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Sim MJW, Long EO. The peptide selectivity model: Interpreting NK cell KIR-HLA-I binding interactions and their associations to human diseases. Trends Immunol 2024; 45:959-970. [PMID: 39578117 DOI: 10.1016/j.it.2024.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/18/2024] [Accepted: 10/20/2024] [Indexed: 11/24/2024]
Abstract
Combinations of the highly polymorphic KIR and HLA-I genes are associated with numerous human diseases. Interpreting these associations requires a molecular understanding of the multiple killer-cell immunoglobulin-like receptor (KIR)-human leukocyte antigen-1 (HLA-I) receptor-ligand interactions on natural killer (NK) cells and identifying the salient features that underlie disease risk. We hypothesize that a critical discriminating factor in KIR-HLA-I interactions is the selective detection of HLA-I-bound peptides by KIRs. We propose a 'peptide selectivity model', where high-avidity KIR-HLA-I interactions reflect low selectivity for peptides conferring consistent NK cell inhibition across different tissue immunopeptidomes. Conversely, lower-avidity interactions (including those with activating KIRs) are more dependent on HLA-I-bound peptide sequence, requiring an appreciation of how HLA-I immunopeptidomes influence KIR binding and regulate NK cell function. Relevant to understanding NK cell function and pathology, we interpret known KIR-HLA-I combinations and their associations with certain human diseases in the context of this 'peptide selectivity model'.
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Affiliation(s)
- Malcolm J W Sim
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, OX3 7DQ, UK.
| | - Eric O Long
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, 20852, USA
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Ohta R, Tanigawa Y, Suzuki Y, Kellis M, Morishita S. A polygenic score method boosted by non-additive models. Nat Commun 2024; 15:4433. [PMID: 38811555 PMCID: PMC11522481 DOI: 10.1038/s41467-024-48654-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 05/08/2024] [Indexed: 05/31/2024] Open
Abstract
Dominance heritability in complex traits has received increasing recognition. However, most polygenic score (PGS) approaches do not incorporate non-additive effects. Here, we present GenoBoost, a flexible PGS modeling framework capable of considering both additive and non-additive effects, specifically focusing on genetic dominance. Building on statistical boosting theory, we derive provably optimal GenoBoost scores and provide its efficient implementation for analyzing large-scale cohorts. We benchmark it against seven commonly used PGS methods and demonstrate its competitive predictive performance. GenoBoost is ranked the best for four traits and second-best for three traits among twelve tested disease outcomes in UK Biobank. We reveal that GenoBoost improves prediction for autoimmune diseases by incorporating non-additive effects localized in the MHC locus and, more broadly, works best in less polygenic traits. We further demonstrate that GenoBoost can infer the mode of genetic inheritance without requiring prior knowledge. For example, GenoBoost finds non-zero genetic dominance effects for 602 of 900 selected genetic variants, resulting in 2.5% improvements in predicting psoriasis cases. Lastly, we show that GenoBoost can prioritize genetic loci with genetic dominance not previously reported in the GWAS catalog. Our results highlight the increased accuracy and biological insights from incorporating non-additive effects in PGS models.
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Affiliation(s)
- Rikifumi Ohta
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
| | - Yosuke Tanigawa
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Yuta Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Manolis Kellis
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Shinichi Morishita
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
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Mitteroecker P, Merola GP. The cliff edge model of the evolution of schizophrenia: Mathematical, epidemiological, and genetic evidence. Neurosci Biobehav Rev 2024; 160:105636. [PMID: 38522813 DOI: 10.1016/j.neubiorev.2024.105636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/27/2024] [Accepted: 03/16/2024] [Indexed: 03/26/2024]
Abstract
How has schizophrenia, a condition that significantly reduces an individual's evolutionary fitness, remained common across generations and cultures? Numerous theories about the evolution of schizophrenia have been proposed, most of which are not consistent with modern epidemiological and genetic evidence. Here, we briefly review this evidence and explore the cliff edge model of schizophrenia. It suggests that schizophrenia is the extreme manifestation of a polygenic trait or a combination of traits that, within a normal range of variation, confer cognitive, linguistic, and/or social advantages. Only beyond a certain threshold, these traits precipitate the onset of schizophrenia and reduce fitness. We provide the first mathematical model of this qualitative concept and show that it requires only very weak positive selection of the underlying trait(s) to explain today's schizophrenia prevalence. This prediction, along with expectations about the effect size of schizophrenia risk alleles, are surprisingly well matched by empirical evidence. The cliff edge model predicts a dynamic change of selection of risk alleles, which explains the contradictory findings of evolutionary genetic studies.
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Affiliation(s)
- Philipp Mitteroecker
- Unit for Theoretical Biology, Department of Evolutionary Biology, University of Vienna, Djerassiplatz 1, Vienna, Austria; Konrad Lorenz Institute for Evolution and Cognition Research, Martinstrasse 12, Klosterneuburg, Vienna, Austria.
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Tsai YY, Qu C, Bonner JD, Sanz-Pamplona R, Lindsey SS, Melas M, McDonnell KJ, Idos GE, Walker CP, Tsang KK, Da Silva DM, Moratalla-Navarro F, Maoz A, Rennert HS, Kast WM, Greenson JK, Moreno V, Rennert G, Gruber SB, Schmit SL. Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer. Front Immunol 2023; 14:1268117. [PMID: 37942321 PMCID: PMC10627840 DOI: 10.3389/fimmu.2023.1268117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/10/2023] [Indexed: 11/10/2023] Open
Abstract
Objective Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). Methods We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Results Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Conclusion Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.
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Affiliation(s)
- Ya-Yu Tsai
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Chenxu Qu
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | - Joseph D. Bonner
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Rebeca Sanz-Pamplona
- Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Hospital Universitario Lozano Blesa, Aragon Health Research Institute (IISA), ARAID Foundation, Aragon Government, Zaragoza, Spain
| | - Sidney S. Lindsey
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Marilena Melas
- Molecular Diagnostics, New York Genome Center, New York, NY, United States
| | - Kevin J. McDonnell
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Gregory E. Idos
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Christopher P. Walker
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Kevin K. Tsang
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Diane M. Da Silva
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | - Ferran Moratalla-Navarro
- Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona, Barcelona, Spain
| | - Asaf Maoz
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
| | - Hedy S. Rennert
- B. Rappaport Faculty of Medicine, Technion and the Association for Promotion of Research in Precision Medicine (APRPM), Haifa, Israel
| | - W. Martin Kast
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | - Joel K. Greenson
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Victor Moreno
- Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona, Barcelona, Spain
| | - Gad Rennert
- B. Rappaport Faculty of Medicine, Technion and the Association for Promotion of Research in Precision Medicine (APRPM), Haifa, Israel
| | - Stephen B. Gruber
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Stephanie L. Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States
- Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, United States
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Sim MJW, Brennan P, Wahl KL, Lu J, Rajagopalan S, Sun PD, Long EO. Innate receptors with high specificity for HLA class I-peptide complexes. Sci Immunol 2023; 8:eadh1781. [PMID: 37683038 DOI: 10.1126/sciimmunol.adh1781] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 08/08/2023] [Indexed: 09/10/2023]
Abstract
Genetic studies associate killer cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands with a variety of human diseases. The basis for these associations and the relative contribution of inhibitory and activating KIR to NK cell responses are unclear. Because KIR binding to HLA-I is peptide dependent, we performed systematic screens, which totaled more than 3500 specific interactions, to determine the specificity of five KIR for peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely peptide sequence agnostic and could bind ~60% of hundreds of HLA-peptide complexes tested. Inhibitory KIR2DL2, KIR2DL3, and activating KIR2DS1 and KIR2DS4 bound only 10% and down to 1% of HLA-peptide complexes tested, respectively. Activating KIR2DS1, previously described as weak, had high binding affinity for HLA-C, with high peptide sequence specificity. Our data revealed MHC-restricted peptide recognition by germline-encoded NK receptors and suggest that NK cell responses can be shaped by HLA-I-bound immunopeptidomes in the context of disease or infection.
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Affiliation(s)
- Malcolm J W Sim
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
| | - Paul Brennan
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
| | - Katherine L Wahl
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
| | - Jinghua Lu
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
| | - Sumati Rajagopalan
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
| | - Peter D Sun
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
| | - Eric O Long
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
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Gunavathy N, Asirvatham A, Chitra A, Jayalakshmi M. Association of Killer Cell Immunoglobulin-Like Receptors and Their HLA-Ligands with Type 1 Diabetes Among South Indian Population. Immunol Invest 2023; 52:270-285. [PMID: 36705596 DOI: 10.1080/08820139.2023.2165940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Type 1 diabetes (T1D) is a multifactorial autoimmune disease, involving strong genetic components with familial predisposition. Killer cell immunoglobulin-like receptors (KIRs) found on the surface of NK cells have ligands of human leukocyte antigen (HLA) class I that are associated with T1D. The present study evaluates the influence of KIR genes and their HLA-ligands in the aetiology of T1D among the South Indian population. METHODS A total of 125 T1D patients, along with their parents (n = 126) and siblings (n = 52) were recruited. PCR-based genotyping was performed for KIR genes and HLA class I ligands. The gene frequencies were compared between patients and siblings/parents. Linkage-disequilibrium (LD) analysis was performed to assess the genetic association between KIR gene pairs. RESULTS The results show significant differences in HLA-ligands of KIR genes between patients and parents. The HLA-C1C1 homozygosity was found to be a predisposing risk factor, and HLA-C1C2 heterozygosity was protective towards T1D along with either the activating KIR2DS2 or inhibitory KIRs 2DL1, 2DL2, 2DL3. However, the frequency of inhibitory KIR3DL1 significantly increased in the presence of HLA-B Bw4 Ile80 in parents when compared to patients showing a protective effect on T1D. Two pairs of KIR genes, 2DS4-3DL1 and 2DS1-2DL5, showed strong LD in patients, siblings and parents. CONCLUSION The KIR-HLA ligand combinations have a significant effect on T1D aetiology among the South Indian population. This study defines a pattern for family-based association studies with genotypic information about KIR genes and their HLA-ligands, providing the first evidence towards T1D among the South Indian population.
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Affiliation(s)
- Nagarajan Gunavathy
- Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Arthur Asirvatham
- Department of Diabetology, Government Rajaji Hospital, Madurai, India
| | - Ayyappan Chitra
- Institute of Child Health and Research Centre, Government Rajaji Hospital, Madurai, India
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Killer-Cell Immunoglobulin-like Receptor Diversity in an Admixed South American Population. Cells 2022; 11:cells11182776. [PMID: 36139351 PMCID: PMC9496851 DOI: 10.3390/cells11182776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Natural Killer (NK) cells are innate immune cells that mediate antiviral and antitumor responses. NK cell activation and induction of effector functions are tightly regulated by the integration of activating and inhibitory receptors such as killer immunoglobulin-like receptors (KIR). KIR genes are characterized by a high degree of diversity due to presence or absence, gene copy number and allelic polymorphism. The aim of this study was to establish the distribution of KIR genes and genotypes, to infer the most common haplotypes in an admixed Colombian population and to compare these KIR gene frequencies with some Central and South American populations and worldwide. A total of 161 individuals from Medellin, Colombia were included in the study. Genomic DNA was used for KIR and HLA genotyping. We analyzed only KIR gene-content (presence or absence) based on PCR-SSO. The KIR genotype, most common haplotypes and combinations of KIR and HLA ligands frequencies were estimated according to the presence or absence of KIR and HLA genes. Dendrograms, principal component (PC) analysis and Heatmap analysis based on genetic distance were constructed to compare KIR gene frequencies among Central and South American, worldwide and Amerindian populations. The 16 KIR genes analyzed were distributed in 37 different genotypes and the 7 most frequent KIR inferred haplotypes. Importantly, we found three new genotypes not previously reported in any other ethnic group. Our genetic distance, PC and Heatmap analysis revealed marked differences in the distribution of KIR gene frequencies in the Medellin population compared to worldwide populations. These differences occurred mainly in the activating KIR isoforms, which are more frequent in our population, particularly KIR3DS1. Finally, we observed unique structural patterns of genotypes, which evidences the potential diversity and variability of this gene family in our population, and the need for exhaustive genetic studies to expand our understanding of the KIR gene complex in Colombian populations.
