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1
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Navid F, Chen L, Bowness P, Colbert RA. HLA-B27 and spondyloarthritis: at the crossroads of innate and adaptive immunity. Nat Rev Rheumatol 2025; 21:77-87. [PMID: 39623156 DOI: 10.1038/s41584-024-01189-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 01/29/2025]
Abstract
HLA-B*27 confers a strong risk of developing spondyloarthritis (SpA), which includes axial SpA with or without peripheral arthritis, enthesitis, acute anterior uveitis and gastrointestinal inflammation. Although no definitive mechanism has been established to explain the role of this HLA class I protein in the pathogenesis of SpA, three main hypotheses have emerged. First is the idea that self-peptides displayed by HLA-B27 resemble microorganism-derived peptides, leading to the expansion of autoreactive CD8+ T cells that trigger disease. The second and third hypotheses focus on aberrant properties of HLA-B27, including its tendency to form cell-surface dimers that can activate innate killer immunoglobulin-like receptors on CD4+ T helper 17 cells, triggering the production of pathogenic cytokines. HLA-B27 also misfolds in the endoplasmic reticulum, which can activate the unfolded protein response, increasing IL-23 expression and thereby promoting the production of type 17 cytokines. HLA-B27 misfolding in mesenchymal stem cells has also been linked to enhanced bone formation by mesenchymal stem cell-derived osteoblasts, which could contribute to structural damage in axial SpA. In this Review we summarize prevailing ideas about the role of HLA-B27 in SpA, discuss the latest developments as well as the gaps in current knowledge, and provide recommendations for future research to address these unmet needs.
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Affiliation(s)
- Fatemeh Navid
- Pediatric Translational Research Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Liye Chen
- Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK
| | - Paul Bowness
- Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK
| | - Robert A Colbert
- Pediatric Translational Research Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
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2
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Penkava F, Sansom S, Bowness P. Pathogenic T-cell clones in axial spondyloarthritis: what is the evidence? Rheumatology (Oxford) 2024; 63:ii4-ii6. [PMID: 39700471 PMCID: PMC11658411 DOI: 10.1093/rheumatology/keae522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/02/2024] [Indexed: 12/21/2024] Open
Affiliation(s)
- Frank Penkava
- Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK
| | - Stephen Sansom
- Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK
| | - Paul Bowness
- Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK
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Ravindranath MH, Ravindranath NM, Amato-Menker CJ, Hilali FE, Filippone EJ. Conformational Alterations of the Cell Surface of Monomeric and Dimeric β2m-Free HLA-I (Proto-HLA) May Enable Novel Immune Functions in Health and Disease. Curr Issues Mol Biol 2024; 46:6961-6985. [PMID: 39057057 PMCID: PMC11276036 DOI: 10.3390/cimb46070416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
Human leukocyte antigens (HLAs) are polymorphic glycoproteins expressed on the cell surface of nucleated cells and consist of two classes, HLA class I and HLA class II. In contrast, in mice, these molecules, known as H-2, are expressed on both nucleated cells and erythrocytes. HLA-I molecules (Face-1) are heterodimers consisting of a polypeptide heavy chain (HC) and a light chain, B2-microglobulin (B2m). The heterodimers bind to antigenic peptides and present them to the T-cell receptors of CD8+ cytotoxic T lymphocytes. The HCs can also independently emerge on the cell surface as B2m-free HC monomers without peptides (Face-2). Early investigators suggested that the occurrence of B2m-free HCs on the cell surface resulted from the dissociation of B2m from Face-1. However, others documented the independent emergence of B2m-free HCs (Face-2) from the endoplasmic reticulum (ER) to the cell surface. The clustering of such HC molecules on either the cell surface or on exosomes resulted in the dimerization of B2m-free HCs to form homodimers (if the same allele, designated as Face-3) or heterodimers (if different alleles, designated as Face-4). Face-2 occurs at low levels on the cell surface of several normal cells but is upregulated on immune cells upon activation by proinflammatory cytokines and other agents such as anti-CD3 antibodies, phytohemagglutinin, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain activated. After activation-induced upregulation, Face-2 molecules undergo homo- and heterodimerization (Face-3 and Face-4). Observations made on the structural patterns of HCs and their dimerization in sharks, fishes, and tetrapod species suggest that the formation of B2m-free HC monomers and dimers is a recapitalization of a phylogenetically conserved event, befitting the term Proto-HLA for the B2m-free HCs. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/+ mice. Anti-HC-specific monoclonal antibodies (mAbs) delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The conformational alterations that occur in the B2m-free HCs enable them to interact with several inhibitory and activating receptors of cellular components of the innate (natural killer (NK) cells) and adaptive (T and B cells) immune systems. The NK cells express killer immunoglobulin-like receptors (KIRs), whereas leukocytes (T and B lymphocytes, monocytes/macrophages, and dendritic cells) express leukocyte immunoglobulin-like receptors (LILRs). The KIRs and LILRs include activating and inhibitory members within their respective groups. This review focuses on the interaction of KIRs and LILRs with B2m-free HC monomers and dimers in patients with spondylarthritis. Several investigations reveal that the conformational alterations occurring in the alpha-1 and alpha-2 domains of B2m-free HCs may facilitate immunomodulation by their interaction with KIR and LILR receptors. This opens new avenues to immunotherapy of autoimmune diseases and even human cancers that express B2m-free HCs.
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Affiliation(s)
- Mepur H. Ravindranath
- Department of Hematology and Oncology, Children’s Hospital, Los Angeles, CA 90027, USA
- Terasaki Foundation Laboratory, Santa Monica, CA 90064, USA
| | - Narendranath M. Ravindranath
- Norris Dental Science Center, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA;
| | - Carly J. Amato-Menker
- Department of Microbiology, Immunology and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA;
| | - Fatiha El Hilali
- Medico-Surgical, Biomedicine and Infectiology Research Laboratory, The Faculty of Medicine and Pharmacy of Laayoune & Agadir, Ibnou Zohr University, Agadir 80000, Morocco;
| | - Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19145, USA;
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P AT, Deogade MS, Nesari TM, Ramachandran A. A short review on deciphering Vyadhikshamatva: insights from HLA-B27-ankylosing spondylitis relation. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2024; 21:264-267. [PMID: 38702944 DOI: 10.1515/jcim-2024-0083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 04/04/2024] [Indexed: 05/06/2024]
Abstract
OBJECTIVES Various aspects of the concept of Vyadhikshamatva have been thoroughly explored, highlighting its profound significance in resisting disease manifestation, particularly in the context of Ankylosing spondylitis. Investigated the relationship between HLA-B27 and Ankylosing spondylitis (AS) by examining current knowledge and hypotheses Furthermore, efforts were made to portray the influence of prakruti (constitution) and balam (strength) on disease manifestation and progression. METHODS Ayurvedic literature along with contemporary research works was analyzed for correlating various aspects like vyadhikshamatva,oja (The final essence of all body elements), and balam along with their influence on the defensive mechanism of the body. A thorough literature search was conducted to explore the strong association between HLA-B27 and AS by examining various hypotheses like the Arthritogenic peptide hypothesis, the Misfolding hypothesis, the Surface Homodimer hypothesis, and the β2 microglobulin hypothesis that attempts to explain the pathogenic role of HLA-B27 in AS. Alongside classical Ayurvedic texts, databases like PubMed and Scopus were searched using keywords such as Immunity, Ankylosing spondylitis, Vyadhikshamatva, HLA-B27, Balam, and Autoimmune disorder with the help of Boolean operators. RESULTS The review highlighted the critical role of Vyadhikshamatva in disease prevention, particularly in influencing the manifestation of conditions like AS despite genetic predisposition (HLA-B27). Further, the understanding of the Ayurvedic concepts can clearly explain the conflict that has arisen in the determination of the positive HLAB27 gene in Ankylosing Spondylitis as a definite diagnosing criteria. CONCLUSIONS This comprehensive understanding will uplift the need for personalized medicine in disease management. Further research must be needed to understand the interaction between genetic factors (HLAb27), individual constitution, and their vyadikshamatva.
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Affiliation(s)
- Athul T P
- Department of Dravyaguna, All India Institute of Ayurveda, NewDelhi, India
| | - Meena S Deogade
- Department of Dravyaguna, All India Institute of Ayurveda, NewDelhi, India
| | - Tanuja M Nesari
- Department of Dravyaguna, All India Institute of Ayurveda, NewDelhi, India
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Bordbar A, Manches O, Nowatzky J. Biology of HLA class I associated inflammatory diseases. Best Pract Res Clin Rheumatol 2024; 38:101977. [PMID: 39085016 PMCID: PMC11441793 DOI: 10.1016/j.berh.2024.101977] [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: 06/04/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024]
Abstract
Human leukocyte antigen (HLA) class I association is a well-established feature of common and uncommon inflammatory diseases, but it is unknown whether it impacts the pathogenesis of these disorders. The "arthritogenic peptide" hypothesis proposed initially for HLA-B27-associated ankylosing spondylitis (AS) seems the most intuitive to serve as a model for other HLA class I-associated diseases, but evidence supporting it has been scarce. Recent technological advances and the discovery of epistatic relationships between disease-associated HLA class I and endoplasmic reticulum aminopeptidase (ERAP) coding variants have led to the generation of new data and conceptual approaches to the problem requiring its re-examination. Continued success in these endeavors holds promise to resolve a Gordian Knot in human immunobiology. It may ultimately benefit patients by enabling the development of new therapies and precision tools for assessing disease risk and predicting treatment responses.
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Affiliation(s)
- Ali Bordbar
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA
| | - Olivier Manches
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA
| | - Johannes Nowatzky
- New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA; New York University Grossman School of Medicine, Department of Pathology, USA; New York University Grossman School of Medicine, Department of Medicine Division of Rheumatology, NYU Langone Ocular Rheumatology Program, New York, NY, USA; New York University Grossman School of Medicine, Department of Medicine, Division of Rheumatology, NYU Langone Center for Behçet's Disease, New York, NY, USA.
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van de Sande MGH, Elewaut D. Pathophysiology and immunolgical basis of axial spondyloarthritis. Best Pract Res Clin Rheumatol 2023; 37:101897. [PMID: 38030467 DOI: 10.1016/j.berh.2023.101897] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/13/2023] [Indexed: 12/01/2023]
Abstract
Over the recent years the wider availability and application of state-of-the-art immunological technologies greatly advanced the insight into the mechanisms that play an important role in axial spondyloarthritis (axSpA) pathophysiology. This increased understanding has facilitated the development of novel treatments that target disease relevant pathways, hereby improving outcome for axSpA patients. In axSpA pathophysiology genetic and environmental factors as well as immune activation by mechanical or bacterial stress resulting in a chronic inflammatory response have a central role. The TNF and IL-23/IL-17 immune pathways play a pivotal role in these disease mechanisms. This review provides an outline of the immunological basis of axSpA with a focus on key genetic risk factors and their link to activation of the pathological immune response, as well as on the role of the gut and entheses in the initiation of inflammation with subsequent new bone formation in axSpA.
