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Tanuwidjaya E, Lim Kam Sian TCC, Steele JR, Goncalves G, Woodhouse IB, Chang J, Ooi JD, Schittenhelm RB, Faridi P. SAPrIm 2.0: a semi-automated protocol for mid-throughput soluble HLA immunopeptidomics. Front Immunol 2025; 16:1546629. [PMID: 40342411 PMCID: PMC12058715 DOI: 10.3389/fimmu.2025.1546629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/02/2025] [Indexed: 05/11/2025] Open
Abstract
Human leukocyte antigen (HLA) molecules are pivotal in guiding human adaptive immune responses through their presentation of peptide ligands, collectively known as the immunopeptidome. This process is central to the development of cancer immunotherapies, such as vaccines and T-cell therapies. Profiling the immunopeptidome from plasma and other biofluids has gained increasing traction, as it offers a minimally invasive approach for monitoring disease states and immune responses toward cancer therapy. Here we present the second iteration of SAPrIm, a refined immunopeptidomics tool optimized for soluble HLA analysis. It can process up to 12 samples per batch within a day. In this plasma-focused iteration, we identified approximately 1,200 to 4,000 immunopeptides from 100 µL to 1 mL of plasma, demonstrating high reproducibility across technical replicates, biological replicates, and inter-day analyses. This robust reproducibility highlights the method's strong potential for reliable relative quantification of immunopeptides in plasma-based studies. This workflow is positioned to advance the field of immunopeptidomics by enabling efficient plasma-based comparative analyses and mid-size cohort studies.
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Affiliation(s)
- Erwin Tanuwidjaya
- Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia
- Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Terry C. C. Lim Kam Sian
- Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia
- Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Joel R. Steele
- Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Gabriel Goncalves
- Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia
- Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Isaac B. Woodhouse
- Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia
- Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Janet Chang
- Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia
| | - Joshua D. Ooi
- Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia
| | - Ralf B. Schittenhelm
- Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Pouya Faridi
- Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia
- Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
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Taheri M, Tehrani HA, Farzad SA, Korourian A, Arefian E, Ramezani M. The potential of mesenchymal stem cell coexpressing cytosine deaminase and secretory IL18-FC chimeric cytokine in suppressing glioblastoma recurrence. Int Immunopharmacol 2024; 142:113048. [PMID: 39236459 DOI: 10.1016/j.intimp.2024.113048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
Glioblastoma multiforme (GBM) patients have a high recurrence rate of 90%, and the 5-year survival rate is only about 5%. Cytosine deaminase (CDA)/5-fluorocytosine (5-FC) gene therapy is a promising glioma treatment as 5-FC can cross the blood-brain barrier (BBB), while 5-fluorouracil (5-FU) cannot. Furthermore, 5-FU can assist reversing the immunological status of cold solid tumors. This study developed mesenchymal stem cells (MSCs) co-expressing yeast CDA and the secretory IL18-FC superkine to prevent recurrent tumor progression by simultaneously exerting cytotoxic effects and enhancing immune responses. IL18 was fused with Igk and IgG2a FC domains to enhance its secretion and serum half-life. The study confirmed the expression and activity of the CDA enzyme, as well as the expression, secretion, and activity of secretory IL18 and IL18-FC superkine, which were expressed by lentiviruses transduced-MSCs. In the transwell tumor-tropism assay, it was observed that the genetically modified MSCs retained their selective tumor-tropism ability following transduction. CDA-expressing MSCs, in the presence of 5-FC (200 µg/ml), induced cell cycle arrest and apoptosis in glioma cells through bystander effects in an indirect transwell co-culture system. They reduced the viability of the direct co-culture system when they constituted only 12.5 % of the cell population. The effectiveness of engineered MSCs in suppressing tumor progression was assessed by intracerebral administration of a lethal dose of GL261 cells combined in a ratio of 1:1 with MSCs expressing CDA, or CDA and sIL18, or CDA and sIL18-FC, into C57BL/6 mice. PET scan showed no conspicuous tumor mass in the MSC-CDA-sIL18-FC group that received 5-FC treatment. The pathological analysis showed that tumor progression suppressed in this group until 20th day after cell inoculation. Cytokine assessment showed that both interferon-gamma (IFN-γ) and interleukin-4 (IL-4) increased in the serum of MSC-CDA-sIL18 and MSC-CDA-sIL18-FC, treated with normal saline (NS) compared to those of the control group. The MSC-CDA-sIL18-FC group that received 5-FC treatment showed reduced serum levels of IL-6 and a considerably improved survival rate compared to the control group. Therefore, MSCs co-expressing yeast CDA and secretory IL18-FC, with tumor tropism capability, may serve as a supplementary approach to standard GBM treatment to effectively inhibit tumor progression and prevent recurrence.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Sara Amel Farzad
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Korourian
- Quality Control Department Pathobiology Laboratory Center, Tehran, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran; Stem Cells Technology and Tissue Regeneration Department, School of Biology, College of Science, University of Tehran, Tehran, Iran.
