HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute ischemic stroke

Antonino Tuttolomondo, ,Calogero Caruso,Alessandra Casuccio,Irene Simonetta,Vittoriano Della Corte,Anna Aiello,Domenico Di Raimondo,Valentina Arnao,Rosaria Pecoraro,Rosario Squatrito,Antonio Pinto,Giulia Accardi,Carlo Maida,Danilo Di Bona,Giuseppe Clemente

doi:10.1186/s12974-019-1469-5

Abstract

IntroductionIn humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs).AimsTo implement the knowledge about the immunological genetic background of acute ischemic stroke susceptibility in relation to the frequency of the KIR genes and HLA alleles.MethodsSubjects with acute ischemic stroke and subjects without stroke were genotyped for the presence of KIR genes and of the three major KIR ligand groups, HLA-C1, HLA-C2, and HLA-Bw4, both HLA-B and HLA-A loci.ResultsBetween November 2013 and February 2016, consecutive patients with acute ischemic stroke were recruited. As healthy controls, we enrolled subjects without acute ischemic stroke. Subjects with acute ischemic stroke in comparison with controls showed a higher frequency of 2DL3, 2DL5B, 2DS2, and 2DS4 KIR genes and a lower frequency of HLA-B-Bw4I alleles. Subjects without acute ischemic stroke showed a higher frequency of interaction between KIR 2DS2 and HLAC2. We also observed a higher frequency of 2DL3 and 2 DL4 KIR genes in subjects with atherosclerotic (LAAS) subtype. Multiple logistic regression analysis showed a protective effect towards stroke of HLA-B-Bw4I and interaction between KIR 2DL2 and HLAC1 and 2DS2-HLAC2 and a detrimental effect of 2DL2-HLA-C1_A interactions.ConclusionOur findings of a higher frequency of activating KIR genes seem to be consistent with findings previously reported patients with coronary syndrome. This higher frequency of “proinflammatory” genes in subjects with ischemic stroke could also explain the immunoinflammatory activation of the acute phase of stroke.

Highlights

In humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs)
A major component of NK and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs), a family of diverse activating or inhibitory receptors that are expressed on the surface of NK cells and T cell subsets
Subjects with acute ischemic stroke showed in comparison with subjects without ischemic stroke higher peripheral percentage of Cluster of differentiation 4 (CD4)+ (50.21 ± 8.31% vs 34.12 ± 6.81%; p < 0.0001) and CD28null (5.70 ± 2.33% vs 2.78 ± 0.93%; p < 0.0001) cells; subjects with stroke showed higher serum levels of TNF-α (18.7 ± 3.28 pg/ml vs 12.34 ± 4.54 pg/ml; p = 0.035) and IL-6 (22.10 ± 12.21 pg/ml vs 4.22 ± 1.44 pg/ml; p < 0.0001)

Summary

Introduction

A major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). Evidence for the contribution of T cell-mediated immunity to cardiovascular diseases has only recently emerged [1, 2]. T-helper type 1 (TH1) and CD8+ cytotoxic T lymphocytes are preponderant [1,2,3,4]. A major component of NK and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs), a family of diverse activating or inhibitory receptors that are expressed on the surface of NK cells and T cell subsets. Our group previously reported [8] that immunocompetent subjects carrying the homozygous A haplotype or the HLABw4T allele are at higher risk of developing symptomatic disease after primary cytomegalovirus (CMV) infection

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Discussion

Conclusion