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Vollmers S, Lobermeyer A, Niehrs A, Fittje P, Indenbirken D, Nakel J, Virdi S, Brias S, Trenkner T, Sauer G, Peine S, Behrens GM, Lehmann C, Meurer A, Pauli R, Postel N, Roider J, Scholten S, Spinner CD, Stephan C, Wolf E, Wyen C, Richert L, Norman PJ, Sauter J, Schmidt AH, Hoelzemer A, Altfeld M, Körner C. Host KIR/HLA-C Genotypes Determine HIV-Mediated Changes of the NK Cell Repertoire and Are Associated With Vpu Sequence Variations Impacting Downmodulation of HLA-C. Front Immunol 2022; 13:922252. [PMID: 35911762 PMCID: PMC9334850 DOI: 10.3389/fimmu.2022.922252] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 06/13/2022] [Indexed: 12/29/2022] Open
Abstract
NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1/L2/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host HLA-C genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between KIR/HLA immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific KIR/HLA-C combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1+ individuals. Compared to 60 HIV-1- controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C+ and KIR3DL2+ NK cell sub-populations from HIV-1+ individuals was enlarged compared to HIV-1- controls. Stratification along KIR/HLA-C genotypes revealed a genotype-dependent expansion of KIR2DL1+ NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host KIR2DL/HLA-C genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1.
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Affiliation(s)
| | | | | | - Pia Fittje
- Leibniz Institute of Virology, Hamburg, Germany
| | | | | | | | - Sebastien Brias
- Leibniz Institute of Virology, Hamburg, Germany
- First Department of Medicine, Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Gabriel Sauer
- Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany
| | - Sven Peine
- Institute for Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Georg M.N. Behrens
- Department for Rheumatology and Clinical Immunology, Hannover Medical School, Hannover, Germany
| | - Clara Lehmann
- Department I for Internal Medicine, Division of Infectious Diseases, University Hospital Cologne, Cologne, Germany
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Anja Meurer
- Center for Internal Medicine and Infectiology, Munich, Germany
| | - Ramona Pauli
- Medizinisches Versorgungszentrum (MVZ) am Isartor, Munich, Germany
| | - Nils Postel
- Prinzmed, Practice for Infectious Diseases, Munich, Germany
| | - Julia Roider
- Department of Internal Medicine IV, Department of Infectious Diseases, Ludwig-Maximilians University Munich, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | | | - Christoph D. Spinner
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
- Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Department of Internal Medicine II, Munich, Germany
| | - Christoph Stephan
- Infectious Diseases Unit, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | | | - Christoph Wyen
- Department I for Internal Medicine, Division of Infectious Diseases, University Hospital Cologne, Cologne, Germany
- Praxis am Ebertplatz, Cologne, Germany
| | - Laura Richert
- University of Bordeaux, Inserm U1219 Bordeaux Population Health, Inria Sistm, Bordeaux, France
| | - Paul J. Norman
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado, Aurora, CO, United States
| | | | | | - Angelique Hoelzemer
- Leibniz Institute of Virology, Hamburg, Germany
- First Department of Medicine, Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Marcus Altfeld
- Leibniz Institute of Virology, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Christian Körner
- Leibniz Institute of Virology, Hamburg, Germany
- *Correspondence: Christian Körner,
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Pollock NR, Harrison GF, Norman PJ. Immunogenomics of Killer Cell Immunoglobulin-Like Receptor (KIR) and HLA Class I: Coevolution and Consequences for Human Health. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2022; 10:1763-1775. [PMID: 35561968 PMCID: PMC10038757 DOI: 10.1016/j.jaip.2022.04.036] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022]
Abstract
Interactions of killer cell immunoglobin-like receptors (KIR) with human leukocyte antigens (HLA) class I regulate effector functions of key cytotoxic cells of innate and adaptive immunity. The extreme diversity of this interaction is genetically determined, having evolved in the ever-changing environment of pathogen exposure. Diversity of KIR and HLA genes is further facilitated by their independent segregation on separate chromosomes. That fetal implantation relies on many of the same types of immune cells as infection control places certain constraints on the evolution of KIR interactions with HLA. Consequently, specific inherited combinations of receptors and ligands may predispose to specific immune-mediated diseases, including autoimmunity. Combinatorial diversity of KIR and HLA class I can also differentiate success rates of immunotherapy directed to these diseases. Progress toward both etiopathology and predicting response to therapy is being achieved through detailed characterization of the extent and consequences of the combinatorial diversity of KIR and HLA. Achieving these goals is more tractable with the development of integrated analyses of molecular evolution, function, and pathology that will establish guidelines for understanding and managing risks. Here, we present what is known about the coevolution of KIR with HLA class I and the impact of their complexity on immune function and homeostasis.
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Affiliation(s)
- Nicholas R Pollock
- Division of Biomedical Informatics and Personalized Medicine and Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, Colo
| | - Genelle F Harrison
- Division of Biomedical Informatics and Personalized Medicine and Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, Colo
| | - Paul J Norman
- Division of Biomedical Informatics and Personalized Medicine and Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, Colo.
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Hojjatipour T, Aslani S, Salimifard S, Mikaeili H, Hemmatzadeh M, Gholizadeh Navashenaq J, Ahangar Parvin E, Jadidi-Niaragh F, Mohammadi H. NK cells - Dr. Jekyll and Mr. Hyde in autoimmune rheumatic diseases. Int Immunopharmacol 2022; 107:108682. [DOI: 10.1016/j.intimp.2022.108682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023]
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11
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Alexandrova M, Manchorova D, Dimova T. Immunity at maternal-fetal interface: KIR/HLA (Allo)recognition. Immunol Rev 2022; 308:55-76. [PMID: 35610960 DOI: 10.1111/imr.13087] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 04/28/2022] [Accepted: 05/09/2022] [Indexed: 12/15/2022]
Abstract
Both KIR and HLA are the most variable gene families in the human genome. The recognition of the semi-allogeneic embryo-derived trophoblasts by maternal decidual NK (dNK) cells is essential for the establishment of the functional placenta. This recognition is based on the KIR-HLA interactions and trophoblast expresses a specific HLA profile that constitutes classical polymorphic HLA-C and non-classical oligomorphic HLA-E, HLA-F, and HLA-G molecules. This review highlights some features of the KIR/HLA-C (allo)recognition by decidual NK (dNK) cells as a main immune cell population specifically enriched at maternal-fetal interface during human early pregnancy. How KIR/HLA-C axis operates in pregnancy disorders and in the context of transplacental infections is discussed as well. We summarized old and new data on dNK-cell functional plasticity, their selective expression of KIR and fetal maternal/paternal HLA-C haplotypes present. Results showed that KIR-HLA-C combinations and the corresponding axis operate differently in each pregnancy, determined by the variability of both maternal KIR haplotypes and fetus' maternal/paternal HLA-C allotype combinations. Moreover, the maturation of NK cells strongly depends on if or not HLA allotypes for certain KIR are present. We suggest that the unique KIR/HLA combinations reached in each pregnancy (normal and pathological) should be studied according to well-defined guidelines and unified methodologies to have comparable results ease to interpret and use in clinics.
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Affiliation(s)
- Marina Alexandrova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Diana Manchorova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Tanya Dimova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria
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12
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de Brito Vargas L, Beltrame MH, Ho B, Marin WM, Dandekar R, Montero-Martín G, Fernández-Viña MA, Hurtado AM, Hill KR, Tsuneto LT, Hutz MH, Salzano FM, Petzl-Erler ML, Hollenbach JA, Augusto DG. Remarkably Low KIR and HLA Diversity in Amerindians Reveals Signatures of Strong Purifying Selection Shaping the Centromeric KIR Region. Mol Biol Evol 2022; 39:msab298. [PMID: 34633459 PMCID: PMC8763117 DOI: 10.1093/molbev/msab298] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR-HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR-HLA interactions among all described worldwide populations, and that 83-97% of their KIR-HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR-HLA coevolution and its impact on human health and survival.
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Affiliation(s)
- Luciana de Brito Vargas
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Marcia H Beltrame
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Brenda Ho
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
| | - Wesley M Marin
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
| | - Ravi Dandekar
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - A Magdalena Hurtado
- School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA
| | - Kim R Hill
- School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA
| | - Luiza T Tsuneto
- Departamento de Análises Clínicas, Universidade Estadual de Maringá, Maringá, PR, Brazil
| | - Mara H Hutz
- Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Francisco M Salzano
- Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Maria Luiza Petzl-Erler
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Jill A Hollenbach
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Danillo G Augusto
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brazil
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
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13
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Marin WM, Dandekar R, Augusto DG, Yusufali T, Heyn B, Hofmann J, Lange V, Sauter J, Norman PJ, Hollenbach JA. High-throughput Interpretation of Killer-cell Immunoglobulin-like Receptor Short-read Sequencing Data with PING. PLoS Comput Biol 2021; 17:e1008904. [PMID: 34339413 PMCID: PMC8360517 DOI: 10.1371/journal.pcbi.1008904] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 08/12/2021] [Accepted: 07/16/2021] [Indexed: 02/07/2023] Open
Abstract
The killer-cell immunoglobulin-like receptor (KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.
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Affiliation(s)
- Wesley M. Marin
- UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America
| | - Ravi Dandekar
- UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America
| | - Danillo G. Augusto
- UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America
| | - Tasneem Yusufali
- UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America
| | | | | | | | | | - Paul J. Norman
- Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Jill A. Hollenbach
- UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, United States of America
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14
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Kucuksezer UC, Aktas Cetin E, Esen F, Tahrali I, Akdeniz N, Gelmez MY, Deniz G. The Role of Natural Killer Cells in Autoimmune Diseases. Front Immunol 2021; 12:622306. [PMID: 33717125 PMCID: PMC7947192 DOI: 10.3389/fimmu.2021.622306] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022] Open
Abstract
Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970's. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don't express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet's disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and "bridge" them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.