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Affiliation(s)
- Marleen G H van de Sande
- Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Infection and Immunity Institute, Amsterdam, the Netherlands; Amsterdam Rheumatology & Immunology Center (ARC), Academic Medical Center, Amsterdam, the Netherlands.
| | - Dirk Elewaut
- Unit Molecular Immunology and Inflammation, VIB Centre for Inflammation Research, Ghent University and Department of Rheumatology, Ghent University Hospital, C. Heymanslaan 10, Ghent, 9000, Belgium.
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7
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Ravindranath MH, Ravindranath NM, Selvan SR, Hilali FE, Amato-Menker CJ, Filippone EJ. Cell Surface B2m-Free Human Leukocyte Antigen (HLA) Monomers and Dimers: Are They Neo-HLA Class and Proto-HLA? Biomolecules 2023; 13:1178. [PMID: 37627243 PMCID: PMC10452486 DOI: 10.3390/biom13081178] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/17/2023] [Accepted: 07/17/2023] [Indexed: 08/27/2023] Open
Abstract
Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, bronchi, epidermis, esophagus, breast, stomach, ilium, colorectum, gall bladder, urinary bladder, seminal vesicles ovarian epithelia, endometrium, thymus, spleen, and lymphocytes. They are upregulated on immune cells upon activation by proinflammatory cytokines, anti-CD3 antibodies, antibiotics (e.g., ionomycin), phytohemagglutinin, retinoic acid, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain in an activated state. After activation-induced upregulation, the Face-2 molecules undergo homo- and hetero-dimerization (Face-3 and Face-4). Alterations in the redox environment promote dimerization. Heterodimerization can occur among and between the alleles of different haplotypes. The glycosylation of these variants differ from that of Face-1, and they may occur with bound exogenous peptides. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/- mice. The mice with HLA-B27 in Face-2 spontaneous configuration develop symptoms such as changes in nails and joints, hair loss, and swelling in paws, leading to ankyloses. Anti-HC-specific mAbs delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The upregulation of Face-2 in human cancers occurs concomitantly with the downregulation of intact HLAs (Face-1). The HLA monomeric and dimeric variants interact with inhibitory and activating ligands (e.g., KIR), growth factors, cytokines, and neurotransmitters. Similarities in the amino acid sequences of the HLA-I variants and HLA-II β-chain suggest that Face-2 could be the progenitor of both HLA classes. These findings may support the recognition of these variants as a neo-HLA class and proto-HLA.
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Affiliation(s)
- Mepur H. Ravindranath
- Department of Hematology and Oncology, Children’s Hospital, Los Angeles, CA 90027, USA
- Terasaki Foundation Laboratory, Santa Monica, CA 90064, USA
| | - Narendranath M. Ravindranath
- Norris Dental Science Center, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA;
| | - Senthamil R. Selvan
- Division of Immunology and Hematology Devices, OHT 7: Office of In Vitro Diagnostics, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, Food and Drug Administration (FDA), Silver Spring, MD 20993, USA;
| | - Fatiha El Hilali
- Medico-Surgical, Biomedicine and Infectiology Research Laboratory, The Faculty of Medicine and Pharmacy of Laayoune & Agadir, Ibnou Zohr University, Agadir 80000, Morocco;
| | - Carly J. Amato-Menker
- Department of Microbiology, Immunology and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA;
| | - Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19145, USA;
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8
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Fatica M, D'Antonio A, Novelli L, Triggianese P, Conigliaro P, Greco E, Bergamini A, Perricone C, Chimenti MS. How Has Molecular Biology Enhanced Our Undertaking of axSpA and Its Management. Curr Rheumatol Rep 2023; 25:12-33. [PMID: 36308677 PMCID: PMC9825525 DOI: 10.1007/s11926-022-01092-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2022] [Indexed: 01/11/2023]
Abstract
PURPOSE This review aims at investigating pathophysiological mechanisms in spondyloarthritis (SpA). Analysis of genetic factors, immunological pathways, and abnormalities of bone metabolism lay the foundations for a better understanding of development of the axial clinical manifestations in patients, allowing physician to choose the most appropriate therapeutic strategy in a more targeted manner. RECENT FINDINGS In addition to the contribution of MHC system, findings emerged about the role of non-HLA genes (as ERAP1 and 2, whose inhibition could represent a new therapeutic approach) and of epigenetic mechanisms that regulate the expression of genes involved in SpA pathogenesis. Increasing evidence of bone metabolism abnormalities secondary to the activation of immunological pathways suggests the development of various bone anomalies that are present in axSpA patients. SpA are a group of inflammatory diseases with a multifactorial origin, whose pathogenesis is linked to the genetic predisposition, the action of environmental risk factors, and the activation of immune response. It is now well known how bone metabolism leads to long-term structural damage via increased bone turnover, bone loss and osteoporosis, osteitis, erosions, osteosclerosis, and osteoproliferation. These effects can exist in the same patient over time or even simultaneously. Evidence suggests a cross relationship among innate immunity, autoimmunity, and bone remodeling in SpA, making treatment approach a challenge for rheumatologists. Specifically, treatment targets are consistently increasing as new drugs are upcoming. Both biological and targeted synthetic drugs are promising in terms of their efficacy and safety profile in patients affected by SpA.
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Affiliation(s)
- Mauro Fatica
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Arianna D'Antonio
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Lucia Novelli
- UniCamillus, Saint Camillus International University of Health Sciences, Rome, Italy
| | - Paola Triggianese
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Paola Conigliaro
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Elisabetta Greco
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Alberto Bergamini
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maria Sole Chimenti
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
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Yang X, Garner LI, Zvyagin IV, Paley MA, Komech EA, Jude KM, Zhao X, Fernandes RA, Hassman LM, Paley GL, Savvides CS, Brackenridge S, Quastel MN, Chudakov DM, Bowness P, Yokoyama WM, McMichael AJ, Gillespie GM, Garcia KC. Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides. Nature 2022; 612:771-777. [PMID: 36477533 PMCID: PMC10511244 DOI: 10.1038/s41586-022-05501-7] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 11/01/2022] [Indexed: 12/12/2022]
Abstract
Human leucocyte antigen B*27 (HLA-B*27) is strongly associated with inflammatory diseases of the spine and pelvis (for example, ankylosing spondylitis (AS)) and the eye (that is, acute anterior uveitis (AAU))1. How HLA-B*27 facilitates disease remains unknown, but one possible mechanism could involve presentation of pathogenic peptides to CD8+ T cells. Here we isolated orphan T cell receptors (TCRs) expressing a disease-associated public β-chain variable region-complementary-determining region 3β (BV9-CDR3β) motif2-4 from blood and synovial fluid T cells from individuals with AS and from the eye in individuals with AAU. These TCRs showed consistent α-chain variable region (AV21) chain pairing and were clonally expanded in the joint and eye. We used HLA-B*27:05 yeast display peptide libraries to identify shared self-peptides and microbial peptides that activated the AS- and AAU-derived TCRs. Structural analysis revealed that TCR cross-reactivity for peptide-MHC was rooted in a shared binding motif present in both self-antigens and microbial antigens that engages the BV9-CDR3β TCRs. These findings support the hypothesis that microbial antigens and self-antigens could play a pathogenic role in HLA-B*27-associated disease.
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Affiliation(s)
- Xinbo Yang
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Lee I Garner
- NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Ivan V Zvyagin
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
| | - Michael A Paley
- Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Ekaterina A Komech
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
| | - Kevin M Jude
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiang Zhao
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ricardo A Fernandes
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Lynn M Hassman
- Department of Ophthalmology, Washington University School of Medicine, St Louis, MO, USA
| | - Grace L Paley
- Department of Ophthalmology, Washington University School of Medicine, St Louis, MO, USA
| | - Christina S Savvides
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Simon Brackenridge
- NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Max N Quastel
- NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Dmitriy M Chudakov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
| | - Paul Bowness
- Nuffield Department of Orthopaedics Rheumatology and Muscuoskeletal Science (NDORMS), Botnar Research Center, University of Oxford, Oxford, UK
| | - Wayne M Yokoyama
- Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
- Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA.
| | - Andrew J McMichael
- NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Geraldine M Gillespie
- NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - K Christopher Garcia
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
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10
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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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11
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Ravindranath MH, Ravindranath NM, Selvan SR, Filippone EJ, Amato-Menker CJ, El Hilali F. Four Faces of Cell-Surface HLA Class-I: Their Antigenic and Immunogenic Divergence Generating Novel Targets for Vaccines. Vaccines (Basel) 2022; 10:vaccines10020339. [PMID: 35214796 PMCID: PMC8878457 DOI: 10.3390/vaccines10020339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/07/2022] [Accepted: 02/17/2022] [Indexed: 12/19/2022] Open
Abstract
Leukocyte cell-surface HLA-I molecules, involved in antigen presentation of peptides to CD8+ T-cells, consist of a heavy chain (HC) non-covalently linked to β2-microglobulin (β2m) (Face-1). The HC amino acid composition varies across all six isoforms of HLA-I, while that of β2m remains the same. Each HLA-allele differs in one or more amino acid sequences on the HC α1 and α2 helices, while several sequences among the three helices are conserved. HCs without β2m (Face-2) are also observed on human cells activated by malignancy, viral transformation, and cytokine or chemokine-mediated inflammation. In the absence of β2m, the monomeric Face-2 exposes immunogenic cryptic sequences on these cells as confirmed by HLA-I monoclonal antibodies (LA45, L31, TFL-006, and TFL-007). Furthermore, such exposure enables dimerization between two Face-2 molecules by SH-linkage, salt linkage, H-bonding, and van der Waal forces. In HLA-B27, the linkage between two heavy chains with cysteines at position of 67 of the amino acid residues was documented. Similarly, several alleles of HLA-A, B, C, E, F and G express cysteine at 67, 101, and 164, and additionally, HLA-G expresses cysteine at position 42. Thus, the monomeric HC (Face-2) can dimerize with another HC of its own allele, as homodimers (Face-3), or with a different HC-allele, as heterodimers (Face-4). The presence of Face-4 is well documented in HLA-F. The post-translational HLA-variants devoid of β2m may expose several cryptic linear and non-linear conformationally altered sequences to generate novel epitopes. The objective of this review, while unequivocally confirming the post-translational variants of HLA-I, is to highlight the scientific and clinical importance of the four faces of HLA and to prompt further research to elucidate their functions and their interaction with non-HLA molecules during inflammation, infection, malignancy and transplantation. Indeed, these HLA faces may constitute novel targets for passive and active specific immunotherapy and vaccines.
