Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA‐A3 and A11 in vivo

Abstract

Although HLA-A3 and A11 have been reported to be ligands for KIR3DL2, evidences for in vivo relevance of this interaction is still missing. To explore the functional importance of KIR3DL2 allelic variation, we analyzed the autoimmune disease pemphigus foliaceus, known to be negatively associated with activating KIR genes. The frequency of KIR3DL2*001 was increased in patients (OR=2.04, p=0.007). The risk was higher for the presence of both KIR3DL2*001 and HLA-A3 or A11 (OR=3.76, p=0.013), providing the first evidence that HLA-A3 and A11 may interact with KIR3DL2 in vivo. The non-synonymous single nucleotide polymorphism 1190T (rs3745902) was associated with protection (OR=0.52, p=0.018). This SNP results in a threonine to methionine substitution. Individuals who have methionine in this position exhibit a lower percentage of KIR3DL2 positive cells and also lower intensity of KIR3DL2 on expressing cells; additionally, we show that the expression of KIR3DL2 is independent of other killer cell immunoglobulin-like receptors. Pemphigus foliaceus is a very unique complex disease strongly associated with immune-related genes. It is the only autoimmune disease known to be endemic, showing a strong correlation with environmental factors. Our data demonstrate that this relatively unknown autoimmune disease may facilitate understanding of the molecular mechanisms of KIR3DL2 ligand recognition.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Similarly, polymorphism in the extracellular domain of KIR2DL1 influences the binding affinity to HLA‐C2 34, 40. Over 200 associations of KIR genes with disease resistance or susceptibility are published,56, 73 and the handful studied at high resolution are proving informative 58, 74, 75, 76. The field is therefore ripe for harvesting new information through in‐depth analyses 68, 77…”

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

“…Both KIR and HLA are highly polymorphic, and recognition of the two molecules is specific (e.g., KIR3DL2 combines with HLA-A03 and HLA-A11) (10,13). Studies have shown that KIR3DL2 is a highly polymorphic framework gene with 86 allelic variants (47,48).…”

“…KIR3DL2 is a framework gene present in all humans, which plays a pivotal role in the modulation of NK-cell function (10)(11)(12). HLA-A11 interacts with KIR3DL2 to protect target cells from lysis by NK cells (13,14), and KIR3DL2 binding to HLA-B27 is crucial to the control of HIV progression (15,16).…”

Can we make a better match or mismatch with KIR genotyping?

“…In vivo 63 and in vitro 64 studies suggest that KIR3DL2 recognizes HLA-A3 and A11 but this binding occurs only in the presence of the Epstein-Barr virus EBNA3A peptide. In contrast to the inhibitory KIRs, the ligands for many activating KIRs are largely unknown.…”