Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population—Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures

Cisneros, Elisa; Moraru, Manuela; Gómez‐Lozano, Natalia; Muntasell, Aura; López‐Botet, Miguel; Vilches, Carlos

doi:10.3389/fimmu.2020.00440

Cited by 29 publications

(37 citation statements)

References 56 publications

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“…These haplotypes likely formed by uneven exchange during meiotic recombination, and have also been observed in other populations (17,45,70,71). Although it remains to be confirmed through full haplotype sequence analysis, the insertions/duplications and the deletions occur in approximately the same location 5' from KIR3DP1, suggesting the crossovers can occur frequently through shared mechanisms (72). In addition, we identified a unique haplotype that lacks any KIR genes in the telomeric region 3' from KIR2DL4, leaving only six genes on the entire KIR haplotype (individual 5; Figure 5D).…”

Section: Kir-a Haplotypes Are More Frequent Than Kir-b Haplotypes Both In Centromeric and Telomeric Regionssupporting

confidence: 56%

High-Resolution Analysis Identifies High Frequency of KIR-A Haplotypes and Inhibitory Interactions of KIR With HLA Class I in Zhejiang Han

Tao

Kichula

et al. 2021

Front. Immunol.

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Killer cell immunoglobulin-like receptors (KIR) interact with human leukocyte antigen (HLA) class I molecules, modulating critical NK cell functions in the maintenance of human health. Characterizing the distribution and characteristics of KIR and HLA allotype diversity across defined human populations is thus essential for understanding the multiple associations with disease, and for directing therapies. In this study of 176 Zhejiang Han individuals from Southeastern China, we describe diversity of the highly polymorphic KIR and HLA class I genes at high resolution. KIR-A haplotypes, which carry four inhibitory receptors specific for HLA-A, B or C, are known to associate with protection from infection and some cancers. We show the Chinese Southern Han from Zhejiang are characterized by a high frequency of KIR-A haplotypes and a high frequency of C1 KIR ligands. Accordingly, interactions of inhibitory KIR2DL3 with C1+HLA are more frequent in Zhejiang Han than populations outside East Asia. Zhejiang Han exhibit greater diversity of inhibitory than activating KIR, with three-domain inhibitory KIR exhibiting the greatest degree of polymorphism. As distinguished by gene copy number and allele content, 54 centromeric and 37 telomeric haplotypes were observed. We observed 6% of the population to have KIR haplotypes containing large-scale duplications or deletions that include complete genes. A unique truncated haplotype containing only KIR2DL4 in the telomeric region was also identified. An additional feature is the high frequency of HLA-B*46:01, which may have arisen due to selection pressure from infectious disease. This study will provide further insight into the role of KIR and HLA polymorphism in disease susceptibility of Zhejiang Chinese.

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Section: Kir-a Haplotypes Are More Frequent Than Kir-b Haplotypes Both In Centromeric and Telomeric Regionssupporting

confidence: 56%

High-Resolution Analysis Identifies High Frequency of KIR-A Haplotypes and Inhibitory Interactions of KIR With HLA Class I in Zhejiang Han

Tao

Kichula

et al. 2021

Front. Immunol.

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“…Although such KIR gene profiles ( KIR2DL2 +/ KIR2DS2 -) are rare, they have previously been described in other Caucasian as well as North American populations [ 51 ]. A possible explanation for these rare haplotypes could be KIR2DS2 deletion from the original cluster, or alternatively, the variant KIR gene profile might stem back to an ancestral haplotype existing before the duplicative event responsable for the two paralogues [ 57 ]. The presence of this variant KIR gene profile ( KIR2DL2 +/ KIR2DS2 -) in the group of severely ill SARS-CoV-2 patients leads to the hypothesis that the presence of KIR2DL2 and the absence of KIR2DS2 determine a lower efficiency of NK cell-mediated defense against viral infection which consequently increases the risk of serious clinical manifestations.…”

Section: Resultsmentioning

confidence: 99%

“…The cB03 motif is present on a single haplotype, whereas the remaining three centromeric and two telomeric motifs can be present on all KIR haplotypes. The centromeric and telomeric regions of the KIR haplotypes in this study were assigned as previously described [ 56 , 57 ]. Analyses were based on the content of the inhibitory (L-long) or activating (S-short) KIR genes and their frequencies among the population group and COVID-19 patients with different clinical manifestations.…”

Section: Methodsmentioning

confidence: 99%

Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection

et al. 2021

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Background The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study’s focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. Methods KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. Results Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1–2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3–0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3–0.7), PM = 0.0005, PMC = 0.005]. Conclusions The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.

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“…However, the overall low cytotoxicity displayed by cells from severe and critical COVID-19 did not seem related to specific KIR genes because there were no changes between the different COVID-19 presentations, despite KIR BX haplotype was predominant in our cohort of patients. In fact, KIR BX is the most common haplotype in Spanish individuals ( 53 ). Besides, patients with critical COVID-19 showed higher predominance of HLA-E heterozygosis, which may be related to a more permissive peptide repertoire presentation that is nevertheless not translated to a better cytotoxic response.…”

Section: Discussionmentioning

confidence: 99%

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity

et al. 2021

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Infection by novel coronavirus SARS-CoV-2 causes different presentations of COVID-19 and some patients may progress to a critical, fatal form of the disease that requires their admission to ICU and invasive mechanical ventilation. In order to predict in advance which patients could be more susceptible to develop a critical form of COVID-19, it is essential to define the most adequate biomarkers. In this study, we analyzed several parameters related to the cellular immune response in blood samples from 109 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centers in Madrid, Spain, during the first pandemic peak between April and June 2020. Hospitalized patients with the most severe forms of COVID-19 showed a potent inflammatory response that was not translated into an efficient immune response. Despite the high levels of effector cytotoxic cell populations such as NK, NKT and CD8+ T cells, they displayed immune exhaustion markers and poor cytotoxic functionality against target cells infected with pseudotyped SARS-CoV-2 or cells lacking MHC class I molecules. Moreover, patients with critical COVID-19 showed low levels of the highly cytotoxic TCRγδ+ CD8+ T cell subpopulation. Conversely, CD4 count was greatly reduced in association to high levels of Tregs, low plasma IL-2 and impaired Th1 differentiation. The relative importance of these immunological parameters to predict COVID-19 severity was analyzed by Random Forest algorithm and we concluded that the most important features were related to an efficient cytotoxic response. Therefore, efforts to fight against SARS-CoV-2 infection should be focused not only to decrease the disproportionate inflammatory response, but also to elicit an efficient cytotoxic response against the infected cells and to reduce viral replication.

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Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population—Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures

Cited by 29 publications

References 56 publications

High-Resolution Analysis Identifies High Frequency of KIR-A Haplotypes and Inhibitory Interactions of KIR With HLA Class I in Zhejiang Han

High-Resolution Analysis Identifies High Frequency of KIR-A Haplotypes and Inhibitory Interactions of KIR With HLA Class I in Zhejiang Han

Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity

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