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Affiliation(s)
- Mepur H. Ravindranath
- Department of Hematology and Oncology, Children’s Hospital, Los Angeles, CA 90027, USA
- Emeritus Research Scientist at Terasaki Foundation Laboratory, Santa Monica, CA 90064, USA
- Correspondence:
| | - Narendranath M. Ravindranath
- Norris Dental Science Center, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA;
| | | | - Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19145, USA;
| | - Carly J. Amato-Menker
- Department of Microbiology, Immunology and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA;
| | - Fatiha El Hilali
- The Faculty of Medicine and Pharmacy of Laayoune, Ibn Zohr University, Agadir 70000, Morocco;
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12
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Al-Moussawy M, Abdelsamed HA, Lakkis FG. Immunoglobulin-like receptors and the generation of innate immune memory. Immunogenetics 2022; 74:179-195. [PMID: 35034136 PMCID: PMC10074160 DOI: 10.1007/s00251-021-01240-7] [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: 09/19/2021] [Accepted: 11/25/2021] [Indexed: 12/22/2022]
Abstract
Host immunity is classically divided into "innate" and "adaptive." While the former has always been regarded as the first, rapid, and antigen-nonspecific reaction to invading pathogens, the latter represents the more sophisticated and antigen-specific response that has the potential to persist and generate memory. Recent work however has challenged this dogma, where murine studies have successfully demonstrated the ability of innate immune cells (monocytes and macrophages) to acquire antigen-specific memory to allogeneic major histocompatibility complex (MHC) molecules. The immunoreceptors so far identified that mediate innate immune memory are the paired immunoglobulin-like receptors (PIRs) in mice, which are orthologous to human leukocyte immunoglobulin-like receptors (LILRs). These receptor families are mainly expressed by the myelomonocytic cell lineage, suggesting an important role in the innate immune response. In this review, we will discuss the role of immunoglobulin-like receptors in the development of innate immune memory across species.
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Affiliation(s)
- Mouhamad Al-Moussawy
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, USA.
| | - Hossam A Abdelsamed
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, USA. .,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, USA.
| | - Fadi G Lakkis
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, USA. .,Department of Immunology, University of Pittsburgh, Pittsburgh, USA. .,Department of Medicine, University of Pittsburgh, Pittsburgh, USA.
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13
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Kocatürk B, Balık Z, Pişiren G, Kalyoncu U, Özmen F, Özen S. Spondyloarthritides: Theories and beyond. Front Pediatr 2022; 10:1074239. [PMID: 36619518 PMCID: PMC9816396 DOI: 10.3389/fped.2022.1074239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 11/24/2022] [Indexed: 12/24/2022] Open
Abstract
Spondyloarthritides (SpA) are a family of interrelated rheumatic disorders with a typical disease onset ranging from childhood to middle age. If left untreated, they lead to a severe decrease in patients' quality of life. A succesfull treatment strategy starts with an accurate diagnosis which is achieved through careful analysis of medical symptoms. Classification criterias are used to this process and are updated on a regular basis. Although there is a lack of definite knowledge on the disease etiology of SpA, several studies have paved the way for understanding plausible risk factors and developing treatment strategies. The significant increase of HLA-B27 positivity in SpA patients makes it a strong candidate as a predisposing factor and several theories have been proposed to explain HLA-B27 driven disease progression. However, the presence of HLA-B27 negative patients underlines the presence of additional risk factors. The current treatment options for SpAs are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), TNF inhibitors (TNFis), Disease-Modifying Anti-Rheumatic Drugs (DMARDs) and physiotherapy yet there are ongoing clinical trials. Anti IL17 drugs and targeted synthetic DMARDs such as JAK inhibitors are also emerging as treatment alternatives. This review discusses the current diagnosis criteria, treatment options and gives an overview of the previous findings and theories to clarify the possible contributors to SpA pathogenesis with a focus on Ankylosing Spondylitis (AS) and enthesitis-related arthritis (ERA).
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Affiliation(s)
- Begüm Kocatürk
- Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Zeynep Balık
- Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Gaye Pişiren
- Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Umut Kalyoncu
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Füsun Özmen
- Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Seza Özen
- Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
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14
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Kubanov AA, Chikin VV, Karamova AE, Znamenskaya LF, Artamonova OG, Verbenko DA. Genetic markers for psoriatic arthritis among patients with psoriasis. Part II: HLA genes. VESTNIK DERMATOLOGII I VENEROLOGII 2021. [DOI: 10.25208/vdv1269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Psoriatic arthritis often leads to the development of severe outcomes ankylosis, deformities of the affected joints with severe impairment of their functions and disability. Early identification of patients with psoriasis with an increased risk of developing psoriatic arthritis for the purpose of its timely diagnosis and early initiation of therapy can prevent the development of severe disease outcomes. It is believed that the genes of the HLA system make the greatest individual genetic contribution to the formation of a predisposition to hereditary diseases with polygenic inheritance. The literature review considers the polymorphisms of the genes of the HLA system, associated with the development of psoriatic arthritis, in patients with psoriasis. The HLA alleles that contribute to the development of psoriatic arthritis and its individual forms have been identified. HLA alleles have been identified, which have a protective effect against the development of psoriatic arthritis.
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15
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Romero-López JP, Elewaut D, Pacheco-Tena C, Burgos-Vargas R. Inflammatory Foot Involvement in Spondyloarthritis: From Tarsitis to Ankylosing Tarsitis. Front Med (Lausanne) 2021; 8:730273. [PMID: 34692724 PMCID: PMC8531414 DOI: 10.3389/fmed.2021.730273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/06/2021] [Indexed: 11/13/2022] Open
Abstract
Spondyloarthritis (SpA) is a group that includes a wide spectrum of clinically similar diseases manifested by oligoarticular arthritis and axial or peripheral ankylosis. Although axial SpA is predominant in Caucasians and adult-onset patients, juvenile-onset and Latin American patients are characterized by severe peripheral arthritis and particularly foot involvement. The peripheral involvement of SpA can vary from tarsal arthritis to the most severe form named ankylosing tarsitis (AT). Although the cause and etiopathogenesis of axSpA are often studied, the specific characteristics of pSpA are unknown. Several animal models of SpA develop initial tarsitis and foot ankylosis as the main signs, emphasizing the role of foot inflammation in the overall SpA spectrum. In this review, we attempt to highlight the clinical characteristics of foot involvement in SpA and update the knowledge regarding its pathogenesis, focusing on animal models and the role of mechanical forces in inflammation.
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Affiliation(s)
- José Pablo Romero-López
- Laboratorio A4, Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Mexico
- Laboratorio de Inmunología Clínica 1, Posgrado en Ciencias Quimicobiológicas, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional de México, Ciudad de México, Mexico
| | - Dirk Elewaut
- Ghent University Hospital, Ghent University, Ghent, Belgium
| | - César Pacheco-Tena
- Facultad de Medicina, Universidad Autónoma de Chihuahua, Chihuahua, Mexico
| | - Rubén Burgos-Vargas
- Department of Rheumatology, Hospital General de México, “Dr. Eduardo Liceaga”, Ciudad de México, Mexico
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16
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Abdallah F, Coindre S, Gardet M, Meurisse F, Naji A, Suganuma N, Abi-Rached L, Lambotte O, Favier B. Leukocyte Immunoglobulin-Like Receptors in Regulating the Immune Response in Infectious Diseases: A Window of Opportunity to Pathogen Persistence and a Sound Target in Therapeutics. Front Immunol 2021; 12:717998. [PMID: 34594332 PMCID: PMC8478328 DOI: 10.3389/fimmu.2021.717998] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/25/2021] [Indexed: 12/19/2022] Open
Abstract
Immunoregulatory receptors are essential for orchestrating an immune response as well as appropriate inflammation in infectious and non-communicable diseases. Among them, leukocyte immunoglobulin-like receptors (LILRs) consist of activating and inhibitory receptors that play an important role in regulating immune responses modulating the course of disease progression. On the one hand, inhibitory LILRs constitute a safe-guard system that mitigates the inflammatory response, allowing a prompt return to immune homeostasis. On the other hand, because of their unique capacity to attenuate immune responses, pathogens use inhibitory LILRs to evade immune recognition, thus facilitating their persistence within the host. Conversely, the engagement of activating LILRs triggers immune responses and the production of inflammatory mediators to fight microbes. However, their heightened activation could lead to an exacerbated immune response and persistent inflammation with major consequences on disease outcome and autoimmune disorders. Here, we review the genetic organisation, structure and ligands of LILRs as well as their role in regulating the immune response and inflammation. We also discuss the LILR-based strategies that pathogens use to evade immune responses. A better understanding of the contribution of LILRs to host-pathogen interactions is essential to define appropriate treatments to counteract the severity and/or persistence of pathogens in acute and chronic infectious diseases lacking efficient treatments.
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Affiliation(s)
- Florence Abdallah
- Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Fontenay-aux-Roses, France
| | - Sixtine Coindre
- Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Fontenay-aux-Roses, France
| | - Margaux Gardet
- Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Fontenay-aux-Roses, France
| | - Florian Meurisse
- Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Fontenay-aux-Roses, France
| | - Abderrahim Naji
- Department of Environmental Medicine, Cooperative Medicine Unit, Research and Education Faculty, Medicine Science Cluster, Kochi Medical School, Kochi University, Nankoku-City, Japan
| | - Narufumi Suganuma
- Department of Environmental Medicine, Cooperative Medicine Unit, Research and Education Faculty, Medicine Science Cluster, Kochi Medical School, Kochi University, Nankoku-City, Japan
| | - Laurent Abi-Rached
- Aix-Marseille University, IRD, APHM, MEPHI, IHU Mediterranean Infection, SNC5039 CNRS, Marseille, France.,SNC5039 CNRS, Marseille, France
| | - Olivier Lambotte
- Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Fontenay-aux-Roses, France.,Public-Hospital Assistance of Paris, Department of Internal Medicine and Clinical Immunology, Paris-Saclay University Hospital Group, Bicêtre Hospital, Le Kremlin-Bicêtre, France
| | - Benoit Favier
- Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Fontenay-aux-Roses, France
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17
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Abstract
Natural Killer (NK) cells are key effectors of the innate immune system which represent the first line of defense against viral infections. NK cell activation depends on the engagement of a complex receptor repertoire expressed on their surface, consisting of both activating and inhibitory receptors. Among the known NK cell receptors, the family of killer Ig-like receptors (KIRs) consists in activating/inhibitory receptors that interact with specific human leukocyte antigen (HLA) molecules expressed on target cells. In particular, the expression of peculiar KIRs have been reported to be associated to viral infection susceptibility. Interestingly, a significant association between the development and onset of different human pathologies, such as tumors, neurodegeneration and infertility, and a clonal KIRs expression on NK cells has been described in presence of viral infections, supporting the crucial role of KIRs in defining the effect of viral infections in different tissues and organs. This review aims to report the state of art about the role of KIRs receptors in NK cell activation and viral infection control.