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Affiliation(s)
- Umut Can Kucuksezer
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Esin Aktas Cetin
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Fehim Esen
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Department of Ophthalmology, Medical Faculty, Istanbul Medeniyet University, Istanbul, Turkey
| | - Ilhan Tahrali
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Nilgun Akdeniz
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Metin Yusuf Gelmez
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Gunnur Deniz
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
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15
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Soltani S, Mostafaei S, Aslani S, Farhadi E, Mahmoudi M. Association of KIR gene polymorphisms with Type 1 Diabetes: a meta-analysis. J Diabetes Metab Disord 2021; 19:1777-1786. [PMID: 33520861 DOI: 10.1007/s40200-020-00569-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 05/20/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022]
Abstract
Purpose Type 1 Diabetes (T1D) is a T cell-mediated disease, in which autoimmune destruction of insulin-producing β-cells in pancreatic islets occurs. In recent decades, the role of Killer cell immunoglobulin-like receptor (KIR) gene polymorphisms in susceptibility to T1D has been demonstrated in an increased number of studies. Nonetheless, inconsistency has been observed in the results of performed association studies. To comprehensively clarify the association among KIR gene polymorphisms and the risk of T1D, this meta-analysis on the previously published association studies was carried out via incorporating multiple research. Methods No publication has been recorded from Nov 2017 until July 2020 about the KIR genes and T1D. The PubMed/MEDLINE and Scopus databases were systematically searched up to November 2017 to identify investigations on the impact of the polymorphisms of KIR genes on susceptibility to T1D. The odds ratio (OR) with a 95% confidence interval (95% CI) was calculated. Funnel plot and Egger test were used to assess the publication bias. Thirteen qualified published case-control articles were found for evaluation in this meta-analysis. Results Our results show statistical significance between the genetic variations in the KIR2DL1 (OR = 0.42, 95% CI = 0.23-0.77; P = 0.005), KIR2DL2 (OR = 1.15, 95% CI = 1.00-1.32; P = 0.048), and KIR2DL5 (OR = 0.86, 95% CI = 0.75-0.98; P = 0.03) with susceptibility to T1D. Conclusions This meta-analysis study provides reliable evidence that KIR gene polymorphisms may contribute to T1D risk. KIR 2DL1 and 2DL5 genes might be considered as a protective factor for T1D, while 2DL2 seemed to be a susceptibility factor.
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Affiliation(s)
- Samaneh Soltani
- Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, PO-BOX: 1411713137, Kargar Ave., Tehran, Iran
| | - Shayan Mostafaei
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Sorkheh-Ligeh Blvd, Kermanshah, Iran
| | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Farhadi
- Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, PO-BOX: 1411713137, Kargar Ave., Tehran, Iran.,Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, PO-BOX: 1411713137, Kargar Ave., Tehran, Iran.,Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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16
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Yang Y, Day J, Souza-Fonseca Guimaraes F, Wicks IP, Louis C. Natural killer cells in inflammatory autoimmune diseases. Clin Transl Immunology 2021; 10:e1250. [PMID: 33552511 PMCID: PMC7850912 DOI: 10.1002/cti2.1250] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells are a specialised population of innate lymphoid cells (ILCs) that help control local immune responses. Through natural cytotoxicity, production of cytokines and chemokines, and migratory capacity, NK cells play a vital immunoregulatory role in the initiation and chronicity of inflammatory and autoimmune responses. Our understanding of their functional differences and contributions in disease settings is evolving owing to new genetic and functional murine proof-of-concept studies. Here, we summarise current understanding of NK cells in several classic autoimmune disorders, particularly in rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1DM), but also less understood diseases such as idiopathic inflammatory myopathies (IIMs). A better understanding of how NK cells contribute to these autoimmune disorders may pave the way for NK cell-targeted therapeutics.
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Affiliation(s)
- Yuyan Yang
- Tsinghua University School of Medicine Beijing China.,Inflammation Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
| | - Jessica Day
- Inflammation Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia.,Medical Biology University of Melbourne Melbourne VIC Australia.,Rheumatology Unit The Royal Melbourne Hospital Parkville VIC Australia
| | | | - Ian P Wicks
- Inflammation Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia.,Medical Biology University of Melbourne Melbourne VIC Australia.,Rheumatology Unit The Royal Melbourne Hospital Parkville VIC Australia
| | - Cynthia Louis
- Inflammation Division The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia.,Medical Biology University of Melbourne Melbourne VIC Australia
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17
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Beigmohammadi F, Mahmoudi M, Karami J, Ahmadzadeh N, Ebrahimi-Daryani N, Rezaei N. Analysis of Killer Cell Immunoglobulin-Like Receptor Genes and Their HLA Ligands in Inflammatory Bowel Diseases. J Immunol Res 2020; 2020:4873648. [PMID: 33015197 PMCID: PMC7520679 DOI: 10.1155/2020/4873648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 08/16/2020] [Accepted: 09/08/2020] [Indexed: 12/12/2022] Open
Abstract
Genetic studies have illustrated that killer cell immunoglobulin-like receptor (KIR) genes could participate in various autoimmune disorders. We aimed to clarify the role of KIR genes, HLA ligands, HLA-KIR interactions, and their genotypes in inflammatory bowel disease (IBD) susceptibility. The study population was composed of 183 IBD subjects, comprising 100 ulcerative colitis (UC) patients, 83 Crohn's disease (CD) patients, and 274 healthy subjects. Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to evaluate the absence or presence of the 15 KIR genes, 5 HLA class I ligands, and 2 pseudogenes. We did not find any significant difference in allele frequency of KIRs and pseudogenes between IBD patients and healthy controls. In the case of HLA genes, there was a significant difference in HLA-B-Bw4Thr80 frequency between UC patients and healthy controls (P = 0.03, OR = 0.06, 95%CI = 0.008-0.4). Furthermore, we found a significant difference in HLA-C1Asn80 frequency between CD patients and healthy controls (P = 0.04, OR = 0.49, 95% CI = 0.3-0.8). In the full-array combination of KIR genes, there was no significant frequency difference between UC patients and healthy controls, while two KIR genotypes showed a significant susceptible association with CD. Our data do not support a strong role of NK cells in IBD susceptibility, but it does not rule out a role for KIR variability in IBD patients. However, there are some protective associations such as Bw4 alleles; these associations may be due to the interaction of the alleles to TCRs rather than KIRs.
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Affiliation(s)
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Rheumatology Expert Group (REG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Jafar Karami
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nooshin Ahmadzadeh
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser Ebrahimi-Daryani
- Department of Gastroenterology and Hepatology, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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18
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Vargas LDB, Dourado RM, Amorim LM, Ho B, Calonga-Solís V, Issler HC, Marin WM, Beltrame MH, Petzl-Erler ML, Hollenbach JA, Augusto DG. Single Nucleotide Polymorphism in KIR2DL1 Is Associated With HLA-C Expression in Global Populations. Front Immunol 2020; 11:1881. [PMID: 32983108 PMCID: PMC7478174 DOI: 10.3389/fimmu.2020.01881] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/13/2020] [Indexed: 12/13/2022] Open
Abstract
Regulation of NK cell activity is mediated through killer-cell immunoglobulin-like receptors (KIR) ability to recognize human leukocyte antigen (HLA) class I molecules as ligands. Interaction of KIR and HLA is implicated in viral infections, autoimmunity, and reproduction and there is growing evidence of the coevolution of these two independently segregating gene families. By leveraging KIR and HLA-C data from 1000 Genomes consortium we observed that the KIR2DL1 variant rs2304224 * T is associated with lower expression of HLA-C in individuals carrying the ligand HLA-C2 (p = 0.0059). Using flow cytometry, we demonstrated that this variant is also associated with higher expression of KIR2DL1 on the NK cell surface (p = 0.0002). Next, we applied next generation sequencing to analyze KIR2DL1 sequence variation in 109 Euro and 75 Japanese descendants. Analyzing the extended haplotype homozygosity, we show signals of positive selection for rs4806553 * G and rs687000 * G, which are in linkage disequilibrium with rs2304224 * T. Our results suggest that lower expression of HLA-C2 ligands might be compensated for higher expression of the receptor KIR2DL1 and bring new insights into the coevolution of KIR and HLA.
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Affiliation(s)
- Luciana de Brito Vargas
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil
| | - Renata M Dourado
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil
| | - Leonardo M Amorim
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil
| | - Brenda Ho
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Verónica Calonga-Solís
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil
| | - Hellen C Issler
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil
| | - Wesley M Marin
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Marcia H Beltrame
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil
| | - Maria Luiza Petzl-Erler
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil
| | - Jill A Hollenbach
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Danillo G Augusto
- Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil.,Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
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19
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Hanson AL, Vukcevic D, Leslie S, Harris J, Lê Cao KA, Kenna TJ, Brown MA. Epistatic interactions between killer immunoglobulin-like receptors and human leukocyte antigen ligands are associated with ankylosing spondylitis. PLoS Genet 2020; 16:e1008906. [PMID: 32804949 PMCID: PMC7451988 DOI: 10.1371/journal.pgen.1008906] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 08/27/2020] [Accepted: 06/03/2020] [Indexed: 12/14/2022] Open
Abstract
The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis. Cells of the immune system utilise various cell-surface receptors to differentiate between healthy and infected or malignant cells, enabling targeted inflammatory responses while minimising damage to self-tissue. In instances where the immune system fails to correctly differentiate healthy from diseased tissue, or inflammatory activity is poorly regulated, autoimmune or autoinflammatory conditions can develop. Here we have investigated a possible role for a class of immune-cell activating and inhibitory receptors in the pathogenesis of ankylosing spondylitis (AS), a common but poorly understood inflammatory arthritis in which the immune system causes severe damage to the joints of the pelvis and spine. Using genetic information from 12,214 healthy controls and 8,107 individuals with AS we were able to identify combinations of independently inherited immune cell receptors and their ligands that increase or decrease an individual’s risk of disease. This research provides new insight into the nature of co-inherited genetic factors that may collectively alter the proinflammatory capacity of immune cells, contributing to the immunopathogenesis of immune-mediated diseases.
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Affiliation(s)
- Aimee L. Hanson
- University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia
| | | | - Damjan Vukcevic
- Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
- Data Science, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
| | - Stephen Leslie
- Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
- Data Science, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- School of Biosciences, University of Melbourne, Parkville, Victoria Australia
| | - Jessica Harris
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
- Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Kim-Anh Lê Cao
- Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
| | - Tony J. Kenna
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
- Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Matthew A. Brown
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
- Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
- * E-mail:
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20
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The Increased Ratio of Blood CD56 bright NK to CD56 dim NK Is a Distinguishing Feature of Primary Sjögren's Syndrome. J Immunol Res 2020; 2020:7523914. [PMID: 32695834 PMCID: PMC7368214 DOI: 10.1155/2020/7523914] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/13/2020] [Indexed: 02/06/2023] Open
Abstract
Objective The aim of this study was to characterize the subsets of circulating CD56+ NK cells in pSS patients and their potential value in the diagnosis and/or prediction of prognosis in patients with pSS. Methods We included 52 pSS patients fulfilling the 2002 AECG criteria or 2012 ACR criteria and 20 age- and gender-matched healthy volunteers. The frequency and absolute number of NK cells and CD56 NK cell subsets in peripheral blood samples were detected by flow cytometry. Other laboratory parameters such as the IgG level and complement protein levels were extracted from the clinical system. Results Both the frequency and the absolute number of peripheral blood NK cells were reduced in pSS patients compared to healthy controls. The proportion of CD56bright NK cell subset was increased, and the proportion of CD56dim NK cell subset was decreased among NK cells, resulting in the ratio of CD56bright NK to CD56dim NK which was significantly elevated in pSS patients. ROC analysis indicated that the AUC of CD56bright NK/CD56dim NK ratio was 0.838, and the best diagnostic cut-off point was 0.0487 for pSS patients. Furthermore, this CD56bright NK/CD56dim NK ratio was positively correlated with the IgG level and negatively correlated with the complement protein C3 and C4 levels. More importantly, the CD56bright/CD56dim NK ratio was either slightly increased or not changed in other autoimmune diseases such as SLE and IgG4-related disease. Conclusion Our findings suggest that the ratio of blood CD56bright NK to CD56dim NK might have a diagnostic value relatively specific for pSS.
