scholarly journals Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumour immunity

2020 ◽  
Author(s):  
Máté Manczinger ◽  
Gergő Balogh ◽  
Benjamin Tamás Papp ◽  
Balázs Koncz ◽  
Leó Asztalos ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Tumour Microenvironment ◽  
Trade Off ◽  
Leukocyte Antigen ◽  
Peptide Binding Specificity ◽  
Worse Prognosis ◽  
Inhibitor Treatment

AbstractThe human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a much wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response is unknown. In this paper, we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles, and found that cancer patients that carry HLA-I alleles with high peptide binding promiscuity are characterized by significantly worse prognosis after immune checkpoint inhibitor treatment. This trend can be explained by a reduced capacity of promiscuous HLA-I molecules to discriminate between human self and tumour peptides, yielding a shift in regulation of T-cells in the tumour microenvironment from activation to tolerance. In summary, HLA-I peptide binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner. It could also underlie a negative trade-off between antitumour immunity and the genetic susceptibility to viral infections.

scholarly journals Association of HLA Class I Genotypes With Severity of Coronavirus Disease-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Maxim Shkurnikov ◽  
Stepan Nersisyan ◽  
Tatjana Jankevic ◽  
Alexei Galatenko ◽  
Ivan Gordeev ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Characteristic Curve ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Specific Immune Response ◽  
Class I ◽  
Leukocyte Antigen ◽  
Hla Class I Molecules ◽  
Severity Of The Disease

Human leukocyte antigen (HLA) class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides at the cell surface where they will be further recognized by T cells. In the present manuscript, we explored whether HLA class I genotypes can be associated with the critical course of Coronavirus Disease-19 by searching possible connections between genotypes of deceased patients and their age at death. HLA-A, HLA-B, and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with next-generation sequencing. Deceased patients were split into two groups according to age at the time of death: n = 26 adult patients aged below 60 and n = 85 elderly patients over 60. With the use of HLA class I genotypes, we developed a risk score (RS) which was associated with the ability to present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides by the HLA class I molecule set of an individual. The resulting RS was significantly higher in the group of deceased adults compared to elderly adults [p = 0.00348, area under the receiver operating characteristic curve (AUC ROC = 0.68)]. In particular, presence of HLA-A*01:01 allele was associated with high risk, while HLA-A*02:01 and HLA-A*03:01 mainly contributed to low risk. The analysis of patients with homozygosity strongly highlighted these results: homozygosity by HLA-A*01:01 accompanied early deaths, while only one HLA-A*02:01 homozygote died before 60 years of age. Application of the constructed RS model to an independent Spanish patients cohort (n = 45) revealed that the score was also associated with the severity of the disease. The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19.

scholarly journals HLA, Immune Response, and Susceptibility to COVID-19

2021 ◽  
Vol 11 ◽  
Author(s):  
Fataneh Tavasolian ◽  
Mohsen Rashidi ◽  
Gholam Reza Hatam ◽  
Marjan Jeddi ◽  
Ahmad Zavaran Hosseini ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Hla Antigens ◽  
Differential Susceptibility ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Global Pandemic ◽  
Subsequent Exposure ◽  
Original Antigenic Sin ◽  
Individual Human

The severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2) that appeared in December 2019 has precipitated the global pandemic Coronavirus Disease 2019 (COVID-19). However, in many parts of Africa fewer than expected cases of COVID-19, with lower rates of mortality, have been reported. Individual human leukocyte antigen (HLA) alleles can affect both the susceptibility and the severity of viral infections. In the case of COVID-19 such an analysis may contribute to identifying individuals at higher risk of the disease and the epidemiological level to understanding the differences between countries in the epidemic patterns. It is also recognized that first antigen exposure influences the consequence of subsequent exposure. We thus propose a theory incorporating HLA antigens, the “original antigenic sin (OAS)” effect, and presentation of viral peptides which could explain with differential susceptibility or resistance to SARS-CoV-2 infections.

scholarly journals The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

2020 ◽  
Vol 117 (21) ◽  
pp. 11636-11647 ◽  
Author(s):  
Philippa M. Saunders ◽  
Bruce J. MacLachlan ◽  
Phillip Pymm ◽  
Patricia T. Illing ◽  
Yuanchen Deng ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Recognition ◽  
Leukocyte Antigen ◽  
Binding Cleft

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

scholarly journals Neolithic genomes reveal a distinct ancient HLA allele pool and population transformation in Europe

2019 ◽  
Author(s):  
Alexander Immel ◽  
Christoph Rinne ◽  
John Meadows ◽  
Rodrigo Barquera ◽  
András Szolek ◽  
...  
Keyword(s):  
Western Europe ◽  
Viral Infections ◽  
Human Leukocyte ◽  
Neolithic Period ◽  
Late Neolithic ◽  
Leukocyte Antigen ◽  
Cultural Transformations ◽  
Farming Community ◽  
Genome Wide ◽  
A Genome

AbstractThe Wartberg culture (WBC, 3,500-2,800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We perform a genome-wide analysis of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3,300-3,200 cal. BCE). Our results highlight that the Niedertiefenbach population indeed emerged at the beginning of the WBC. This farming community was genetically heterogeneous and carried a surprisingly large hunter-gatherer ancestry component (40%). We detect considerable differences in the human leukocyte antigen gene pool between contemporary Europeans and the Niedertiefenbach individuals whose immune response was primarily geared towards defending viral infections.

scholarly journals Innate Immunity Protein Tag7 Induces 3 Distinct Populations of Cytotoxic Cells That Use Different Mechanisms to Exhibit Their Antitumor Activity on Human Leukocyte Antigen-Deficient Cancer Cells

2017 ◽  
Vol 9 (6) ◽  
pp. 598-608 ◽  
Author(s):  
Tatiana N. Sharapova ◽  
Olga K. Ivanova ◽  
Natalia V. Soshnikova ◽  
Elena A. Romanova ◽  
Lidia P. Sashchenko ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
T Lymphocytes ◽  
Human Leukocyte Antigen ◽  
Tumor Cells ◽  
Human Peripheral Blood ◽  
Human Leukocyte ◽  
Peripheral Blood Lymphocytes ◽  
Immunity Protein ◽  
Leukocyte Antigen

The search for new immune response mechanisms capable of controlling immune-evasive tumor cells devoid of the MHC antigen is a challenging task for immunologists. In this study, we found that the treatment of human peripheral blood lymphocytes with the innate immunity protein Tag7 (PGRP-S, PGLYRP1) induces differentiation of the populations of NK (natural killer) cells and CD8+ and CD4+ T lymphocytes that are cytotoxic for human leukocyte antigen-negative tumor cells. These populations employ different mechanisms of tumor cell lysis (based on the release of granzymes in the case of NK cells and on the FasL-Fas interaction in the case of CD8+ and CD4+ T lymphocytes) and induce different death pathways (apoptosis or necroptosis) in tumor cells. An analysis of genes activated in leukocyte populations after Tag7 treatment and experiments with specific inhibitors have shown that the TREM-1 receptor expressed on the monocyte cell surface is essential for activation of cytotoxic activity. Overall, the results of this study provide evidence for a novel role of the Tag7 protein in the immune response.

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