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18
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Tay SH, Yeo JG, Leong JY, Albani S, Arkachaisri T. Juvenile Spondyloarthritis: What More Do We Know About HLA-B27, Enthesitis, and New Bone Formation? Front Med (Lausanne) 2021; 8:666772. [PMID: 34095174 PMCID: PMC8174582 DOI: 10.3389/fmed.2021.666772] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022] Open
Abstract
Juvenile spondyloarthritis (JSpA) refers to a diverse spectrum of immune-mediated inflammatory arthritides whose onset occurs in late childhood and adolescence. Like its adult counterpart, JSpA is typified by a strong association with human leukocyte antigen-B27 (HLA-B27) and potential axial involvement, while lacking rheumatoid factor (RF) and distinguishing autoantibodies. A characteristic manifestation of JSpA is enthesitis (inflammation of insertion sites of tendons, ligaments, joint capsules or fascia to bone), which is commonly accompanied by bone resorption and new bone formation at affected sites. In this Review, advances in the role of HLA-B27, enthesitis and its associated osteoproliferation in JSpA pathophysiology and treatment options will be discussed. A deeper appreciation of how these elements contribute to the JSpA disease mechanism will better inform diagnosis, prognosis and therapy, which in turn translates to an improved quality of life for patients.
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Affiliation(s)
- Shi Huan Tay
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Joo Guan Yeo
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore.,Rheumatology and Immunology Service, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore
| | - Jing Yao Leong
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Salvatore Albani
- SingHealth Duke-National University of Singapore Academic Medical Centre, Translational Immunology Institute, Singapore, Singapore.,Duke-National University of Singapore Medical School, Singapore, Singapore.,Rheumatology and Immunology Service, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore
| | - Thaschawee Arkachaisri
- Duke-National University of Singapore Medical School, Singapore, Singapore.,Rheumatology and Immunology Service, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore
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19
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Kavadichanda CG, Geng J, Bulusu SN, Negi VS, Raghavan M. Spondyloarthritis and the Human Leukocyte Antigen (HLA)-B *27 Connection. Front Immunol 2021; 12:601518. [PMID: 33763060 PMCID: PMC7982681 DOI: 10.3389/fimmu.2021.601518] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 02/08/2021] [Indexed: 01/12/2023] Open
Abstract
Heritability of Spondyloarthritis (SpA) is highlighted by several familial studies and a high association with the presence of human leukocyte antigen (HLA)-B*27. Though it has been over four decades since the association of HLA-B*27 with SpA was first determined, the pathophysiological roles played by specific HLA-B*27 allotypes are not fully understood. Popular hypotheses include the presentation of arthritogenic peptides, triggering of endoplasmic reticulum (ER) stress by misfolded HLA-B*27, and the interaction between free heavy chains or heavy chain homodimers of HLA-B*27 and immune receptors to drive IL-17 responses. Several non-HLA susceptibility loci have also been identified for SpA, including endoplasmic reticulum aminopeptidases (ERAP) and those related to the IL-23/IL-17 axes. In this review, we summarize clinical aspects of SpA including known characteristics of gut inflammation, enthesitis and new bone formation and the existing models for understanding the association of HLA-B*27 with disease pathogenesis. We also examine newer insights into the biology of HLA class I (HLA-I) proteins and their implications for expanding our understanding of HLA-B*27 contributions to SpA pathogenesis.
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Affiliation(s)
- Chengappa G Kavadichanda
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Jie Geng
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Sree Nethra Bulusu
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Vir Singh Negi
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Malini Raghavan
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
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20
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Sharif K, Bridgewood C, Dubash S, McGonagle D. Intestinal and enthesis innate immunity in early axial spondyloarthropathy. Rheumatology (Oxford) 2021; 59:iv67-iv78. [PMID: 33053197 PMCID: PMC7566539 DOI: 10.1093/rheumatology/keaa408] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/10/2020] [Indexed: 12/23/2022] Open
Abstract
Axial SpA (axSpA), encompassing AS, is a multifactorial disease that localizes to sites of high spinal biomechanical stress. Much has been written on T cells and adaptive immunity in axSpA, which is understandable given the very strong HLA-B27 disease association. Extra-axial disease characteristically involves the anterior uveal tract, aortic root, lung apex and terminal ileum. Under recent classification, axSpA is classified as an intermediate between autoimmunity and autoinflammatory disease, with the latter term being synonymous with innate immune dysregulation. The purpose of this review is to evaluate the ‘danger signals’ from both the exogenous intestinal microbiotal adjuvants or pathogen-associated molecular patterns that access the circulation and endogenously derived damaged self-tissue or damage-associated molecular patterns derived from entheses and other sites of high biomechanical stress or damage that may serve as key drivers of axSpA onset, evolution, disease flares and eventual outcomes.
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Affiliation(s)
- Kassem Sharif
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.,Sheba Medical Center, Tel Aviv, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Charlie Bridgewood
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Sayam Dubash
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.,National Institute for Health Research, Leeds Biomedical Research Centre, Leeds Teaching Hospitals, Leeds, UK
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.,National Institute for Health Research, Leeds Biomedical Research Centre, Leeds Teaching Hospitals, Leeds, UK
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21
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Gill T, Rosenbaum JT. Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy. Front Immunol 2021; 11:586494. [PMID: 33537028 PMCID: PMC7848169 DOI: 10.3389/fimmu.2020.586494] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.
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Affiliation(s)
- Tejpal Gill
- Division of Arthritis and Rheumatic Diseases, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - James T Rosenbaum
- Departments of Ophthalmology, Medicine, and Cell Biology, Oregon Health & Science University, Portland, OR, United States.,Legacy Devers Eye Institute, Portland, OR, United States
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22
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Sharip A, Kunz J. Understanding the Pathogenesis of Spondyloarthritis. Biomolecules 2020; 10:biom10101461. [PMID: 33092023 PMCID: PMC7588965 DOI: 10.3390/biom10101461] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/07/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
Spondyloarthritis comprises a group of inflammatory diseases of the joints and spine, with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B*27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B*27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B*27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.
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MESH Headings
- Arthritis, Psoriatic/genetics
- Arthritis, Psoriatic/immunology
- Arthritis, Psoriatic/metabolism
- Arthritis, Psoriatic/pathology
- Arthritis, Reactive/genetics
- Arthritis, Reactive/immunology
- Arthritis, Reactive/metabolism
- Arthritis, Reactive/pathology
- HLA-B27 Antigen/genetics
- HLA-B27 Antigen/immunology
- Humans
- Inflammation/genetics
- Inflammation/immunology
- Inflammation/metabolism
- Inflammation/pathology
- Inflammatory Bowel Diseases/genetics
- Inflammatory Bowel Diseases/immunology
- Inflammatory Bowel Diseases/metabolism
- Inflammatory Bowel Diseases/pathology
- Joints/immunology
- Joints/pathology
- Spine/immunology
- Spine/pathology
- Spondylarthritis/genetics
- Spondylarthritis/immunology
- Spondylarthritis/metabolism
- Spondylarthritis/pathology
- Spondylitis, Ankylosing/genetics
- Spondylitis, Ankylosing/immunology
- Spondylitis, Ankylosing/metabolism
- Spondylitis, Ankylosing/pathology
- Unfolded Protein Response/genetics
- Unfolded Protein Response/immunology
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23
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The Genetics of Spondyloarthritis. J Pers Med 2020; 10:jpm10040151. [PMID: 33023259 PMCID: PMC7711559 DOI: 10.3390/jpm10040151] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/17/2020] [Accepted: 09/24/2020] [Indexed: 12/12/2022] Open
Abstract
The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory diseases with common features in terms of clinical presentation and genetic predisposition. SpA is characterized by inflammation of the spine and peripheral joints, and is also be associated with extra-articular inflammatory manifestations such as psoriasis, uveitis, or inflammatory bowel disease (IBD). The etiology of SpA is not completely understood, but it is known to have a strong genetic component dominated by the human leukocyte antigen (HLA)-B27. In the last few years, our understanding of genetic susceptibility to SpA, particularly ankylosing spondylitis (AS), has greatly improved thanks to the findings derived from powered genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays. These studies have identified many candidate genes, therefore providing new potential directions in the exploration of disease mechanisms, especially with regard to the key role of the immune system in the pathogenesis of SpA. SpA is a complex disease where genetic variability, environmental factors, and random events interact to trigger pathological pathways. The aim of this review is to summarize current findings on the genetics of SpA, some of which might help to study new treatment approaches.
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24
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Rademacher J, Poddubnyy D, Pleyer U. Uveitis in spondyloarthritis. Ther Adv Musculoskelet Dis 2020; 12:1759720X20951733. [PMID: 32963592 PMCID: PMC7488890 DOI: 10.1177/1759720x20951733] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 07/30/2020] [Indexed: 12/17/2022] Open
Abstract
Uveitis is the most frequent extra-articular manifestation of axial spondyloarthritis (SpA), occurring in up to one-third of the patients. In the majority of patients, uveitis is acute, anterior and unilateral and presents with photosensitivity, sudden onset of pain and blurred vision. Topical steroids are an effective treatment; however, recurrent or refractory cases may need conventional disease-modifying antirheumatic drugs or biological treatment with monoclonal tumor necrosis factor (TNF) inhibitors, thus also influencing treatment strategy of the underlying SpA. Though the exact pathogenesis of SpA and uveitis remains unknown, both seem to result from the interaction of a specific, mostly shared genetical background (among other HLA-B27 positivity), external influences such as microbiome, bacterial infection or mechanical stress and activation of the immune system resulting in inflammation. Up to 40% of patients presenting with acute anterior uveitis (AAU) have an undiagnosed SpA. Therefore, an effective referral strategy for AAU patients is needed to shorten the diagnostic delay of SpA and enable an early effective treatment. Further, the risk for ophthalmological manifestations increases with the disease duration in SpA; and patients presenting with ocular symptoms should be referred to an ophthalmologist. Thus, a close collaboration between patient, rheumatologist and ophthalmologist is needed to optimally manage ocular inflammation in SpA.