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21
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Chaisri S, Jumnainsong A, Romphruk A, Leelayuwat C. The effect of KIR and HLA polymorphisms on dengue infection and disease severity in northeastern Thais. Med Microbiol Immunol 2020; 209:613-620. [PMID: 32524212 DOI: 10.1007/s00430-020-00685-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 06/02/2020] [Indexed: 10/24/2022]
Abstract
Killer cell immunoglobulin-like receptors (KIRs) are cell surface receptors on natural killer (NK) cells and subsets of T cells. The interaction between KIRs and their cognate ligands (Human leukocyte antigen class I molecules, HLA class I) modulates the immune response of NK cells, in particular through clearance of virus-infected cells. Here, we investigated the effect of KIRs and HLA ligands on dengue infections and disease severity. The KIRs and HLA ligands were identified in 235 healthy controls (HC) and 253 dengue patients (DEN) using polymerase chain reaction with sequence specific primer (PCR-SSP); moreover, DEN was classified to 100 dengue fever (DF) and 153 dengue haemorrhagic fever (DHF). Risks were expressed as odds ratios (ORs) and 95% confidence intervals (CIs) with significance set at a two-tailed P value of < 0.05. The Bonferroni correction was applied for multiple comparisons. Twelve significant associations were observed in dengue infections and disease severity; however, two outcomes survived after the Bonferroni correction. Of these, HLA-A11 was associated with an increased risk to develop dengue disease (OR 2.41, 95% CI 1.62-3.60, Pc = 0.004), while KIR3DS1+ Bw4 was a protective genotype to developing DHF (OR 0.28, 95% CI 0.16-0.48, Pc < 0.001). This study revealed an important role of KIR and HLA ligands in innate immune responses to dengue viral infections and, in particular, their effect on clinical outcomes and disease severity.
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Affiliation(s)
- Suwit Chaisri
- Chulabhorn International College of Medicine (CICM), Thammasat University, Pathum Thani, 12121, Thailand.,The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Amonrat Jumnainsong
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.,Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Amornrat Romphruk
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.,Blood Transfusion Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chanvit Leelayuwat
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand. .,Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
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22
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Significance of KIR like natural killer cell receptors in autoimmune disorders. Clin Immunol 2020; 216:108449. [PMID: 32376502 DOI: 10.1016/j.clim.2020.108449] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 04/21/2020] [Accepted: 04/27/2020] [Indexed: 12/26/2022]
Abstract
Killer cell immunoglobulin-like receptors (KIRs), act as the regulators for the cytolytic activity of natural killer and certain T cells by interacting with the HLA class I ligands. KIRs have been shown to contribute to the pathogenesis of several autoimmune diseases. However, their specific roles are still not very clear. Autoimmune diseases are multifactorial in nature, highlighting the influence of both genetic and environmental factors. The innate immune response plays an important role in autoimmunity as it alters the self-glycans that mimic molecular patterns found on different intracellular pathogens. Natural killer (NK) cells have an important position in the innate immune response. NK cell receptors are encoded by the leukocyte receptor complex located on the chromosome 19q13.4 and lectin-like receptors on chromosome 12p13. This review focuses on the role of KIRs and their relationship with different autoimmune diseases.
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23
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Reduced Efficacy of Biological Drugs in Psoriatic Patients with HLA-A Bw4-80I KIR Ligands. Mol Diagn Ther 2020; 24:311-314. [PMID: 32189206 DOI: 10.1007/s40291-020-00457-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Biological drugs (biologics) are a highly effective therapy for the moderate to severe form of psoriasis, an immune-mediated dermatosis with a strong immunogenetic component. The interaction between human leukocyte antigen (HLA) class I ligands and killer immunoglobulin-like receptors (KIR) has a functional significance in the education of natural killer (NK) cells, and can thus influence the response to biologics. OBJECTIVE In this study, we investigated the impact of HLA-A and -B KIR ligands in the response to biologics in a cohort of psoriatic patients. METHODS Eighty-five patients with moderate to severe psoriasis treated with biologics (adalimumab, etanercept, infliximab, ustekinumab and secukinumab) were enrolled in the study. Clinical response was evaluated as patients attaining 50%, 75% or 90% reduction in the Psoriasis Area and Severity Index (PASI) (PASI 50, 75 or 90, respectively) over 6 months' follow-up. Poor response was defined as PASI 50, and in this case patients shifted to treatment with a different biologic. Fifty-two patients (61.2%) showed excellent response (PASI 90) to the first biologic, while 33 patients (38.8%), needed two or more biologics before reaching an excellent response (PASI 90) and were considered difficult to treat. RESULTS Only HLA-A Bw4-80I ligands were associated with the response to biologics; in particular, they were linked with reduced response both at univariable analysis (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.19-8.07; p = 0.019) and multivariable analysis (OR 5.02, 95% CI 1.40-17.97; p = 0.013). CONCLUSION We suggest that the HLA-A Bw4-80I epitope could be a marker of reduced responsiveness to biologics. The possible reason for this is an increase of tumour necrosis factor (TNF)-α and the silencing of NK cells through the predominant interaction with the KIR3DL/S pair. HLA-KIR affinities might lead to a more efficient way to prescribe biologics.
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24
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Enciso-Vargas M, Alvarado-Ruíz L, Suárez-Villanueva AS, Macías-Barragán J, Montoya-Buelna M, Oceguera-Contreras E, Alvarado-Navarro A, Graciano-Machuca O. Association Study between Psoriatic Arthritis and Killer Immunoglobulin-Like Receptor ( KIR) Genes: A Meta-Analysis. Immunol Invest 2020; 50:152-163. [PMID: 31957514 DOI: 10.1080/08820139.2020.1713145] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background: Psoriatic Arthritis (PsA) is a seronegative spondyloarthropathy frequently associated with psoriasis. Studies have shown different members of the KIR (Killer Immunoglobulin-like Receptor) gene family may act as potential susceptibility factors; however, data have been inconsistent or with a reduced sample size. Therefore, the objective of this investigation was to determine associations between KIR genes and PsA susceptibility a meta-analysis approach. Methods: We performed a systemic search on PubMed, Scopus, and Web of Science to identify association studies linking KIR genes with PsA susceptibility. The search cut-off was May 2019. Odds Ratio (OR), 95% Confidence Intervals (95% CI), and forest plots were obtained for each KIR gene. Publication bias was evaluated by Begg and Egger linear regression tests. Results: Five articles were included in this meta-analysis. The KIR2DL2, 2DS1, 2DS2, and 2DS3 genes were positively associated with susceptibility to PsA (OR = 1.269, p = .003; OR = 1.392, p < .001; OR = 1.279, p = .002; and OR = 1.230, p = .038, respectively). In Caucasians, positive association with susceptibility to PsA were maintained by KIR2DL2, 2DS1, and 2DS2 genes (OR = 1.257, p = .005; OR = 1.535, p = .003; and OR = 1.267, p = .004, respectively). Conclusion: These associations suggest that KIR2DL2, 2DS1, 2DS2, and 2DS3 genes are susceptibility factors for PsA.
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Affiliation(s)
- Moisés Enciso-Vargas
- Departamento de Ciencias Médicas y de la Vida, Centro Universitario de la Ciénega, Universidad de Guadalajara (UDG) , Ocotlán, México
| | - Liliana Alvarado-Ruíz
- Escuela de Ciencias de la Salud, Campus Zapopan, Universidad del Valle de México , Zapopan, México
| | - Alexis Sayuri Suárez-Villanueva
- Escuela de Ciencias de la Salud, Campus Zapopan, Universidad del Valle de México , Zapopan, México.,Laboratorio de Inmunobiología, Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, UDG , Zapopan, México
| | - José Macías-Barragán
- Laboratorio de Sistemas Biológicos, Departamento de Ciencias de la Salud, Centro Universitario de los Valles (CUValles), UDG , Ameca, México
| | - Margarita Montoya-Buelna
- Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud (CUCS), UDG , Guadalajara, México
| | - Edén Oceguera-Contreras
- Laboratorio de Sistemas Biológicos, Departamento de Ciencias de la Salud, Centro Universitario de los Valles (CUValles), UDG , Ameca, México
| | - Anabell Alvarado-Navarro
- Centro de Investigación en Inmunología y Dermatología, Departamento de Fisiología, CUCS, UDG , Guadalajara, México
| | - Omar Graciano-Machuca
- Laboratorio de Sistemas Biológicos, Departamento de Ciencias de la Salud, Centro Universitario de los Valles (CUValles), UDG , Ameca, México
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25
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Ren GF, Zhu L, Zhuang YL, Liu YX, Huang J, Wang H, Wang Q. Association of Killer Cell Immunoglobulin-like Receptor Genotypes and Haplotypes in Dry Eye Disease Patients Treated with Restasis and Systane. Ocul Immunol Inflamm 2020; 29:877-882. [PMID: 31906768 DOI: 10.1080/09273948.2019.1698751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Purpose: whether the Killer immunoglobulin-like receptor (KIR) genotypes and haplotypes are associated with the improvement in dry eye disease (DED) patients treated with Restasis and Systane (RS) remain unclear.Methods: Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to analyze KIR genes in a Chinese Han population of 198 severe DED patients treated with RS.Results: The higher frequencies of KIR genotype M, AF, AJ and haplotype 2 and 8 (P = .001, P = .03, P = .004, P = .000 and P = .023, respectively) and the lower frequencies of genotype AG and haplotype 1 (P = .000 and P = .000, respectively) were observed in complete responders (CR) than those in null or partial responders (NPR) of DED patients treated by RS.Conclusions: The patients with KIR genotype M, AF and AJ might be of advantage to therapy with RS, which are useful for improving novel personalized precise therapy strategy in DED patients.
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Affiliation(s)
- Gui-Fang Ren
- Department of Ophthalmology, The 4th People's Hospital of Jinan, Jinan, Shandong Province, P. R. China
| | - Lin Zhu
- Quality Control Department, Doying Central Blood Station, Dongying, Shandong Province, P. R. China
| | - Yun-Long Zhuang
- Quality Control Department, Blood Center of Shandong Province, Jinan, Shandong Province, P. R. China
| | - Yun-Xia Liu
- Department of Ophthalmology, The 4th People's Hospital of Jinan, Jinan, Shandong Province, P. R. China
| | - Jing Huang
- Department of Ophthalmology, The 4th People's Hospital of Jinan, Jinan, Shandong Province, P. R. China
| | - Hui Wang
- Department of Ophthalmology, The 4th People's Hospital of Jinan, Jinan, Shandong Province, P. R. China
| | - Qun Wang
- Department of Ophthalmology, The 4th People's Hospital of Jinan, Jinan, Shandong Province, P. R. China
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26
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Abstract
Psoriasis is a multisystemic, inflammatory skin condition that can affect many areas of the body, but most commonly the extensor surfaces of the elbows and knees, and sometimes the intergluteal and umbilical area. It has a prevalence of 2–4% in western adults, and 20–30% of psoriasis patients will develop psoriatic arthritis (PsA). PsA is an inflammatory musculoskeletal disease associated with cutaneous psoriasis. It affects men and women almost equally with a peak age at onset of 40 and 50 years. It is a diverse disease that affects multiple organ systems includes peripheral and axial joints, entheses, skin, and nails. PsA is associated with comorbidities such as osteoporosis, uveitis, subclinical bowel inflammation, and cardiovascular disease. Given this heterogeneity, its diagnosis has been difficult. Here we present an updated review of its classification criteria CASPAR (classification criteria for PsA), use of screening tools to aid in early diagnosis, recent findings on pathogenesis, and new therapeutic approaches including new biologic medications.