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Redondo-García S, Barritt C, Papagregoriou C, Yeboah M, Frendeus B, Cragg MS, Roghanian A. Human leukocyte immunoglobulin-like receptors in health and disease. Front Immunol 2023; 14:1282874. [PMID: 38022598 PMCID: PMC10679719 DOI: 10.3389/fimmu.2023.1282874] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 09/20/2023] [Indexed: 12/01/2023] Open
Abstract
Human leukocyte immunoglobulin (Ig)-like receptors (LILR) are a family of 11 innate immunomodulatory receptors, primarily expressed on lymphoid and myeloid cells. LILRs are either activating (LILRA) or inhibitory (LILRB) depending on their associated signalling domains (D). With the exception of the soluble LILRA3, LILRAs mediate immune activation, while LILRB1-5 primarily inhibit immune responses and mediate tolerance. Abnormal expression and function of LILRs is associated with a range of pathologies, including immune insufficiency (infection and malignancy) and overt immune responses (autoimmunity and alloresponses), suggesting LILRs may be excellent candidates for targeted immunotherapies. This review will discuss the biology and clinical relevance of this extensive family of immune receptors and will summarise the recent developments in targeting LILRs in disease settings, such as cancer, with an update on the clinical trials investigating the therapeutic targeting of these receptors.
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Affiliation(s)
- Silvia Redondo-García
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Christopher Barritt
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- Lister Department of General Surgery, Glasgow Royal Infirmary, Glasgow, United Kingdom
- School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United Kingdom
| | - Charys Papagregoriou
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Muchaala Yeboah
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Björn Frendeus
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- BioInvent International AB, Lund, Sweden
| | - Mark S. Cragg
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Ali Roghanian
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
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Gunavathy N, Asirvatham A, Chitra A, Jayalakshmi M. Evaluation of HLA-G 14bp Ins/Del and +3142 C/G Polymorphisms in Type 1 Diabetes among South Indian Population. Indian J Endocrinol Metab 2023; 27:223-229. [PMID: 37583409 PMCID: PMC10424110 DOI: 10.4103/ijem.ijem_7_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/02/2023] [Accepted: 04/22/2023] [Indexed: 08/17/2023] Open
Abstract
Background Type 1 diabetes (T1D) is a multifactorial autoimmune disease, involving strong genetic components with familial predisposition. Human leukocyte antigen-G (HLA-G) is a non-classical HLA-class I molecule having several immunomodulatory functions. Polymorphisms in HLA-G are associated with several autoimmune diseases including T1D. This study aims to evaluate the association of HLA-G 14bp Ins/Del and +3142 C/G polymorphisms with T1D among the South Indian population. Methods The study was performed in a cohort of 123 T1D patients along with their 51 siblings and 126 parents. The association and linkage of HLA-G 14bp Ins/Del and +3142 C/G polymorphisms with T1D were analysed, and transmission disequilibrium test (TDT) was performed. Results Significantly increased frequencies of HLA-G 14bp Del/Del genotype (OR = 2.16, pc = 0.0302) and Del allele (OR = 1.71, pc = 0.0398) were observed in female patients compared to parents. Higher frequencies of DelDel/GG combined genotype (OR = 4.45, pc = 0.0049) and Del/G haplotype (OR = 2.91, pc = 0.0277) were observed in female patients compared to parents. TDT also revealed over-transmission of Del/G haplotype (25T vs 7UT; P = 0.0015) and a strong linkage disequilibrium between the studied polymorphisms. Conclusion This familial study shows the association of HLA-G 3'UTR 14bp Ins/Del polymorphism with the risk of T1D among the South Indian population, especially in females.