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Affiliation(s)
- Judith Rademacher
- Department of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Hindenburgdamm 30, Berlin, 10117, Germany
| | - Denis Poddubnyy
- Department of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Uwe Pleyer
- Department of Ophthalmology, Campus Virchow, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
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25
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Identification of a tumor-specific allo-HLA-restricted γδTCR. Blood Adv 2020; 3:2870-2882. [PMID: 31585951 DOI: 10.1182/bloodadvances.2019032409] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 07/28/2019] [Indexed: 12/25/2022] Open
Abstract
γδT cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how γδT-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8α-dependent Vγ5Vδ1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of γδTCRs, we show that classic anti-HLA-directed, γδTCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive γδT-cell repertoires provide therapeutic opportunities, either within the context of haplotransplantation or as individual γδTCRs for genetic engineering of tumor-reactive T cells.
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26
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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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27
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Busch R, Kollnberger S, Mellins ED. HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications. Nat Rev Rheumatol 2020; 15:364-381. [PMID: 31092910 DOI: 10.1038/s41584-019-0219-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Our understanding of the mechanisms underlying HLA associations with inflammatory arthritis continues to evolve. Disease associations have been refined, and interactions of HLA genotype with other genes and environmental risk factors in determining disease risk have been identified. This Review provides basic information on the genetics and molecular function of HLA molecules, as well as general features of HLA associations with disease. Evidence is discussed regarding the various peptide-dependent and peptide-independent mechanisms by which HLA alleles might contribute to the pathogenesis of three types of inflammatory arthritis: rheumatoid arthritis, spondyloarthritis and systemic juvenile idiopathic arthritis. Also discussed are HLA allelic associations that shed light on the genetic heterogeneity of inflammatory arthritides and on the relationships between adult and paediatric forms of arthritis. Clinical implications range from improved diagnosis and outcome prediction to the possibility of using HLA associations in developing personalized strategies for the treatment and prevention of these diseases.
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Affiliation(s)
- Robert Busch
- Department of Life Sciences, University of Roehampton, Whitelands College, London, UK.
| | - Simon Kollnberger
- School of Medicine, Cardiff University, UHW Main Building, Heath Park, Cardiff, UK
| | - Elizabeth D Mellins
- Department of Pediatrics, Program in Immunology, Stanford University Medical Center, Stanford, CA, USA.
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28
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Lim Kam Sian TCC, Indumathy S, Halim H, Greule A, Cryle MJ, Bowness P, Rossjohn J, Gras S, Purcell AW, Schittenhelm RB. Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation. J Biol Chem 2019; 294:20185-20195. [PMID: 31740583 DOI: 10.1074/jbc.ra119.010257] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/31/2019] [Indexed: 12/17/2022] Open
Abstract
Expression of human leukocyte antigen (HLA)-B27 is strongly associated with predisposition toward ankylosing spondylitis (AS) and other spondyloarthropathies. However, the exact involvement of HLA-B27 in disease initiation and progression remains unclear. The homodimer theory, which proposes that HLA-B27 heavy chains aberrantly form homodimers, is a central hypothesis that attempts to explain the role of HLA-B27 in disease pathogenesis. Here, we examined the ability of the eight most prevalent HLA-B27 allotypes (HLA-B*27:02 to HLA-B*27:09) to form homodimers. We observed that HLA-B*27:03, a disease-associated HLA-B27 subtype, showed a significantly reduced ability to form homodimers compared with all other allotypes, including the non-disease-associated/protective allotypes HLA-B*27:06 and HLA-B*27:09. We used X-ray crystallography and site-directed mutagenesis to unravel the molecular and structural mechanisms in HLA-B*27:03 that are responsible for its compromised ability to form homodimers. We show that polymorphism at position 59, which differentiates HLA-B*27:03 from all other allotypes, is responsible for its compromised ability to form homodimers. Indeed, histidine 59 in HLA-B*27:03 leads to a series of local conformational changes that act in concert to reduce the accessibility of the nearby cysteine 67, an essential amino acid residue for the formation of HLA-B27 homodimers. Considered together, the ability of both protective and disease-associated HLA-B27 allotypes to form homodimers and the failure of HLA-B*27:03 to form homodimers challenge the role of HLA-B27 homodimers in AS pathoetiology. Rather, this work implicates other features, such as peptide binding and antigen presentation, as pivotal mechanisms for disease pathogenesis.
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Affiliation(s)
- Terry C C Lim Kam Sian
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Saranjah Indumathy
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Hanim Halim
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Anja Greule
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.,EMBL Australia, Monash University, Clayton, Victoria 3800, Australia
| | - Max J Cryle
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.,EMBL Australia, Monash University, Clayton, Victoria 3800, Australia
| | - Paul Bowness
- Botnar Research Centre, Nuffield, Department of Orthopaedics Rheumatology and Musculoskeletal Science, Nuffield Orthopaedic Centre, University of Oxford, Windmill Road, Headington, Oxford OX3 7LD, United Kingdom
| | - Jamie Rossjohn
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.,Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom
| | - Stephanie Gras
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia .,ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
| | - Anthony W Purcell
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Ralf B Schittenhelm
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia .,Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
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29
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Siegel RJ, Bridges SL, Ahmed S. HLA-C: An Accomplice in Rheumatic Diseases. ACR Open Rheumatol 2019; 1:571-579. [PMID: 31777841 PMCID: PMC6858028 DOI: 10.1002/acr2.11065] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 07/08/2019] [Indexed: 01/14/2023] Open
Abstract
Human leukocyte antigen c (HLA-C) is a polymorphic membrane protein encoded by the HLA-C gene in the class I major histocompatibility complex. HLA-C plays an essential role in protection against cancer and viruses but has also been implicated in allograft rejection, preeclampsia, and autoimmune disease. This review summarizes reports and proposed mechanisms for the accessory role of HLA-C in rheumatic diseases. Historically, contributions of HLA-C to rheumatic diseases were eclipsed by the stronger association with HLA-DRB1 alleles containing the "shared epitope" with rheumatoid arthritis. Larger genetic association studies and more powerful analytical approaches have revealed independent associations of HLA-C with rheumatic disease-associated phenotypes, including development of anticitrullinated peptide antibodies. HLA-C functions by presenting antigens to T cells and by binding activatory and inhibitory receptors on natural killer (NK) cells, but the exact mechanisms by which the HLA-C locus contributes to autoimmunity are largely undefined. Studies have suggested that HLA-C and NK cell receptor polymorphisms may predict responsiveness to pharmacotherapy. Understanding the mechanisms of the role of HLA-C in rheumatic disease could uncover therapeutic targets or guide precision pharmacologic treatments.
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Affiliation(s)
- Ruby J. Siegel
- Department of Pharmaceutical SciencesWashington State University College of Pharmacy and Pharmaceutical SciencesSpokaneWashington
| | - S. Louis Bridges
- Division of Clinical Immunology and RheumatologyUniversity of Alabama at BirminghamBirminghamAlabama
| | - Salahuddin Ahmed
- Department of Pharmaceutical SciencesWashington State University College of Pharmacy and Pharmaceutical SciencesSpokaneWashington
- Division of RheumatologyUniversity of Washington School of MedicineSeattleWashington
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30
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Abstract
Spondyloarthritis (SpA) describes the group of inflammatory diseases characterized by inflammation within axial joints and/or peripheral arthritis, enthesitis, and dactylitis. Disease development is strongly determined by genes and particularly associated with the presence of HLA-B27. Transgenic expression in animal models leads to induction of a SpA-like disease, suggesting a direct effect of HLA-B27 on disease development. Genome-wide association studies in SpA patients have identified further associations between polymorphisms in genes with an immune function, in particular in genes controlling the interleukin (IL)-23/IL-17 signaling pathway. The efficacy of IL-17 inhibitors in SpA patients underscores the impact of this pathway in this disease. Microscopic gut inflammation or chronic inflammatory bowel disease is found in the majority of patients with SpA, suggesting a pathogenic impact of commensal microbiota. In histopathologic examinations of axial manifestations, replacement of the subchondral bone marrow by granulation tissue with bone destructive and reparative properties is found. The mechanisms governing how genetic predisposition and gut inflammation promote inflammatory reactions at sites of mechanical stress is a matter of current research.
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31
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TCR repertoire and CDR3 motif analyses depict the role of αβ T cells in Ankylosing spondylitis. EBioMedicine 2019; 47:414-426. [PMID: 31477563 PMCID: PMC6796593 DOI: 10.1016/j.ebiom.2019.07.032] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 07/10/2019] [Accepted: 07/11/2019] [Indexed: 12/17/2022] Open
Abstract
Background Ankylosing spondylitis (AS) is a chronic inflammatory disease with worldwide high prevalence. Although AS is strongly associated with HLA-B27 MHC-I antigen presentation, the role played by αβ T cells in AS remains elusive. Methods Utilizing TCRβ repertoire sequencing and bioinformatics tools developed in house, we analyzed overall TCR repertoire structures and antigen-recognizing CDR3 motifs in AS patients with different disease activities. Findings We found that disease progression is associated with both CD4+ and CD8+ T cell oligo-clonal expansion, which suggests that αβ T cell activation may mediate AS disease progression. By developing a bioinformatics platform to dissect antigen-specific responses, we discovered a cell population consisting of both CD4+ and CD8+ T cells expressing identical TCRs, herein termed CD4/8 T cells. CD4/8 clonotypes were highly enriched in the spondyloarthritic joint fluid of patients, and their expansion correlated with the activity of disease. Interpretation These results provide evidence on the T cell clone side to reveal the potential role of CD4/8 T cells in the etiology of AS development.