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Affiliation(s)
- Vanessa Ocampo D
- University of Toronto, Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Dafna Gladman
- University of Toronto, Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.,Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada
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27
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Biassoni R, Malnati MS. Human Natural Killer Receptors, Co-Receptors, and Their Ligands. ACTA ACUST UNITED AC 2019; 121:e47. [PMID: 30040219 DOI: 10.1002/cpim.47] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In the last 20 years, the study of human natural killer (NK) cells has moved from the first molecular characterizations of very few receptor molecules to the identification of a plethora of receptors displaying surprisingly divergent functions. We have contributed to the description of inhibitory receptors and their signaling pathways, important in fine regulation in many cell types, but unknown until their discovery in the NK cells. Inhibitory function is central to regulating NK-mediated cytolysis, with different molecular structures evolving during speciation to assure its persistence. More recently, it has become possible to characterize the NK triggering receptors mediating natural cytotoxicity, unveiling the existence of a network of cellular interactions between effectors of both natural and adaptive immunity. This unit reviews the contemporary history of molecular studies of receptors and ligands involved in NK cell function, characterizing the ligands of the triggering receptor and the mechanisms for finely regulating their expression in pathogen-infected or tumor cells. © 2018 by John Wiley & Sons, Inc.
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Affiliation(s)
- Roberto Biassoni
- IRCCS Istituto Giannina Gaslini, Laboratory of Molecular Medicine, Genova, Italy
| | - Mauro S Malnati
- IRCCS Ospedale San Raffaele, Unit of Human Virology, Division of Immunology, Transplantation and Infectious Diseases, Milan, Italy
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28
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de Winter JJ, Blijdorp IC, de Jong HM, Sauter J, Schmidt AH, van Gaalen FA, van der Heijde D, Poddubnyy D, Yeremenko NG, van de Sande MG, Baeten DL. HLA-C*07 in axial spondyloarthritis: data from the German Spondyloarthritis Inception Cohort and the Spondyloarthritis Caught Early cohort. Genes Immun 2019; 20:671-677. [PMID: 30809016 DOI: 10.1038/s41435-019-0061-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/19/2018] [Accepted: 01/21/2019] [Indexed: 11/09/2022]
Abstract
We aimed to assess the mRNA expression of MHC class 1-related molecules in ankylosing spondylitis (AS) patients vs healthy controls (HCs) and, subsequently, if the absence of HLA-C*07 is associated with genetic susceptibility to axial spondyloarthritis (axSpA). HLA-C*07 was assessed in (a) an exploratory cohort of 24 AS patients vs 40 HCs, (b) a confirmatory cohort of 113 AS patients and 83 non-radiographic axSpA patients from the GErman SPondyloarthritis Inception Cohort (GESPIC) vs 134,528 German potential stem cell donors, and (c) an early back pain cohort with 94 early axSpA patients vs 216 chronic back pain (CBP) patients from the SPondyloArthritis Caught Early (SPACE) cohort. In the exploratory cohort, 79% of the AS patients were HLA-C*07 negative compared to 35% of the HCs (p < 0.001). This difference was confirmed in GESPIC with 73% of AS patients being HLA-C*07 negative compared to 50% of the controls (p < 0.0001); 59% of the nr-axSpA patients were HLA-C*07 negative. In the SPACE cohort, 70% of the axSpA patients were HLA-C*07 negative compared to 44% of CBP patients (p < 0.0001); the association between HLA-C*07 negativity and a diagnosis of axSpA was independent from HLA-B*27. In conclusion, the absence of HLA-C*07 is associated with genetic susceptibility to axSpA.
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Affiliation(s)
- Janneke J de Winter
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Iris C Blijdorp
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.,Laboratory of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Henriëtte M de Jong
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Jürgen Sauter
- DKMS German Bone Marrow Donor Center, Tübingen, Germany
| | | | - Floris A van Gaalen
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Denis Poddubnyy
- Department of Rheumatology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Nataliya G Yeremenko
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.,Laboratory of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Marleen G van de Sande
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Dominique L Baeten
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
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29
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Sun HS, Liu DX, Bai YY, Hu NW. Disease-association of different killer cell immunoglobulin-like receptors (KIR) and HLA-C gene combinations in reactive arthritis. Mod Rheumatol 2018; 29:531-537. [PMID: 29848119 DOI: 10.1080/14397595.2018.1483292] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Hong Sheng Sun
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Dong Xia Liu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Yan Yan Bai
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Nai Wen Hu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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30
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Wang SS, Carrington M, Berndt SI, Slager SL, Bracci PM, Voutsinas J, Cerhan JR, Smedby KE, Hjalgrim H, Vijai J, Morton LM, Vermeulen R, Paltiel O, Vajdic CM, Linet MS, Nieters A, de Sanjose S, Cozen W, Brown EE, Turner J, Spinelli JJ, Zheng T, Birmann BM, Flowers CR, Becker N, Holly EA, Kane E, Weisenburger D, Maynadie M, Cocco P, Albanes D, Weinstein SJ, Teras LR, Diver WR, Lax SJ, Travis RC, Kaaks R, Riboli E, Benavente Y, Brennan P, McKay J, Delfau-Larue MH, Link BK, Magnani C, Ennas MG, Latte G, Feldman AL, Doo NW, Giles GG, Southey MC, Milne RL, Offit K, Musinsky J, Arslan AA, Purdue MP, Adami HO, Melbye M, Glimelius B, Conde L, Camp NJ, Glenn M, Curtin K, Clavel J, Monnereau A, Cox DG, Ghesquières H, Salles G, Bofetta P, Foretova L, Staines A, Davis S, Severson RK, Lan Q, Brooks-Wilson A, Smith MT, Roman E, Kricker A, Zhang Y, Kraft P, Chanock SJ, Rothman N, Hartge P, Skibola CF. HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes. Cancer Res 2018; 78:4086-4096. [PMID: 29735552 PMCID: PMC6065509 DOI: 10.1158/0008-5472.can-17-2900] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 02/07/2018] [Accepted: 04/24/2018] [Indexed: 01/07/2023]
Abstract
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.
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Affiliation(s)
- Sophia S. Wang
- Department of Population Sciences, Beckman Research Institute and the City of Hope, Duarte, California,To whom correspondence should be addressed: Sophia S. Wang, Ph.D., Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, Phone: (626) 471-7316, Fax: (626) 471-7308,
| | - Mary Carrington
- Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD and Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Susan L. Slager
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Paige M. Bracci
- Department of Epidemiology and Biostatistics, University of California–San Francisco, San Francisco, CA
| | - Jenna Voutsinas
- Department of Population Sciences, Beckman Research Institute and the City of Hope, Duarte, California
| | - James R. Cerhan
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Karin E. Smedby
- Department of Medicine Solna, unit of clinical epidemiology, Karolinska Institutet, Stockholm, Sweden,Hematology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Henrik Hjalgrim
- Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark,Department of Hematology, Rishospitalet, Copenhagen, Denmark
| | - Joseph Vijai
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY
| | - Lindsay M. Morton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Roel Vermeulen
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands,Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ora Paltiel
- Braun School of Public Health and Community Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Claire M. Vajdic
- Centre for Big Data Research in Health, The University of New South Wales, Sydney, New South Wales, Australia
| | - Martha S. Linet
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Alexandra Nieters
- Centre for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg, Germany
| | - Silvia de Sanjose
- Unit of Infections and Cancer, Cancer Epidemiology Research Programme, Institut Català d’ Oncologia, IDIBELL, 08908 L’Hospitalet de Llobregat, Barcelona, Spain,CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Wendy Cozen
- Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Departments of Preventive Medicine and Pathology, University of Southern California, Los Angeles, CA
| | - Elizabeth E. Brown
- Department of Pathology, School of Medicine and the UAB Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL
| | - Jennifer Turner
- Department of Histopathology, Douglass Hanly Moir Pathology, Sydney, Australia,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
| | - John J. Spinelli
- Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tongzhang Zheng
- Department of Epidemiology, School of Public Health, Brown University, Providence, RI
| | - Brenda M. Birmann
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Christopher R. Flowers
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
| | - Nikolaus Becker
- Division of Clinical Epidemiology, German Cancer Research Centre, Heidelberg, Baden-Württemberg, Germany
| | - Elizabeth A. Holly
- Department of Epidemiology and Biostatistics, University of California–San Francisco, San Francisco, CA
| | - Eleanor Kane
- Department of Health Sciences, University of York, York, United Kingdom
| | | | - Marc Maynadie
- Registry of Hematological Malignancies of Cote d’Or, INSERM UMR1231, University of Burgundy and Dijon University Hospital, Dijon, France
| | - Pierluigi Cocco
- Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | | | - Lauren R. Teras
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - W. Ryan Diver
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - Stephanie J. Lax
- Department of Health Sciences, University of York, York, United Kingdom
| | - Ruth C. Travis
- Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom
| | - Rudolph Kaaks
- Division of Clinical Epidemiology, German Cancer Research Centre, Heidelberg, Baden-Württemberg, Germany
| | - Elio Riboli
- School of Public Health, Imperial College London, London, United Kingdom
| | - Yolanda Benavente
- Unit of Infections and Cancer, Cancer Epidemiology Research Programme, Institut Català d’ Oncologia, IDIBELL, 08908 L’Hospitalet de Llobregat, Barcelona, Spain,CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Paul Brennan
- International Agency for Research on Cancer, Lyon, France
| | - James McKay
- Department of Immunology, CHU Henri Mondor, Créteil, France
| | - Marie-Hélène Delfau-Larue
- Department of Immunology, CHU Henri Mondor, Créteil, France,INSERM U 955, CHU Henri Mondor, Créteil, France
| | - Brian K. Link
- Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Corrado Magnani
- Center of Oncological Prevention (CPO) Piemonte and Unit of Medical Statistics and Epidemiology, Department Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Maria Grazia Ennas
- Department of Biomedical Science, University of Cagliari, Monserrato, Cagliari, Italy
| | | | - Andrew L. Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Nicole Wong Doo
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia
| | - Graham G. Giles
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Melissa C. Southey
- Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
| | - Roger L. Milne
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Kenneth Offit
- Department of Hematology, Rishospitalet, Copenhagen, Denmark
| | - Jacob Musinsky
- Department of Hematology, Rishospitalet, Copenhagen, Denmark
| | - Alan A. Arslan
- Department of Obstetrics and Gynecology, New York University School of Medicine, New York City, NY,Department of Environmental Medicine, New York University School of Medicine, New York City, NY,Perlmutter Cancer Center, NYU Langone Medical Center, New York City, NY
| | - Mark P. Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Hans-Olov Adami
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Mads Melbye
- Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark,Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Bengt Glimelius
- Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, WC1E 6DD, London, United Kingdom
| | - Lucia Conde
- Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT
| | - Nicola J. Camp
- Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris, France
| | - Martha Glenn
- Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris, France
| | - Karen Curtin
- Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris, France
| | - Jacqueline Clavel
- Université Paris Descartes, Paris, France,Registre des hémopathies malignes de la Gironde, Institut Bergonié, University of Bordeaux, Inserm, Team EPICENE, UMR 1219, France
| | - Alain Monnereau
- Université Paris Descartes, Paris, France,Registre des hémopathies malignes de la Gironde, Institut Bergonié, University of Bordeaux, Inserm, Team EPICENE, UMR 1219, France,Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. Cancer Research Center of Lyon, INSERM UMR1052, Center Léon Bérard, Lyon, France
| | - David G. Cox
- Department of Hematology, Centre Léon Bérard, Lyon, France
| | - Hervé Ghesquières
- Laboratoire de Biologie Moléculaire de la Cellule UMR 5239, Centre National de la Recherche Scientifique, Pierre benite Cedex, France,Department of Hematology, Hospices Civils De Lyon, Centre Hospitalier Lyon-Sud and Université Claude Bernard, Lyon, France
| | - Gilles Salles
- Department of Hematology, Hospices Civils De Lyon, Centre Hospitalier Lyon-Sud and Université Claude Bernard, Lyon, France,The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York
| | - Paulo Bofetta
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, MF MU, Brno, Czech Republic
| | - Lenka Foretova
- School of Nursing and Human Sciences, Dublin City University, Dublin, Ireland
| | - Anthony Staines
- Fred Hutchinson Cancer Research Center & School of Public Health and Community Medicine, University of Washington, Seattle, WA
| | - Scott Davis
- Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI
| | - Richard K. Severson
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Qing Lan
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Angela Brooks-Wilson
- Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada,Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA
| | - Martyn T Smith
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
| | - Eve Roman
- Department of Health Sciences, University of York, York, United Kingdom
| | - Anne Kricker
- Department of Surgery, Yale School of Medicine, New Haven, CT
| | - Yawei Zhang
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Peter Kraft
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Christine F. Skibola
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
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31
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Kennedy AE, Ozbek U, Dorak MT. What has GWAS done for HLA and disease associations? Int J Immunogenet 2018; 44:195-211. [PMID: 28877428 DOI: 10.1111/iji.12332] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 06/16/2017] [Accepted: 07/20/2017] [Indexed: 12/14/2022]
Abstract
The major histocompatibility complex (MHC) is located in chromosome 6p21 and contains crucial regulators of immune response, including human leucocyte antigen (HLA) genes, alongside other genes with nonimmunological roles. More recently, a repertoire of noncoding RNA genes, including expressed pseudogenes, has also been identified. The MHC is the most gene dense and most polymorphic part of the human genome. The region exhibits haplotype-specific linkage disequilibrium patterns, contains the strongest cis- and trans-eQTLs/meQTLs in the genome and is known as a hot spot for disease associations. Another layer of complexity is provided to the region by the extreme structural variation and copy number variations. While the HLA-B gene has the highest number of alleles, the HLA-DR/DQ subregion is structurally most variable and shows the highest number of disease associations. Reliance on a single reference sequence has complicated the design, execution and analysis of GWAS for the MHC region and not infrequently, the MHC region has even been excluded from the analysis of GWAS data. Here, we contrast features of the MHC region with the rest of the genome and highlight its complexities, including its functional polymorphisms beyond those determined by single nucleotide polymorphisms or single amino acid residues. One of the several issues with customary GWAS analysis is that it does not address this additional layer of polymorphisms unique to the MHC region. We highlight alternative approaches that may assist with the analysis of GWAS data from the MHC region and unravel associations with all functional polymorphisms beyond single SNPs. We suggest that despite already showing the highest number of disease associations, the true extent of the involvement of the MHC region in disease genetics may not have been uncovered.
