6
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Non-classical human leucocyte antigens in ankylosing spondylitis: possible association with HLA-E and HLA-F

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objectives

          Ankylosing spondylitis (AS) is the most prevalent form of spondyloarthritis, with a known genetic association with the HLA-B27 molecule. The aim of this study was to assess the contribution of the HLA-G, HLA-E and HLA-F to AS susceptibility/protection in Portuguese patients with HLA-B27 AS and HLA-B27 unaffected controls.

          Methods

          High-resolution typing of HLA-G, HLA-E and HLA-F was performed in 228 patients with HLA-B27 AS and 244 HLA-B27 unaffected controls. Allelic, genotypic and haplotypic frequencies were compared between cohorts. To replicate the results, single nucleotide polymorphisms (SNPs) in HLA-E and HLA-F genes were typed in Australian cohorts. For further confirmation, a group of European-descent patients with AS and unaffected controls were genotyped for Major Histocompatibility Complex SNPs using the Illumina microarray.

          Results

          In the Portuguese population, no significant differences were found in HLA-G. For HLA-E, a significant difference was detected for the genotype HLA-E*01:01:01/01:03:01 (p=0.009; pc=0.009; OR=0.51), with a protection effect. For HLA-F, significant differences were detected in the allele HLA-F*01:01:02 (p=0.0049; pc=0.0098; OR=0.60) and corresponding SNP rs2075682 (p=0.0004; pc=0.0008; OR=0.53), suggesting protection and in the genotype HLA-F*01:01:01/01:03:01 (p=0.011; pc=0.043; OR=2.00), suggesting a susceptibility effect. Three G-E-F haplotypes with significant differences were detected but occur in a very small number of individuals. The only significant differences detected in the replication studies were for HLA-E rs1059510 in the Australians and for HLA-F rs1736924 in the European-descent cohorts.

          Conclusion

          Our results reveal suggestive AS protective and susceptibility effects from both HLA-E and HLA-F loci, however with population differences. To our knowledge, this is the first study showing association of HLA-F with AS.

          Related collections

          Most cited references47

          • Record: found
          • Abstract: found
          • Article: not found

          HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

          The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

            We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European-ancestry we identified 244 independent multi-disease signals including 27 novel genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multi-disease signals with expression data sets from human, rat and mouse, and epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases that is genetically identical to another disease, possibly due to diagnostic misclassification, molecular subtypes, or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Broadly targeted CD8⁺ T cell responses restricted by major histocompatibility complex E.

              Major histocompatibility complex E (MHC-E) is a highly conserved, ubiquitously expressed, nonclassical MHC class Ib molecule with limited polymorphism that is primarily involved in the regulation of natural killer (NK) cells. We found that vaccinating rhesus macaques with rhesus cytomegalovirus vectors in which genes Rh157.5 and Rh157.4 are deleted results in MHC-E-restricted presentation of highly varied peptide epitopes to CD8αβ(+) T cells, at ~4 distinct epitopes per 100 amino acids in all tested antigens. Computational structural analysis revealed that MHC-E provides heterogeneous chemical environments for diverse side-chain interactions within a stable, open binding groove. Because MHC-E is up-regulated to evade NK cell activity in cells infected with HIV, simian immunodeficiency virus, and other persistent viruses, MHC-E-restricted CD8(+) T cell responses have the potential to exploit pathogen immune-evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.
                Bookmark

                Author and article information

                Journal
                RMD Open
                RMD Open
                rmdopen
                rmdopen
                RMD Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2056-5933
                2018
                28 June 2018
                : 4
                : 1
                : e000677
                Affiliations
                [1 ] departmentServiço Especializado de Epidemiologia e Biologia Molecular , Hospital de Santo Espirito da Ilha Terceira, EPER , Angra do Heroismo, Portugal
                [2 ] departmentInstitute of Health and Biomedical Innovation , Translational Research Institute, Queensland University of Technology , Brisbane, Australia
                [3 ] departmentCEDOC , Faculdade de Ciências Médicas, Universidade Nova de Lisboa , Lisboa, Portugal
                [4 ] departmentIMM , Universidade de Lisboa , Lisboa, Portugal
                [5 ] departmentCentro de Histocompatibilidade do Norte , Instituto Português do Sangue e da Transplantação , Porto, Portugal
                [6 ] departmentCentro de Sangue e Transplantação de Coimbra , Instituto Português do Sangue e da Transplantação , Coimbra, Portugal
                [7 ] departmentFaculdade de Ciências e Tecnologia , Universidade dos Açores , Ponta Delgada, Portugal
                Author notes
                [Correspondence to ] Margarida Rodrigues Santos; margarida.mp.santos@ 123456azores.gov.pt
                Article
                rmdopen-2018-000677
                10.1136/rmdopen-2018-000677
                6045739
                30018800
                5f62a2da-4a44-4a0a-8988-acbd7b65e42d
                © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an Open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 02 March 2018
                : 18 May 2018
                : 10 June 2018
                Categories
                Spondyloarthritis
                1506
                Original article
                Custom metadata
                unlocked

                spondyloarthritis,ankylosing spondylitis,autoimmune diseases,inflammation,gene polymorphism,hla

                Comments

                Comment on this article