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32
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Simone D, Al Mossawi MH, Bowness P. Progress in our understanding of the pathogenesis of ankylosing spondylitis. Rheumatology (Oxford) 2019; 57:vi4-vi9. [PMID: 30445483 PMCID: PMC6238220 DOI: 10.1093/rheumatology/key001] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Indexed: 12/31/2022] Open
Abstract
AS is a common rheumatic condition characterized by inflammation and new bone formation. The pathogenesis of AS is likely multifactorial and has not been fully elucidated to date. A major genetic role has been demonstrated. The strongest genetic association is with HLA B27. Numerous other associated genetic polymorphisms have been identified, including those affecting the type 17 immune pathway, although the precise link between genetics and pathogenesis remains unexplained. Several immunological alterations, together with recent therapeutic advances, support a central role for IL-23- and IL-17-producing immune cells in disease pathogenesis. Recently, perturbations of gut microbiota of AS patients have further catalysed research and offer potential for future therapeutic intervention. In this review we outline the genetic basis of AS and describe the current hypotheses for disease pathogenesis. We synthesize recent experimental research data and clinical studies to support a central role for the type 17/23 immune axis in AS.
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Affiliation(s)
- Davide Simone
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - M Hussein Al Mossawi
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Paul Bowness
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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33
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Gwozdowicz S, Nestorowicz K, Graczyk-Pol E, Szlendak U, Rogatko-Koros M, Mika-Witkowska R, Pawliczak D, Zubala M, Malinowska A, Witkowska A, Nowak J. KIR specificity and avidity of standard and unusual C1, C2, Bw4, Bw6 and A3/11 amino acid motifs at entire HLA:KIR interface between NK and target cells, the functional and evolutionary classification of HLA class I molecules. Int J Immunogenet 2019; 46:217-231. [PMID: 31210416 DOI: 10.1111/iji.12433] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/04/2019] [Accepted: 04/23/2019] [Indexed: 12/19/2022]
Abstract
Natural killer (NK) cells make vital contributions to the immune system and the reproductive system. Notably, NK cells of donor origin can recognize and kill residual leukaemic cells and cure malignant patients in hematopoietic stem cell (HSC) transplant setting. NK cell function is regulated by KIRs that recognize cognate HLA class I molecules on target cells, depending on their amino acid residues. In review, we addressed the question of binding capacity and avidity of HLA class I molecules to different killer cell immunoglobulin-like receptors (KIRs) depending on all interacting amino acid residues both on HLA and KIR side. We searched PubMed database and analysed available HLA:KIR crystallographic data for amino acid residues in HLA molecules, those physically involved in binding KIRs (termed here the "entire KIR interface"). Within entire KIR interface, we selected five functional sequence motifs (14-19, 66-76, 77-84, 88-92 and 142-151) and classified them according to the conservation of their amino acid sequences among 8,942 HLA class I molecules. Although some conserved amino acid motifs were shared by different groups of KIR ligands, the HLA motif combinations were exclusive for the ligand groups. In 135 common HLA class I molecules with known HLA:KIR recognition, we found 54 combinations of five motifs in each of the KIR-binding interfaces (C1, C2, Bw4, A3/11) and conserved non-KIR-binding interfaces. Based on the entire KIR interface, this analysis allowed to classify 8,942 HLA class I molecules into KIR specificity groups. This functional and evolutionary classification of entire KIR interfaces provides a tool for unambiguously predicting HLA:KIR interactions for common and those HLA molecules that have not yet been functionally tested. Considering the entire KIR interface in HLA class I molecules, functional interactions of HLA and KIR can be predicted in immune responses, reproduction and allotransplantation. Further functional studies are needed on the HLA:KIR interaction variations caused by the repertoires of peptides presented by HLA molecules and KIR polymorphisms at allelic level.
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Affiliation(s)
- Slawomir Gwozdowicz
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Klaudia Nestorowicz
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Elzbieta Graczyk-Pol
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Urszula Szlendak
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marta Rogatko-Koros
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Renata Mika-Witkowska
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Daria Pawliczak
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marta Zubala
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Agnieszka Malinowska
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Agnieszka Witkowska
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Jacek Nowak
- Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
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RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients. Nat Commun 2019; 10:9. [PMID: 30602780 PMCID: PMC6315029 DOI: 10.1038/s41467-018-07911-6] [Citation(s) in RCA: 179] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 12/04/2018] [Indexed: 12/16/2022] Open
Abstract
Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but their contribution to SpA is still unclear. Here we describe the presence of particular RORγt+T-betloPLZF- iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt+ iNKT and γδ-hi T cells show IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed unique and Th17-skewed phenotype and gene expression profiles. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, our findings highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.
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López-Medina C, Moltó A. Update on the epidemiology, risk factors, and disease outcomes of axial spondyloarthritis. Best Pract Res Clin Rheumatol 2018; 32:241-253. [PMID: 30527429 DOI: 10.1016/j.berh.2018.10.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 08/03/2018] [Accepted: 09/09/2018] [Indexed: 12/17/2022]
Abstract
Axial spondyloarthritis (axSpA) is the prototype of a class of a rheumatic chronic inflammatory disease named spondyloarthritis (SpA). The prevalence of axSpA ranges between 0.1% and 1.4% globally, hence showing geographic differences that can be explained mostly by the prevalence of the HLA-B27 antigen. However, not many studies have evaluated the incidence of this disease. Inflammation may be initiated in the enthesis as a consequence of the action of IL-23, which can activate resident T cells. The elevated expression of IL-23 has been explained by three hypotheses: the presence of HLA-B27, variations in the gut microbiome and the biomechanical stress at the enthesis. However, the role of IL-23 in this whole context is still unclear. In axSpA, the presence of syndesmophytes at baseline, systemic inflammation, and smoking may promote the spinal radiographic damage in these patients. The most frequent comorbidity in these patients is osteoporosis, which is directly associated with ankylosis and inflammation.
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Affiliation(s)
- Clementina López-Medina
- Rheumatology Department, Cochin Hospital, Paris, France; Inserm (U1153), Clinical Epidemiology and Biostatistics, PRES Sorbonne Paris-Cité, Paris, France; Rheumatology Department, Reina Sofía University Hospital, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), University of Cordoba, Cordoba, Spain.
| | - Anna Moltó
- Rheumatology Department, Cochin Hospital, Paris, France; Inserm (U1153), Clinical Epidemiology and Biostatistics, PRES Sorbonne Paris-Cité, Paris, France
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Garcia-Montoya L, Gul H, Emery P. Recent advances in ankylosing spondylitis: understanding the disease and management. F1000Res 2018; 7. [PMID: 30345001 PMCID: PMC6173104 DOI: 10.12688/f1000research.14956.1] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/11/2018] [Indexed: 12/14/2022] Open
Abstract
The term spondyloarthritis refers to a group of immune-mediated diseases characterised by inflammation of the axial skeleton, peripheral joints, and entheses. Ankylosing spondylitis (AS) is the most common and characteristic of these entities and even though it was first described over two centuries ago, the understanding of the underlying disease mechanism remains incomplete. It is known that around 40% of patients with AS have subclinical bowel inflammation, suggesting that the origin of the disease could be in the gut. Also, more genes and new molecules have demonstrated a role in the pathogenesis of AS. In this review, we analyse the latest therapies for spondyloarthritis and the most relevant discoveries over the last three years, together with their implications for different aspects of the disease.
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Affiliation(s)
- Leticia Garcia-Montoya
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK.,NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Hanna Gul
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK.,NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Paul Emery
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK.,NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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Vanaki N, Aslani S, Jamshidi A, Mahmoudi M. Role of innate immune system in the pathogenesis of ankylosing spondylitis. Biomed Pharmacother 2018; 105:130-143. [DOI: 10.1016/j.biopha.2018.05.097] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 05/19/2018] [Accepted: 05/20/2018] [Indexed: 12/11/2022] Open
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Colbert RA, Navid F, Gill T. The role of HLA-B*27 in spondyloarthritis. Best Pract Res Clin Rheumatol 2018; 31:797-815. [PMID: 30509441 DOI: 10.1016/j.berh.2018.07.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 07/20/2018] [Indexed: 02/08/2023]
Abstract
The mechanism by which HLA-B*27 predisposes to spondyloarthritis remains unresolved. Arthritogenic peptides have not been defined in humans and are not involved in experimental models of spondyloarthritis. Aberrant properties of HLA-B*27 can activate the IL-23/IL-17 axis in HLA-B*27 transgenic rats and humans. In HLA-B*27-independent rodent models, spondyloarthritis can be driven by IL-23 triggering entheseal-resident CD4-/CD8- T cells or CD4+ Th17 T cells. These findings point toward noncanonical mechanisms linking HLA-B*27 to the disease and provide a potential explanation for HLA-B*27-negative spondyloarthritis. Gut microbial dysbiosis may be important in the development of spondyloarthritis. HLA-B*27-induced changes in gut microbiota are complex and suggest an ecological model of dysbiosis in rodents. The importance of the IL-23/IL-17 axis in ankylosing spondylitis has been demonstrated by studies showing efficacy of IL-17. Although deciphering the precise role(s) of HLA-B*27 in disease requires further investigation, considerable progress has been made in understanding this complex relationship.
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Affiliation(s)
- Robert A Colbert
- Pediatric Translational Research Branch, NIAMS Intramural Research Program, NIH, USA.
| | - Fatemeh Navid
- Pediatric Translational Research Branch, NIAMS Intramural Research Program, NIH, USA.
| | - Tejpal Gill
- Pediatric Translational Research Branch, NIAMS Intramural Research Program, NIH, USA.
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Cauli A, Dessole G, Piga M, Angioni MM, Pinna S, Floris A, Congia M, Mascia E, Paladini F, Tedeschi V, Sorrentino R, Fiorillo MT, Mathieu A. Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis. RMD Open 2018; 4:e000597. [PMID: 30018803 PMCID: PMC6045714 DOI: 10.1136/rmdopen-2017-000597] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 05/23/2018] [Accepted: 06/19/2018] [Indexed: 12/25/2022] Open
Abstract
Background Ankylosing spondylitis (AS) is a complex chronic inflammatory disease strongly associated with the majority of human leucocyte antigen (HLA)-B27 alleles. HLA-E molecules are non-classical major histocompatibility complex (MHC) class I molecules that specifically interact with the natural killer receptors NKG2A (inhibitory) and NKG2C (activating), and have been recently proposed to be involved in AS pathogenesis.''. Objective To analyse the expression of HLA-E and the CD94/NKG2 pair of receptors in HLA-B27-positive patients with AS and healthy controls (HC) bearing the AS-associated B*2705 and the non-AS-associated B*2709 alleles. Methods The level of surface expression of HLA-E molecules on CD14+ peripheral blood mononuclear cell was evaluated in 21 HLA-B*2705 patients with AS, 12 HLA-B*2705 HC, 12 HLA-B*2709 HC and 6 HLA-B27-negative HC using the monoclonal antibody MEM-E/08 by quantitative cytofluorimetric analysis. The percentage and density of expression of HLA-E ligands NKG2A and NKG2C were also measured on CD3-CD56+ NK cells. Results HLA-E expression in CD14+ cells was significantly higher in patients with AS (587.0, IQR 424-830) compared with B*2705 HC (389, IQR 251.3-440.5; p=0.0007), B*2709 HC (294.5, IQR 209.5-422; p=0.0004) and HLA-B27-negative HC (380, IQR 197.3-515.0; p=0.01). A higher number of NK cells expressing NKG2A compared with NKG2C were found in all cohorts analysed, as well as a higher cell surface density. Conclusion The higher surface level of HLA-E molecules in patients with AS compared with HC, concurrently with a prevalent expression of NKG2A, suggests that the crosstalk between these two molecules might play a role in AS pathogenesis, accounting for the previously reported association between HLA-E and AS.