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Affiliation(s)
- A E Kennedy
- Center for Research Strategy, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - U Ozbek
- Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - M T Dorak
- Head of School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, UK
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32
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Pu Y, Mi X, Chen P, Zhou B, Zhang P, Wang Y, Song Y, Zhang L. Genetic association of polymorphisms in AXIN1 gene with clear cell renal cell carcinoma in a Chinese population. Biomark Med 2017; 11:947-955. [PMID: 29053018 DOI: 10.2217/bmm-2016-0377] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Aim: The purpose of the present study is to investigate the association between the polymorphisms in AXIN1 with susceptibility to clear cell renal cell carcinoma (ccRCC). Materials & methods: A total of 284 ccRCC patients and 439 healthy volunteers were enrolled. Totally three tag single nucleotide polymorphisms in AXIN1 gene were genotyped using PCR & restriction fragment length polymorphism. Results: Significantly increased ccRCC risk was observed to be associated with the CT/CC genotypes of rs1805105 and AA genotype of rs12921862. Patients carrying the rs1805105 CT genotype had a 1.92-fold increased risk to developing clinical stage III and IV cancer. Conclusion: Our results suggested the rs1805105 CT/CC genotypes and rs12921862 AA genotype may relate to ccRCC development.
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Affiliation(s)
- Yan Pu
- Department of Forensic Biology, West China School of Basic sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Xuhua Mi
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Peng Chen
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, P.R. China
| | - Bin Zhou
- Laboratory of Molecular Translational Medicine, West China Institute of Women & Children's Health, Key Laboratory of Obstetric & Gynecologic & Pediatric Diseases & Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Peng Zhang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Yanyun Wang
- Laboratory of Molecular Translational Medicine, West China Institute of Women & Children's Health, Key Laboratory of Obstetric & Gynecologic & Pediatric Diseases & Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Yaping Song
- Laboratory of Molecular Translational Medicine, West China Institute of Women & Children's Health, Key Laboratory of Obstetric & Gynecologic & Pediatric Diseases & Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Lin Zhang
- Department of Forensic Biology, West China School of Basic sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
- Laboratory of Molecular Translational Medicine, West China Institute of Women & Children's Health, Key Laboratory of Obstetric & Gynecologic & Pediatric Diseases & Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
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Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol 2017. [PMID: 28449694 DOI: 10.1186/s13059-017-1207-1.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic effects, have contributed to a better understanding of the shared and specific roles of MHC variants in different diseases. We review these advances and discuss the relationships between MHC variants involved in autoimmune and infectious diseases. Further work in this area will help to distinguish between alternative hypotheses for the role of pathogens in autoimmune disease development.
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Affiliation(s)
- Vasiliki Matzaraki
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Vinod Kumar
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands. .,Department of Immunology, KG Jebsen Coeliac Disease Research Centre, University of Oslo, PO Box 4950 Nydalen, 0424, Oslo, Norway.
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
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34
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Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol 2017; 18:76. [PMID: 28449694 PMCID: PMC5406920 DOI: 10.1186/s13059-017-1207-1] [Citation(s) in RCA: 343] [Impact Index Per Article: 42.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic effects, have contributed to a better understanding of the shared and specific roles of MHC variants in different diseases. We review these advances and discuss the relationships between MHC variants involved in autoimmune and infectious diseases. Further work in this area will help to distinguish between alternative hypotheses for the role of pathogens in autoimmune disease development.
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Affiliation(s)
- Vasiliki Matzaraki
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Vinod Kumar
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands. .,Department of Immunology, KG Jebsen Coeliac Disease Research Centre, University of Oslo, PO Box 4950 Nydalen, 0424, Oslo, Norway.
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands
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35
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The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk. J Immunol Res 2016; 2016:1376595. [PMID: 28078307 PMCID: PMC5204097 DOI: 10.1155/2016/1376595] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 11/08/2016] [Indexed: 12/24/2022] Open
Abstract
Although NK cells are considered part of the innate immune system, a series of evidences has demonstrated that they possess characteristics typical of the adaptive immune system. These NK adaptive features, in particular their memory-like functions, are discussed from an ontogenetic and evolutionary point of view.
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36
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Kandilarova SM, Paschen A, Mihaylova A, Ivanova M, Schadendorf D, Naumova E. The Influence of HLA and KIR Genes on Malignant Melanoma Development and Progression. Arch Immunol Ther Exp (Warsz) 2016; 64:73-81. [PMID: 28083606 DOI: 10.1007/s00005-016-0437-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 10/25/2016] [Indexed: 11/25/2022]
Abstract
Many studies have described the role of killer immunoglobulin-like receptors (KIRs) and their cognate human leukocyte antigen (HLA) class I ligands in the immune protection against melanoma, but the effect of these markers on intra-individual variations in tumor development and progression has remained less clear. We performed KIR, HLA, and KIR/ligand analysis in 283 patients with malignant melanoma in order to evaluate their integrated influence on disease stage and progression. The patients were grouped according to AJCC staging, histological type of the primary tumor, progression, and survival rate. Analysis of HLA class I alleles revealed positive association of HLA-C*14 (Pc = 0.026, OR = 5.99) and negative association of HLA-C*02 (Pc = 0.026, OR = 0.43) with the disease. Decreased frequency of KIR2DS5 was observed in patients with rapid progression, as compared to those with slow progression. KIR BB genotype was prevalent in patients with metastasis (p = 0.004, OR = 0.025). KIR AA genotype was nearly twice as frequent in rapidly progressive cases, but without statistical relevance (p = 0.055, OR = 2.6). Significantly increased frequency of KIR2DL2 in the presence of C1 ligand (strong inhibition) was found in patients with AJCC III and IV, as compared to individuals with AJCC I stage (p = 0.045, OR = 1.93). In summary, our data imply that KIR/ligand gene content in patients could modulate the disease course towards unfavorable tumor behavior.
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Affiliation(s)
- Snezhina Mihailova Kandilarova
- Department of Clinical Immunology with Stem Cell Bank, Alexandrovska University Hospital, Medical University, 1431, Sofia, Bulgaria.
| | - Annette Paschen
- Department of Dermatology, University Hospital Essen, Essen, Germany
| | - Anastassia Mihaylova
- Department of Clinical Immunology with Stem Cell Bank, Alexandrovska University Hospital, Medical University, 1431, Sofia, Bulgaria
| | - Milena Ivanova
- Department of Clinical Immunology with Stem Cell Bank, Alexandrovska University Hospital, Medical University, 1431, Sofia, Bulgaria
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, Essen, Germany
| | - Elissaveta Naumova
- Department of Clinical Immunology with Stem Cell Bank, Alexandrovska University Hospital, Medical University, 1431, Sofia, Bulgaria
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37
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Analysis of killer cell immunoglobulin-like receptors and their human leukocyte antigen-ligands gene polymorphisms in Iranian patients with systemic lupus erythematosus. Lupus 2016; 25:1244-53. [DOI: 10.1177/0961203316638931] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 02/22/2016] [Indexed: 01/18/2023]
Abstract
Objective Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease. Natural killer (NK) cells play a critical role in the pathogenesis of autoimmune disorders that mainly express killer cell immunoglobulin-like receptors (KIRs). The present study was undertaken to determine the association of the KIR alleles, genotypes, and KIR–human leukocyte antigen ( HLA) ligand gene combinations with the susceptibility to SLE. Methods The genotyping of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method. The study population consisted of 230 SLE patients and 273 ethnical-, age-, and sex-matched healthy controls. The association of the polymorphisms with the prevalence of 11 clinical criteria in patients was analyzed. Results The carrier frequency of HLA-A-Bw4 was modestly decreased in the SLE patients. The prevalence of hematological and renal disorders was significantly increased in patients with combination of KIR3DL1+; HLA-B-Bw4Thr80+ and KIR2DS1+; HLA-C2+ genes, respectively. Female patients with combination of KIR2DL2+; HLA-C1− genes were more likely to develop serositis. In addition the prevalence of renal disorders, oral ulcer and serositis was significantly increased in male patients with KIR3DP1+, KIR2DS1+, and KIR2DS3+ genotypes respectively. Conclusion Our results showed that the presence of activating KIR receptors alone or in combination with their HLA ligands and the absence of inhibitory KIRs in combination with their HLA ligands may activate NK cells and are significantly correlated with the prevalence of renal disease, hematologic disorders, serositis, and oral ulcer in SLE patients.