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Affiliation(s)
- Nagarajan Gunavathy
- Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, India
| | - Arthur Asirvatham
- Department of Diabetology, Government Rajaji Hospital, Madurai, Tamil Nadu, India
| | - Ayyappan Chitra
- Institute of Child Health and Research Centre, Government Rajaji Hospital, Madurai, Tamil Nadu, India
| | - Mariakuttikan Jayalakshmi
- Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, India
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Hu Y, Lu X, Qiu W, Liu H, Wang Q, Chen Y, Liu W, Feng F, Sun H. The Role of Leukocyte Immunoglobulin-Like Receptors Focusing on the Therapeutic Implications of the Subfamily B2. Curr Drug Targets 2022; 23:1430-1452. [PMID: 36017847 DOI: 10.2174/1389450123666220822201605] [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: 03/23/2022] [Revised: 05/31/2022] [Accepted: 06/21/2022] [Indexed: 01/25/2023]
Abstract
The leukocyte immunoglobulin (Ig)-like receptors (LILRs) are constituted by five inhibitory subpopulations (LILRB1-5) and six stimulatory subpopulations (LILRA1-6). The LILR populations substantially reside in immune cells, especially myeloid cells, functioning as a regulator in immunosuppressive and immunostimulatory responses, during which the nonclassical major histocompatibility complex (MHC) class I molecules are widely involved. In addition, LILRs are also distributed in certain tumor cells, implicated in the malignancy progression. Collectively, the suppressive Ig-like LILRB2 is relatively well-studied to date. Herein, we summarized the whole family of LILRs and their biologic function in various diseases upon ligation to the critical ligands, therefore providing more information on their potential roles in these pathological processes and giving the clinical significance of strategies targeting LILRs.
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Affiliation(s)
- Yanyu Hu
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Xin Lu
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Weimin Qiu
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Hui Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Qinghua Wang
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Yao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Wenyuan Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.,Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 211198, People's Republic of China
| | - Feng Feng
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China.,Jiangsu Food and Pharmaceuticals Science College, Institute of Food and Pharmaceuticals Research, 223005, People's Republic of China
| | - Haopeng Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China
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Negrini S, Contini P, Murdaca G, Puppo F. HLA-G in Allergy: Does It Play an Immunoregulatory Role? Front Immunol 2022; 12:789684. [PMID: 35082780 PMCID: PMC8784385 DOI: 10.3389/fimmu.2021.789684] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/15/2021] [Indexed: 11/29/2022] Open
Abstract
Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.
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Affiliation(s)
| | | | | | - Francesco Puppo
- Department of Internal Medicine, University of Genoa, Genoa, Italy
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The HLA-G Immune Checkpoint Plays a Pivotal Role in the Regulation of Immune Response in Autoimmune Diseases. Int J Mol Sci 2021; 22:ijms222413348. [PMID: 34948145 PMCID: PMC8706866 DOI: 10.3390/ijms222413348] [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: 10/31/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022] Open
Abstract
The human G-leukocyte antigen (HLA-G) molecule is a non-classical major histocompatibility complex (MHC) class I molecule. The pertinence of HLA-G has been investigated in numerous studies which have sought to elucidate the relevance of HLA-G in pathologic conditions, such as autoimmune diseases, cancers, and hematologic malignancies. One of the main goals of the current research on HLA-G is to use this molecule in clinical practice, either in diagnostics or as a therapeutic target. Since HLA-G antigens are currently considered as immunomodulatory molecules that are involved in reducing inflammatory and immune responses, in this review, we decided to focus on this group of antigens as potential determinants of progression in autoimmune diseases. This article highlights what we consider as recent pivotal findings on the immunomodulatory function of HLA-G, not only to establish the role of HLA-G in the human body, but also to explain how these proteins mediate the immune response.