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Affiliation(s)
- Alberto Cauli
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Grazia Dessole
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Matteo Piga
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Maria Maddalena Angioni
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Silvia Pinna
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Alberto Floris
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Mattia Congia
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Enrico Mascia
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Fabiana Paladini
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Valentina Tedeschi
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Rosa Sorrentino
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Maria Teresa Fiorillo
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Alessandro Mathieu
- Rheumatology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
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Romero-López JP, Domínguez-López ML, Burgos-Vargas R, García-Latorre E. Stress proteins in the pathogenesis of spondyloarthritis. Rheumatol Int 2018; 39:595-604. [PMID: 29855675 DOI: 10.1007/s00296-018-4070-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 05/26/2018] [Indexed: 12/15/2022]
Abstract
Spondyloarthritis is an autoinflammatory rheumatic disease in which arthritis and osteoproliferation lead the patients who suffer from it to chronic disability. This disease is associated with the expression of class I MHC molecule HLA-B27, which tends to be misfolded in the endoplasmic reticulum and, therefore, expressed in aberrant forms. This phenomena lead to endoplasmic reticulum stress, which in time, evokes a whole response to cellular injury. Under these conditions, the molecules involved in restoring cell homeostasis play a key role. Such is the case of the "heat-shock proteins", which usually regulate protein folding, but also have important immunomodulatory functions, as well as some roles in tissue modeling. In this review, we attempt to summarize the involvement of cell stress and heat-shock proteins in the homeostatic disturbances and pathological conditions associated with this disease.
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Affiliation(s)
- José Pablo Romero-López
- Laboratorio de Inmunoquímica I, Departmento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación Manuel Carpio y Plan de Ayala SN, CP 11340, Ciudad de México, México
| | - María Lilia Domínguez-López
- Laboratorio de Inmunoquímica I, Departmento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación Manuel Carpio y Plan de Ayala SN, CP 11340, Ciudad de México, México
| | - Rubén Burgos-Vargas
- Departamento de Reumatología, Hospital General de México "Dr. Eduardo Liceaga", Ciudad de México, México
| | - Ethel García-Latorre
- Laboratorio de Inmunoquímica I, Departmento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación Manuel Carpio y Plan de Ayala SN, CP 11340, Ciudad de México, México.
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Dashti N, Mahmoudi M, Aslani S, Jamshidi A. HLA-B*27 subtypes and their implications in the pathogenesis of ankylosing spondylitis. Gene 2018; 670:15-21. [PMID: 29803000 DOI: 10.1016/j.gene.2018.05.092] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/14/2018] [Accepted: 05/23/2018] [Indexed: 12/25/2022]
Abstract
Ankylosing spondylitis (AS) is a highly heritable kind of arthritis that affects the vertebral column. AS risk has been associated strongly with Human leukocyte antigen (HLA)-B*27. In fact, some HLA-B*27 subtypes have been associated with the increased disease risk, although some specific subtypes have not shown such associations. It is supposed that HLA-B*27 plays a major role in the etiopathogenesis of the disease. However, the difference in pathogenic outcomes of HLA-B*27 certain subtypes needs to be clarified. The purpose of this review article is to overview on the detailed implications of the HLA-B*27 subtypes in the etiopathogenesis of AS. Moreover, the role of ERAP1 in AS and its epistasis with HLA-B*27 have been reviewed.
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Affiliation(s)
- Navid Dashti
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, TehranUniversity of Medical Sciences, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Saeed Aslani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Reinhardt A, Prinz I. Whodunit? The Contribution of Interleukin (IL)-17/IL-22-Producing γδ T Cells, αβ T Cells, and Innate Lymphoid Cells to the Pathogenesis of Spondyloarthritis. Front Immunol 2018; 9:885. [PMID: 29922283 PMCID: PMC5996894 DOI: 10.3389/fimmu.2018.00885] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 04/10/2018] [Indexed: 12/15/2022] Open
Abstract
γδ T cells, αβ T cells, and innate lymphoid cells (ILCs) are capable of producing interleukin (IL)-17A, IL-17F, and IL-22. Among these three families of lymphocytes, it is emerging that γδ T cells are, at least in rodents, the main source of these key pro-inflammatory cytokines. γδ T cells were implicated in multiple inflammatory and autoimmune diseases, including psoriasis, experimental autoimmune encephalomyelitis and uveitis, colitis, and rheumatoid arthritis. Recent findings pointed toward a central role of γδ T cells in the pathogenesis of spondyloarthritis (SpA), a group of inflammatory rheumatic diseases affecting the axial skeleton. SpA primarily manifests as inflammation and new bone formation at the entheses, which are connecting tendons or ligaments with bone. In SpA patients, joint inflammation is frequently accompanied by extra-articular manifestations, such as inflammatory bowel disease or psoriasis. In humans, genome-wide association studies could link the IL-23/IL-17 cytokine axis to SpA. Accordingly, antibodies targeting IL-23/IL-17 for SpA treatment already showed promising results in clinical studies. However, the contribution of IL-17-producing γδ T cells to SpA pathogenesis is certainly not an open-and-shut case. Indeed, the cell types that are chiefly involved in local inflammation in human SpA still remain largely unclear. Some studies focusing on blood or synovium from SpA patients reported augmented IL-17-producing and IL-23 receptor-expressing γδ T cells, but other cell types might contribute as well. Here, we summarize the current understanding of how γδ T cells, αβ T cells, and ILCs contribute to the pathogenesis of human and experimental SpA.
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MESH Headings
- Animals
- Arthritis, Experimental/immunology
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Humans
- Immunity, Innate
- Interleukin-17/immunology
- Interleukin-17/metabolism
- Interleukins/immunology
- Interleukins/metabolism
- Lymphocytes/immunology
- Receptors, Antigen, T-Cell, alpha-beta/immunology
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Spondylarthritis/immunology
- Interleukin-22
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Affiliation(s)
- Youn-Soo Hahn
- Department of Pediatrics, Chungbuk National University College of Medicine, Cheongju, Korea
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Targeted Delivery of the HLA-B ∗27-Binding Peptide into the Endoplasmic Reticulum Suppresses the IL-23/IL-17 Axis of Immune Cells in Spondylarthritis. Mediators Inflamm 2017; 2017:4016802. [PMID: 29463951 PMCID: PMC5804395 DOI: 10.1155/2017/4016802] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 09/19/2017] [Accepted: 10/23/2017] [Indexed: 01/01/2023] Open
Abstract
Ankylosing spondylitis (AS) is highly associated with the expression of human leukocyte antigen-B27 (HLA-B∗27). HLA-B∗27 heavy chain (B27-HC) has an intrinsic propensity to fold slowly, leading to the accumulation of the misfolded B27-HC in the endoplasmic reticulum (ER) and formation of the HLA-B∗27 HC homodimer, (B27-HC)2, by a disulfide linkage at Cys-67. (B27-HC)2 displayed on the cell surface can act as a ligand of the killer-cell Ig-like receptor (KIR3DL2). (B27-HC)2 binds to KIR3DL2 of NK and Th17 cells and activates both cells, resulting in the activation of the IL-23/IL-17 axis to launch the inflammatory reaction in AS patients. However, activation of the IL-23/IL-17 axis originally derived from the HLA-B∗27 misfolding in the ER needs to be characterized. In this study, we delivered two HLA-B∗27-binding peptides, KRGILTLKY and SRYWAIRTR, into the ER by using a tat-derived peptide (GRKKRRQRRR)-His6-ubiquitin (THU) vehicle. Both peptides are derived from the human actin and nucleoprotein of influenza virus, respectively. Our results demonstrated that targeted delivery of both HLA-B∗27-binding peptides into the ER can promote the HLA-B∗27 folding, decrease the levels of (B27-HC)2, and suppress the activation of the IL-23/IL-17 axis in response to lipopolysaccharide. Our findings can provide a new therapeutic strategy in AS.
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Schmitt C, Marie-Cardine A, Bensussan A. Therapeutic Antibodies to KIR3DL2 and Other Target Antigens on Cutaneous T-Cell Lymphomas. Front Immunol 2017; 8:1010. [PMID: 28912774 PMCID: PMC5582066 DOI: 10.3389/fimmu.2017.01010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 08/07/2017] [Indexed: 11/13/2022] Open
Abstract
KIR3DL2 is a member of the killer cell immunoglobulin-like receptor (KIR) family that was initially identified at the surface of natural killer (NK) cells. KIR3DL2, also known as CD158k, is expressed as a disulfide-linked homodimer. Each chain is composed of three immunoglobulin-like domains and a long cytoplasmic tail containing two immunoreceptor tyrosine-based inhibitory motifs. Beside its expression on NK cells, it is also found on rare circulating T lymphocytes, mainly CD8+. Although the KIR gene number varies between haplotype, KIR3DL2 is a framework gene present in all individuals. Together with the presence of genomic regulatory sequences unique to KIR3DL2, this suggests some particular functions for the derived protein in comparison with other KIR family members. Several ligands have been identified for KIR3DL2. As for other KIRs, binding to HLA class I molecules is essential for NK development by promoting phenomena such as licensing and driving NK cell maturation. For KIR3DL2, this includes binding to HLA-A3 and -A11 and to the free heavy chain form of HLA-B27. In addition, KIR3DL2 binds to CpG oligonucleotides (ODN) and ensures their transport to endosomal toll-like receptor 9 that promotes cell activation. These characteristics have implicated KIR3DL2 in several pathologies: ankylosing spondylitis and cutaneous T-cell lymphomas such as Sézary syndrome, CD30+ cutaneous lymphoma, and transformed mycosis fungoides. Consequently, a new generation of humanized monoclonal antibodies (mAbs) directed against KIR3DL2 has been helpful in the diagnosis, follow-up, and treatment of these diseases. In addition, preliminary clinical studies of a novel targeted immunotherapy for cutaneous T-cell lymphomas using the anti-KIR3DL2 mAb IPH4102 are now underway. In this review, we discuss the various aspects of KIR3DL2 on the functions of CD4+ T cells and how targeting this receptor helps to develop innovative therapeutic strategies.
