The distribution of KIR‐HLA functional blocks is different from North to South of Italy

Abstract

The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution.

Genetic risk for co‐occurrence of type 1 diabetes and celiac disease is modified byHLA‐C and killer immunoglobulin‐like receptors

“…It seems that Bw4 epitope carried on HLA-A types neutralized this effect. This is in concordance with the observation that HLA-A plays a vicarious role toward the HLA-B Bw4 ligands (45) A substantial body of evidence shows an association of the HLA class I ligands and their KIRs in several autoimmune diseases including T1D (35). In active CD, a subset of intraepithelial cytotoxic T lymphocytes undergoes an NK cell-like transformation -a profound deregulation of genetic program with increased expression levels of NK receptor genes, including the KIR gene family (36).…”

“…It seems that Bw4 epitope carried on HLA‐A types neutralized this effect. This is in concordance with the observation that HLA‐A plays a vicarious role toward the HLA‐B Bw4 ligands …”

Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility

“…We compared the frequencies of each KIR gene and pseudogene between our 100 KD children and 270 Italian Caucasian controls (unrelated blood or bone marrow donors (UBMD)). 17 We only found a borderline significant lower frequency of the activating KIR2DS3 gene in KD (29.00% KD vs 38.52% UBMD, P = 0.09). Figure 1 shows the frequencies of all KIR genes in both KD and UBMD.…”

Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients

“…UPN360 also showed a very peculiar genetic setting, characterized by C2 KIR‐L only and by lack of KIR2DL1 . The lack of KIR2DL1 has been observed only in 3–5% of the population and the concomitant presence of C2/C2 without Bw4 appears very rare . UPN360 lacked KIR‐mediated tolerance and showed the most striking defective self‐iNKR repertoire.…”