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38
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Genetic associations of killer immunoglobulin like receptors and class I human leukocyte antigens on childhood acute lymphoblastic leukemia among north Indians. Hum Immunol 2015; 77:41-46. [PMID: 26472014 DOI: 10.1016/j.humimm.2015.10.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 10/06/2015] [Accepted: 10/11/2015] [Indexed: 11/23/2022]
Abstract
BACKGROUND Molecular interactions between KIRs and their cognate HLA class-I ligands, play a central role in the regulation of natural killer (NK) cell responses in malignancies. We aimed to determine the role of KIR genes and their HLA ligands in genetic predisposition of childhood acute lymphoblastic leukemia (ALL). METHODS Genotyping of 16 KIR genes, along with HLA class-I groups C1/C2 and Bw4 super-type ligands, was carried-out in 137 childhood ALL cases and 274 healthy controls. RESULTS We observed an increased incidence of activating KIRs namely; 2DS2 (OR=2.23, p=<0.001), 2DS3 (OR=1.74, p=0.011), 3DS1 (OR=2.22, p=<0.001), 2DS5 (OR=2.10, p=0.001), 2DS1 (OR=4.42, p=<0.001) and 2DS4 (OR=2.88, p=<0.001) genes in childhood ALL cases compared to controls. Frequency of BB genotype that possess 2-6 activating KIR genes was predominant in cases compared to controls (OR=2.55, p=<0.001). KIR-receptor/HLA-ligand combinations analysis revealed a moderate risk of almost 2-fold for activating KIR-ligand combinations namely; KIR2DS1-HLAC2, KIR2DS2-HLAC1 and KIR3DS1-HLABw4 in childhood ALL cases. CONCLUSION Our data suggests the role for KIR genes and their HLA ligands in aetiology of childhood ALL.
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39
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Dunphy SE, Sweeney CM, Kelly G, Tobin AM, Kirby B, Gardiner CM. Natural killer cells from psoriasis vulgaris patients have reduced levels of cytotoxicity associated degranulation and cytokine production. Clin Immunol 2015; 177:43-49. [PMID: 26477484 DOI: 10.1016/j.clim.2015.10.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 10/08/2015] [Accepted: 10/15/2015] [Indexed: 12/28/2022]
Abstract
Psoriasis vulgaris is a chronic inflammatory disease of the skin with a strong genetic component and immune system involvement. Although some evidence suggests that Natural Killer (NK) cells may play a part in psoriasis, their role is relatively unstudied and results are controversial. In this current study, NK cells from psoriasis patients exhibited reduced degranulation and produced lower levels of the pro-inflammatory cytokines IFN-γ and TNF-α. Further investigation found that NK cells from psoriasis patients and healthy controls expressed similar levels of activation markers, NK cell receptors and apoptosis-inducing molecules. In addition, comparable levels of several cytokines important in NK cell biology were found in the serum of psoriasis patients and healthy controls. Genotyping analysis revealed that HLA-C2, which provides a ligand for killer-cell immunoglobulin-like receptors (KIR) expressed by NK cells, was strongly associated with psoriasis susceptibility. However, no link between the KIR genes themselves and disease was found.
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Affiliation(s)
- S E Dunphy
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College, Dublin 2, Ireland
| | - C M Sweeney
- Department of Dermatology, St Vincent's University Hospital, Dublin 4, Ireland
| | - G Kelly
- Department of Dermatology, St Vincent's University Hospital, Dublin 4, Ireland
| | - A M Tobin
- Department of Dermatology, Tallaght Hospital, Dublin 24, Ireland
| | - B Kirby
- Department of Dermatology, St Vincent's University Hospital, Dublin 4, Ireland
| | - C M Gardiner
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College, Dublin 2, Ireland.
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40
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Sanati G, Aryan Z, Barbadi M, Rezaei N. Innate lymphoid cells are pivotal actors in allergic, inflammatory and autoimmune diseases. Expert Rev Clin Immunol 2015; 11:885-95. [DOI: 10.1586/1744666x.2015.1050382] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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41
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Ayo CM, Reis PG, Dalalio MMDO, Visentainer JEL, Oliveira CDF, de Araújo SM, de Oliveira Marques DS, Sell AM. Killer Cell Immunoglobulin-like Receptors and Their HLA Ligands are Related with the Immunopathology of Chagas Disease. PLoS Negl Trop Dis 2015; 9:e0003753. [PMID: 25978047 PMCID: PMC4433128 DOI: 10.1371/journal.pntd.0003753] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 04/11/2015] [Indexed: 02/03/2023] Open
Abstract
The aim of this study was to investigate the influence of killer cell immunoglobulin-like receptor (KIR) genes and their human leucocyte antigen (HLA) ligands in the susceptibility of chronic Chagas disease. This case-control study enrolled 131 serologically-diagnosed Chagas disease patients (59 men and 72 women, mean age of 60.4 ± 9.8 years) treated at the University Hospital of Londrina and the Chagas Disease Laboratory of the State University of Maringa. A control group was formed of 165 healthy individuals - spouses of patients or blood donors from the Regional Blood Bank in Maringa (84 men and 81 women, with a mean age of 59.0 ± 11.4 years). Genotyping of HLA and KIR was performed by PCR-SSOP. KIR2DS2-C1 in the absence of KIR2DL2 (KIR2DS2+/2DL2-/C1+) was more frequent in Chagas patients (P = 0.020; Pc = 0.040; OR = 2.14) and, in particular, those who manifested chronic chagasic cardiopathy—CCC (P = 0.0002; Pc = 0.0004; OR = 6.64; 95% CI = 2.30–18.60) when compared to the control group, and when CCC group was compared to the patients without heart involvement (P = 0.010; Pc = 0.020; OR = 3.97). The combination pair KIR2DS2+/2DL2-/KIR2DL3+/C1+ was also positively associated with chronic chagasic cardiopathy. KIR2DL2 and KIR2DS2 were related to immunopathogenesis in Chagas disease. The combination of KIR2DS2 activating receptor with C1 ligand, in the absence of KIR2DL2, may be related to a risk factor in the chronic Chagas disease and chronic chagasic cardiopathy. Chagas disease is an infection caused by the haemoflagellate protozoan Trypanosoma cruzi. It is one of the most important public health problems in Latin America, and was first described by Carlos Justiniano Ribeiro das Chagas, a Brazilian physician and scientist, in 1909. It is mostly vector-borne transmitted to humans by contact with faeces of triatomine bugs. The World Health Organization estimates that about 6 to 7 million people are currently infected with T. cruzi worldwide. The disease is characterised by acute and chronic phases. The immune response during disease development is crucial for protection because immunological imbalances can lead to heart and digestive tract lesions in chagasic patients. In this work we analysed the role of receptors of immune cells known as Natural Killer cells (killer cell immunoglobulin-like receptor—KIR) and their ligands (Human leukocyte antigens—HLA) in chagasic patients compared to healthy individuals. The uncontrolled activation of NK cells can lead to tissue damage, which, in turn, leads to the development of serious chronic illness. We found that KIR-HLA complex may be related to a risk factor in the chronic Chagas disease and chronic chagasic cardiopathy.
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Affiliation(s)
- Christiane Maria Ayo
- Post Graduation Program of Biosciences Applied to Pharmacy, Department of Analysis Clinical and Biomedicine, Maringa State University, Maringa, Parana, Brazil
| | - Pâmela Guimarães Reis
- Post Graduation Program of Biosciences Applied to Pharmacy, Department of Analysis Clinical and Biomedicine, Maringa State University, Maringa, Parana, Brazil
| | | | | | - Camila de Freitas Oliveira
- Post Graduation Program of Biosciences Applied to Pharmacy, Department of Analysis Clinical and Biomedicine, Maringa State University, Maringa, Parana, Brazil
| | | | | | - Ana Maria Sell
- Basic Health Sciences, Maringa State University, Maringa, Parana, Brazil
- * E-mail: ,
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El-Beblawy NMS, Elbarbary NS, Kamal TM, Mahmoud PM. A Study of Human Killer Cell Immunoglobulin-Like Receptor and Multidrug Resistance Gene Polymorphisms in Children With Immune Thrombocytopenia. Clin Appl Thromb Hemost 2015; 22:429-40. [PMID: 25792670 DOI: 10.1177/1076029615576738] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
THE OBJECTIVE This study was undertaken to detect characterization of the different gene polymorphisms in Human killer cell immunoglobulin-like receptor (KIR2) gene and multi-drug resistance (MDR1) gene, among childhood ITP Egyptian patients. In addition to assess the potential role of these polymorphisms in relation to types of ITP and response to different treatment modalities. PATIENTS AND METHODS A total of 48 pediatric patients with immune thrombocytopenia (ITP; 24 newly diagnosed and 24 chronic) and 35 healthy controls were investigated via polymerase chain reaction-restriction fragment length polymorphism analysis for multidrug resistance (MDR) 1 and killer cell immunoglobulin-like receptor (KIR) 2 genes. RESULTS The frequency of MDR1 gene in patients and control was not significant (P = .090). The CT genotype was the highest distribution among all ITP cases (62.50%, n = 30) and control (48.60%, n = 17). There was a significant difference in age at diagnosis of MDR1 gene with the CC genotype had the eldest age and lowest initial platelets count (P = .029 and P = .004). The distribution of KIR2 gene among all patients with ITP and controls was significant (P = .026) with (KIRDL2-/KIRDS2-) genotype was the most prevalent among patients. CONCLUSION The frequency of MDR1 polymorphisms was not associated with susceptibility to the development and clinical progression of the disease. However, KIR2 gene polymorphisms were independently associated with childhood ITP in Egyptian patients with highest prevalence among (KIRDL2-/KIRDS2-) genotypes.
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Affiliation(s)
| | - Nancy Samir Elbarbary
- Department of Pediatrics, Hematology and Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Tarek Mostafa Kamal
- Department of Pediatrics, Human Genetics Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Perehan Mohsen Mahmoud
- Department of Pediatrics, Hematology and Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Fasano ME, Rendine S, Pasi A, Bontadini A, Cosentini E, Carcassi C, Capittini C, Cornacchini G, Espadas de Arias A, Garbarino L, Carella G, Mariotti ML, Mele L, Miotti V, Moscetti A, Nesci S, Ozzella G, Piancatelli D, Porfirio B, Riva MR, Romeo G, Tagliaferri C, Lombardo C, Testi M, Amoroso A, Martinetti M. The distribution of KIR-HLA functional blocks is different from north to south of Italy. ACTA ACUST UNITED AC 2014; 83:168-73. [PMID: 24571475 DOI: 10.1111/tan.12299] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 12/03/2013] [Accepted: 01/06/2014] [Indexed: 01/02/2023]
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.
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Affiliation(s)
- M E Fasano
- Transplant Immunology Service, Hospital Città della Salute e della Scienza, Torino, Italy
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Schneeberger EE, Citera G, Rodríguez Gil G, Granel A, Arturi A, Rosemffet GM, Maldonado Cocco JA, Berman A, Spindler A, Morales VH. Clinical and immunogenetic characterization in psoriatic arthritis patients. Clin Rheumatol 2014; 34:1413-8. [PMID: 25008283 DOI: 10.1007/s10067-014-2739-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 06/29/2014] [Indexed: 11/29/2022]
Abstract
In psoriatic arthritis (PsA), genetic factors play a substantial role in disease susceptibility as well as in its expression. This study aims to determine the distribution of class I and class II HLA antigens in PsA patients and secondly to analyze the influence of genetic factors in the clinical expression of the disease. Consecutive PsA patients (CASPAR criteria) with less than 1 year of disease duration were included. Sociodemographic and clinical data were recorded. Blood samples were obtained, DNA was extracted by polymerase chain reaction (PCR), and class I (A, B, and C) and class II (DR) HLA antigens were determined by oligotyping. A control group of 100 nonrelated healthy controls from the general population served as control. p values were corrected (pc) according to the number of alleles tested. A total of 73 patients were included, 37 were females (50.7 %) with a median disease duration of 72 months (interquartile range (IQR) 24-149). Thirty-three patients (45.2 %) had a family history of psoriasis. When analyzing all the class I and class II HLA antigens, a significantly higher frequency of B38 (odds ratio (OR) 2.95, p = 0.03) and Cw6 (OR 2.78, p = 0.009) was found in PsA patients compared to the control group. On the contrary, the HLA-A11 (OR 0.14, p = 0.04) and B7 (OR 0.31, p = 0.03) were significantly more frequent among healthy controls. Furthermore, B18 was significantly more frequent in patients with early arthritis onset (less than 40 years): seven patients (22.6 %) with early onset compared to two patients (4.8 %) with late onset (p = 0.03). No association between HLA-B27 and spondylitis or HLA-DR4 with polyarticular involvement was observed. The HLA-B38 and Cw6 alleles are associated with a greater PsA susceptibility in Argentine population.