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Affiliation(s)
- Christian Schmitt
- INSERM U976, Hôpital Saint-Louis, Paris, France.,Paris Diderot University, Sorbonne Paris Cité, Paris, France
| | - Anne Marie-Cardine
- INSERM U976, Hôpital Saint-Louis, Paris, France.,Paris Diderot University, Sorbonne Paris Cité, Paris, France
| | - Armand Bensussan
- INSERM U976, Hôpital Saint-Louis, Paris, France.,Paris Diderot University, Sorbonne Paris Cité, Paris, France
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van Tok MN, Satumtira N, Dorris M, Pots D, Slobodin G, van de Sande MG, Taurog JD, Baeten DL, van Duivenvoorde LM. Innate Immune Activation Can Trigger Experimental Spondyloarthritis in HLA-B27/Huβ2m Transgenic Rats. Front Immunol 2017; 8:920. [PMID: 28824645 PMCID: PMC5545590 DOI: 10.3389/fimmu.2017.00920] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 07/20/2017] [Indexed: 01/06/2023] Open
Abstract
Spondyloarthritis (SpA) does not display the typical features of auto-immune disease. Despite the strong association with MHC class I, CD8+ T cells are not required for disease induction in the HLA-B27/Huβ2m transgenic rats. We used Lewis HLA-B27/Huβ2m transgenic rats [21-3 × 283-2]F1, HLA-B7/Huβ2m transgenic rats [120-4 × 283-2]F1, and wild-type rats to test our hypothesis that SpA may be primarily driven by the innate immune response. In vitro, splenocytes were stimulated with heat-inactivated Mycobacterium tuberculosis and cytokine expression and production was measured. In vivo, male and female rats were immunized with 30, 60, or 90 µg of heat-inactivated M. tuberculosis and clinically monitored for spondylitis and arthritis development. After validation of the model, we tested whether prophylactic and therapeutic TNF targeting affected spondylitis and arthritis. In vitro stimulation with heat-inactivated M. tuberculosis strongly induced gene expression of pro-inflammatory cytokines such as TNF, IL-6, IL-1α, and IL-1β, in the HLA-B27 transgenic rats compared with controls. In vivo immunization induced an increased spondylitis and arthritis incidence and an accelerated and synchronized onset of spondylitis and arthritis in HLA-B27 transgenic males and females. Moreover, immunization overcame the protective effect of orchiectomy. Prophylactic TNF targeting resulted in delayed spondylitis and arthritis development and reduced arthritis severity, whereas therapeutic TNF blockade did not affect spondylitis and arthritis severity. Collectively, these data indicate that innate immune activation plays a role in the initiation of HLA-B27-associated disease and allowed to establish a useful in vivo model to study the cellular and molecular mechanisms of disease initiation and progression.
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Affiliation(s)
- Melissa N van Tok
- Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Nimman Satumtira
- Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Martha Dorris
- Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Desirée Pots
- Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Gleb Slobodin
- Internal Medicine, Bnai Zion Medical Center, Haifa, Israel
| | - Marleen G van de Sande
- Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Joel D Taurog
- Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Dominique L Baeten
- Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Leonie M van Duivenvoorde
- Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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Abstract
Ankylosing spondylitis (AS) is a common inflammatory arthritis in which genetic factors are the primary determinants of disease risk and severity. Substantial progress has been made in identifying genetic pathways involved in the disease, and in translating those discoveries to drug discovery programs. Recently discovered novel disease pathways include those involved in control of DNA methylation, bacterial sensing, and mucosal immunity. Additional pathways are likely to be identified as a higher proportion of the genetic risk of AS is determined.
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Affiliation(s)
- Aimee Hanson
- Translational Research Institute, Princess Alexandra Hospital, University of Queensland Diamantina Institute, Woolloongabba, Brisbane, Queensland, Australia
| | - Matthew A Brown
- Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Woolloongabba, Brisbane, Queensland, Australia.
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Guiliano DB, North H, Panayoitou E, Campbell EC, McHugh K, Cooke FGM, Silvestre M, Bowness P, Powis SJ, Antoniou AN. Polymorphisms in the F Pocket of HLA-B27 Subtypes Strongly Affect Assembly, Chaperone Interactions, and Heavy-Chain Misfolding. Arthritis Rheumatol 2017; 69:610-621. [PMID: 27723268 DOI: 10.1002/art.39948] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 09/29/2016] [Indexed: 01/06/2023]
Abstract
OBJECTIVE HLA-B27 is associated with the inflammatory spondyloarthritides (SpA), although subtypes HLA-B*27:06 and HLA-B*27:09 are not. These subtypes differ from the HLA-B*27:05 disease-associated allele primarily at residues 114 and 116 of the heavy chain, part of the F pocket of the antigen-binding groove. Dimerization of HLA-B27 during assembly has been implicated in disease onset. The purpose of this study was to investigate the factors that influence differences in dimerization between disease-associated and non-disease-associated HLA-B27 alleles. METHODS HLA-B*27:05 and mutants resembling the HLA-B*27:06 and 09 subtypes were expressed in the rat C58 T cell line, the human CEM T cell line and its calnexin-deficient variant CEM.NKR. Immunoprecipitation, pulse-chase experiments, flow cytometry, and immunoblotting were performed to study the assembly kinetics, heavy-chain dimerization, and chaperone associations. RESULTS By expressing HLA-B*27:05, 06-like, and 09 alleles on a restrictive rat transporter associated with antigen processing background, we demonstrate that a tyrosine expressed at p116, either alone or together with an aspartic acid residue at p114, inhibited HLA-B27 dimerization and increased the assembly rate. F-pocket residues altered the associations with chaperones of the early major histocompatibility complex class I folding pathway. Calnexin was demonstrated to participate in endoplasmic reticulum (ER) stress-mediated degradation of dimers, whereas the oxidoreductase ERp57 does not appear to influence dimerization. CONCLUSION Residues within the F pocket of the peptide-binding groove, which differ between disease-associated and non-disease-associated HLA-B27 subtypes, can influence the assembly process and heavy-chain dimerization, events which have been linked to the initiation of disease pathogenesis.
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Affiliation(s)
| | - Helen North
- NHS Blood and Transplant, Colindale Blood Centre, London, UK
| | - Eleni Panayoitou
- NHS North West Surrey Clinical Commissioning Group, Weybridge, UK
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Spondyloarthritis: Matrix Metalloproteinasesas Biomarkers of Pathogenesis and Response to Tumor Necrosis Factor (TNF) Inhibitors. Int J Mol Sci 2017; 18:ijms18040830. [PMID: 28420081 PMCID: PMC5412414 DOI: 10.3390/ijms18040830] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/05/2017] [Accepted: 04/10/2017] [Indexed: 01/14/2023] Open
Abstract
The term spondyloarthritis (SpA) is used to describe a group of multifactorial chronic inflammatory diseases characterized by a predisposing genetic background and clinical manifestations typically involving the sacroiliac joint. The absence of pathognomonic clinical and/or laboratory findings generally results in a delay in diagnosis and, consequently, in treatment. In addition, 20–40% of SpA patients are non-responders to tumor necrosis factor (TNF) inhibitor therapies. Given these considerations, it is important to identify biomarkers that can facilitate the diagnosis and assessment of disease activity. As inflammation plays a key role in the pathogenesis of SpA, inflammatory mediators have been investigated as potential biomarkers for diagnosing the disease and predicting response to therapy. Some investigators have focused their attention on the role of matrix metalloproteinases (MMPs), which are known to be markers of synovial inflammation that is generated in the joint in reaction to inflammatory stimuli. Several studies have been carried out to verify if serum MMPs levels could be useful to diagnose SpA, to assess disease severity, and to predict response to TNF inhibitor therapy. The current review focuses on MMPs’ role in SpA pathogenesis, diagnosis and therapeutic implications.
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van der Ploeg K, Chang C, Ivarsson MA, Moffett A, Wills MR, Trowsdale J. Modulation of Human Leukocyte Antigen-C by Human Cytomegalovirus Stimulates KIR2DS1 Recognition by Natural Killer Cells. Front Immunol 2017; 8:298. [PMID: 28424684 PMCID: PMC5372792 DOI: 10.3389/fimmu.2017.00298] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 03/03/2017] [Indexed: 02/02/2023] Open
Abstract
The interaction of inhibitory killer cell Ig-like receptors (KIRs) with human leukocyte antigen (HLA) class I molecules has been characterized in detail. By contrast, activating members of the KIR family, although closely related to inhibitory KIRs, appear to interact weakly, if at all, with HLA class I. KIR2DS1 is the best studied activating KIR and it interacts with C2 group HLA-C (C2-HLA-C) in some assays, but not as strongly as KIR2DL1. We used a mouse 2B4 cell reporter system, which carries NFAT-green fluorescent protein with KIR2DS1 and a modified DAP12 adaptor protein. KIR2DS1 reporter cells were not activated upon coculture with 721.221 cells transfected with different HLA-C molecules, or with interferon-γ stimulated primary dermal fibroblasts. However, KIR2DS1 reporter cells and KIR2DS1+ primary natural killer (NK) cells were activated by C2-HLA-C homozygous human fetal foreskin fibroblasts (HFFFs) but only after infection with specific clones of a clinical strain of human cytomegalovirus (HCMV). Active viral gene expression was required for activation of both cell types. Primary NKG2A-KIR2DS1+ NK cell subsets degranulated after coculture with HCMV-infected HFFFs. The W6/32 antibody to HLA class I blocked the KIR2DS1 reporter cell interaction with its ligand on HCMV-infected HFFFs but did not block interaction with KIR2DL1. This implies a differential recognition of HLA-C by KIR2DL1 and KIR2DS1. The data suggest that modulation of HLA-C by HCMV is required for a potent KIR2DS1-mediated NK cell activation.
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Affiliation(s)
| | - Chiwen Chang
- Department of Pathology, University of Cambridge, Cambridge, UK
| | | | - Ashley Moffett
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Mark R. Wills
- Department of Medicine, University of Cambridge, Cambridge, UK,*Correspondence: Mark R. Wills, ; John Trowsdale,
| | - John Trowsdale
- Department of Pathology, University of Cambridge, Cambridge, UK,*Correspondence: Mark R. Wills, ; John Trowsdale,
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