiral arteries in maternal decidua and by high blood pressure during pregnancy. Vascular remodeling is required to provide the fetus with an adequate blood supply. Susceptibility is associated with the combination of HLA-C2 on fetal trophoblast cells and KIR2DL1 on maternal cells, and is further increased by the absence of activating KIR2DS
). A potential explanation of these findings is that KIR2DL1 confers a strong inhibition, compared with KIR2DL2 or KIR2DL3, which prevents activation of NK cells during interaction with fetal trophoblast cells in the decidua. In this context, activation of NK cells is thought to facilitate implantation through cytokine production.