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Affiliation(s)
- Emilce Edith Schneeberger
- Section of Rheumatology, Instituto de Rehabilitación Psicofísica, Echeverría 955, 1428, Buenos Aires, Argentina,
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Olaniyan SA, Amodu OK, Yindom LM, Conway DJ, Aka P, Bakare AA, Omotade OO. Killer-cell immunoglobulin-like receptors and falciparum malaria in southwest Nigeria. Hum Immunol 2014; 75:816-21. [PMID: 24929143 DOI: 10.1016/j.humimm.2014.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 06/03/2014] [Accepted: 06/03/2014] [Indexed: 11/30/2022]
Abstract
Killer-cell immunoglobulin-like receptors (KIRs) are a group of natural killer cell receptors (NKRs) that regulate NK-cell-mediated production of interferon gamma (IFN-γ) in response to infection. These receptors have recently been suggested to influence the severity of clinical Plasmodium falciparum malaria infection. We examined the KIR locus in relation to malaria in children from southwest Nigeria. Sequence specific priming (SSP)-PCR was used to detect the KIR genes. The presence or absence of fifteen different KIR genes was determined in each individual and the proportions compared across 3 clinical groups; asymptomatic malaria, uncomplicated clinical malaria and severe clinical malaria. The genes KIR2DL5, KIR2DS3 and KIR2DS5 were present in a significantly higher proportion of individuals in the asymptomatic control group than in the malaria cases. Furthermore, KIR2DS3 and KIR2DS5 were present in a higher proportion of uncomplicated malaria cases than severe malaria cases. Carriage c-AB2 genotype (which comprises all centromeric KIR genes including KIR2DL5, KIR2DS3 and KIR2DS5) decreases with severity of the disease suggesting that the KIR AB profile might be associated with protection from severe malaria infection in this population in Nigeria.
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Affiliation(s)
- Subulade A Olaniyan
- Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
| | - Olukemi K Amodu
- Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
| | - Louis-Marie Yindom
- Medical Research Council Laboratories, Fajara, Banjul, Gambia; University of Oxford, Nuffield Department of Medicine, Oxford, UK.
| | - David J Conway
- Medical Research Council Laboratories, Fajara, Banjul, Gambia; London School of Hygiene and Tropical Medicine, London, UK.
| | - Peter Aka
- National Institutes of Health, Bethesda, MD, USA.
| | | | - Olayemi O Omotade
- Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
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Prakash S, Alam S, Bharadwaj U, Aggarwal A, Mishra RN, Agrawal S. Associations of killer cell immunoglobulin like receptors with rheumatoid arthritis among North Indian population. Hum Immunol 2014; 75:802-7. [PMID: 24912006 DOI: 10.1016/j.humimm.2014.05.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 03/11/2014] [Accepted: 05/29/2014] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease of unknown etiology. Killer cell immunoglobulin-like receptors (KIR) expressed on surface of natural killer cells and CD28 null T-cells which are present in synovial membrane of RA. The present study has evaluated associations of KIR genes with RA among North Indian population from Uttar Pradesh. MATERIALS AND METHODS KIR genotypes were determined in 100 RA cases and 100 healthy controls using sequence specific primer polymerase chain reaction (PCR-SSP) method. RESULTS RA cases positive for KIR3DS1 (OR = 1.17, p-value = 0.0498) and KIR2DS2 (OR = 2.21, p-value = 0.0120) showed risk associations. While, KIR2DL2 (OR = 0.40, p-value = 0.0026), KIR2DL3 (OR = 0.44, p-value = 0.0283) and KIR3DL1 (OR=0.32, p-value = 0.0012) showed protective associations. Increased incidence of BB genotype (45%) was revealed among cases. Risk association was noted against telomeric region (OR = 2.12, p = 0.0120) genes for RA. Pair-wise linkage disequilibrium (LD) analysis among RA cases revealed KIR2DS1-2DL1 (D' = 0.83, r(2) = 0.36), KIR3DL1-3DS1 (D' = 1, r(2) = 0.58) and KIR2DL1-2DL2 (D' = 1, r(2)=0.61) to be in significant LD. KIR3DS1 and KIR2DS3 genes showed significant risk associations among RA patients with extra-articular manifestations (OR = 5.14, p-value = 0.0018; OR = 3.79, p-value = 0.0106) and in limited range of motion in affected joints (OR = 14.91, p-value = 0.0001; OR = 2.95, p-value=0.0126). CONCLUSION The KIR activating genes have risk association with RA in the present study.
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Affiliation(s)
- Swayam Prakash
- Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareily Road, Lucknow, Uttar Pradesh, India
| | - Shahnawaz Alam
- Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareily Road, Lucknow, Uttar Pradesh, India
| | - Uddalak Bharadwaj
- Margaret M. and Albert B. Alkek Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, United States
| | - Amita Aggarwal
- Department of Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareily Road, Lucknow, Uttar Pradesh, India
| | - Ram Nath Mishra
- Department of Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareily Road, Lucknow, Uttar Pradesh, India
| | - Suraksha Agrawal
- Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareily Road, Lucknow, Uttar Pradesh, India.
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Dastmalchi R, Farazmand A, Noshad S, Mozafari M, Mahmoudi M, Esteghamati A, Amirzargar A. Polymorphism of killer cell immunoglobulin-like receptors (KIR) and their HLA ligands in Graves' disease. Mol Biol Rep 2014; 41:5367-74. [PMID: 24852304 DOI: 10.1007/s11033-014-3408-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 05/11/2014] [Indexed: 12/11/2022]
Abstract
Killer immunoglobulin-like receptors (KIR) play a pivotal role in commencement of both innate and adaptive immunity. Dysregulation of KIRs is associated with an increased risk of autoimmune disorders. This study was designed to assess whether polymorphisms in KIR gene family and their respective HLA class I ligands confer protection or susceptibly to Graves' disease (GD). Eighty patients with confirmed GD (cases) and 176 healthy unrelated subjects (controls) were recruited. Using a polymerase chain reaction sequence-specific primer directed method (PCR-SSP), presence or absence of KIR genes and their HLA ligands were determined. No significant differences were observed between case and control groups regarding individual KIR gene frequencies (p > 0.05 in all cases). The frequency of group A haplotype (the most common KIR haplotype, encompassing 2DL1/2DL3/3DL1/2DS4/2DP1/3DP1/2DL4/3DL2/3DL3), was not different between individuals with and without GD. Moreover, among all other haplotypes (group Bx), no significant differences regarding distribution of centromeric and telomeric gene clusters were identifiable. Inhibitory/activatory gene contents were also comparable between the two groups. Four models of KIR-HLA interaction (inhibition, activation, unrestrained inhibition, and unrestrained activation) were constructed. No combination proved to confer susceptibility to, or offer protection against GD. It seems that the contribution of KIR gene polymorphism to natural killer cell dysfunction and other autoimmune abnormalities observed in GD is limited.
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Affiliation(s)
- Romina Dastmalchi
- Department of Cellular and Molecular Biology, Kish International Campus, University of Tehran, Kish Island, Iran,
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Cichocki F, Sitnicka E, Bryceson YT. NK cell development and function – Plasticity and redundancy unleashed. Semin Immunol 2014; 26:114-26. [DOI: 10.1016/j.smim.2014.02.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 02/02/2014] [Accepted: 02/04/2014] [Indexed: 01/16/2023]
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Salim PH, Jobim M, Bredemeier M, Chies JAB, Brenol JCT, Jobim LF, Xavier RM. Characteristics of NK cell activity in patients with systemic sclerosis. REVISTA BRASILEIRA DE REUMATOLOGIA 2014; 53:66-74. [PMID: 23588517 DOI: 10.1016/s2255-5021(13)70007-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 12/13/2012] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION Previous studies have shown an increased expression of natural killer (NK) cells in the peripheral blood of patients with systemic sclerosis (SSc). NK cells are part of innate immunity, recognizing infected cells through killer immunoglobulin-like receptors (KIR), which show marked polymorphism. A novel model has been proposed predicting the activity of NK cells, evaluating whether there is excessive activation (EA), excessive inhibition (EI) or balance (B) (neutral). OBJECTIVE To evaluate the activity of NK cells in patients with SSc and compare it with that of a control group. METHOD This study comprised 110 patients with SSc and 115 healthy controls. A novel model that predicts the activity of NK cells was used. For that, cells with their respective KIR/HLA-C and Bw4 ligands were considered. The activity of NK cells was defined as EA, EI, or B. RESULTS Our results showed that 63.5% of healthy controls had the KIR phenotype characterized by EI, as compared with 39.1% of the patients with SSc (P = 0.001). Considering only KIR2DL2-positive individuals, 34.7% of EI was found in healthy controls and 10.9% in patients with SSc (P < 0.001). CONCLUSION In our study, the model that predicts the action of NK cells showed that healthy controls have higher frequency of EI as compared with SSc patients, suggesting a protective effect of the EI profile against the development of SSc. These results suggest a potential role of NK cells in the pathogenesis of SSc, but further studies should be conducted to confirm our data.
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Affiliation(s)
- Patricia Hartstein Salim
- Serviço de Reumatologia and Serviço de Imunologia, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul –HCPA-UFRGS, Brazil
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Human leukocyte antigen (HLA)-C polymorphisms are associated with a decreased risk of rheumatoid arthritis. Mol Biol Rep 2014; 41:4103-8. [PMID: 24566686 DOI: 10.1007/s11033-014-3280-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 02/13/2014] [Indexed: 02/08/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune rheumatological disease thought to have substantial genetic contributions. Several genetic factors involved in the susceptibility to psoriasis and psoriatic arthritis (PsA) have been identified with genome-wide association studies, including human leukocyte antigen (HLA)-C, junction adhesion molecule 2 (JAM2) and REL. Psoriasis and PsA may share many features in common with RA. We hypothesized that this polymorphism may contribute to RA susceptibility in a Chinese population. We studied HLA-C rs10484554 C/T, HLA-C rs12212594 T/C, HLA-C rs12191877 C/T, JAM2 rs2829866 A/T and REL rs702873 G/A polymorphisms in 520 patients with RA and 520 controls in a Chinese population. HLA-C rs12191877 C/T polymorphism was in complete linkage disequilibrium (LD) (D' = 1.0, r (2) = 1.0) with HLA-C rs10484554 C/T polymorphism. When the HLA-C rs10484554 CC homozygote genotype was used as the reference group, the TT/CT genotypes were associated with a significantly decreased risk for RA (adjusted OR = 0.72, 95% CI = 0.52-0.99, p = 0.044). We found that the HLA-C rs12191877 C/T polymorphism was also associated with a decreased risk of RA. HLA-C rs12212594 T/C, JAM2 rs2829866 A/T and REL rs702873 G/A polymorphisms were not associated with the risk of RA. These results provide evidence that HLA-C polymorphisms are associated with a decreased risk of RA.
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