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8
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Storm L, Bruijnesteijn J, de Groot NG, Bontrop RE. The Genomic Organization of the LILR Region Remained Largely Conserved Throughout Primate Evolution: Implications for Health And Disease. Front Immunol 2021; 12:716289. [PMID: 34737739 PMCID: PMC8562567 DOI: 10.3389/fimmu.2021.716289] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 10/01/2021] [Indexed: 11/13/2022] Open
Abstract
The genes of the leukocyte immunoglobulin-like receptor (LILR) family map to the leukocyte receptor complex (LRC) on chromosome 19, and consist of both activating and inhibiting entities. These receptors are often involved in regulating immune responses, and are considered to play a role in health and disease. The human LILR region and evolutionary equivalents in some rodent and bird species have been thoroughly characterized. In non-human primates, the LILR region is annotated, but a thorough comparison between humans and non-human primates has not yet been documented. Therefore, it was decided to undertake a comprehensive comparison of the human and non-human primate LILR region at the genomic level. During primate evolution the organization of the LILR region remained largely conserved. One major exception, however, is provided by the common marmoset, a New World monkey species, which seems to feature a substantial contraction of the number of LILR genes in both the centromeric and the telomeric region. Furthermore, genomic analysis revealed that the killer-cell immunoglobulin-like receptor gene KIR3DX1, which maps in the LILR region, features one copy in humans and great ape species. A second copy, which might have been introduced by a duplication event, was observed in the lesser apes, and in Old and New World monkey species. The highly conserved gene organization allowed us to standardize the LILR gene nomenclature for non-human primate species, and implies that most of the receptors encoded by these genes likely fulfill highly preserved functions.
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Affiliation(s)
- Lisanne Storm
- Comparative Genetics and Refinement, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Jesse Bruijnesteijn
- Comparative Genetics and Refinement, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Natasja G de Groot
- Comparative Genetics and Refinement, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | - Ronald E Bontrop
- Comparative Genetics and Refinement, Biomedical Primate Research Centre, Rijswijk, Netherlands.,Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, Netherlands
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Salerno-Gonçalves R, Rezwan T, Luo D, Tettelin H, Sztein MB. B Cells Control Mucosal-Associated Invariant T Cell Responses to Salmonella enterica Serovar Typhi Infection Through the CD85j HLA-G Receptor. Front Immunol 2021; 12:728685. [PMID: 34659215 PMCID: PMC8517411 DOI: 10.3389/fimmu.2021.728685] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/16/2021] [Indexed: 11/13/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are an innate-like population of T cells that display a TCR Vα7.2+ CD161+ phenotype and are restricted by the nonclassical MHC-related molecule 1 (MR1). Although B cells control MAIT cell development and function, little is known about the mechanisms underlying their interaction(s). Here, we report, for the first time, that during Salmonella enterica serovar Typhi (S. Typhi) infection, HLA-G expression on B cells downregulates IFN-γ production by MAIT cells. In contrast, blocking HLA-G expression on S. Typhi-infected B cells increases IFN-γ production by MAIT cells. After interacting with MAIT cells, kinetic studies show that B cells upregulate HLA-G expression and downregulate the inhibitory HLA-G receptor CD85j on MAIT cells resulting in their loss. These results provide a new role for HLA-G as a negative feedback loop by which B cells control MAIT cell responses to antigens.
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Affiliation(s)
- Rosângela Salerno-Gonçalves
- Center for Vaccine Development and Global Health (CVD), Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Tasmia Rezwan
- Center for Vaccine Development and Global Health (CVD), Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
| | - David Luo
- Center for Vaccine Development and Global Health (CVD), Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Hervé Tettelin
- Department of Microbiology and Immunology and Institute for Genome Sciences (IGS), University of Maryland School of Medicine, Baltimore, MD, United States
| | - Marcelo B. Sztein
- Center for Vaccine Development and Global Health (CVD), Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
- Program in Oncology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States
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Farghaly WM, Saad Eldien HM, Sayed MA, Elnady HM, Khodeary A, Abdel-Gawad AR, El-Tallawy HN, Abdellatif MG, Alhewaig HK. The relationship of HLA-G 14-bp insertion/deletion genetic polymorphism to the risk of multiple sclerosis and its clinical phenotypes. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2021. [DOI: 10.1186/s41983-021-00312-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Abstract
Background
Human leukocyte antigen (HLA)-G molecule has been suggested to have a potential immunomodulatory role in multiple sclerosis (MS). Genetic variant sites of HLA-G molecule have been reported to be associated with autoimmune diseases. Identifying the genetic risk factors of MS may help in preventive strategies and anticipating disease progression. The aim of this work was to investigate the effect of HLA-G 14-base-pair insertion/deletion (14-bp INS/DEL) genetic polymorphism on MS risk and clinical characteristics and to observe the clinical characteristics of the MS patients’ group. The study included 48 MS patients and 50 cross-matched healthy controls, who were recruited from Sohag and Assiut university hospitals. Genetic testing (14-bp Ins/Del gene polymorphism) using polymerase chain reaction (PCR) was performed for patients and control groups. All patients had a detailed clinical assessment and have undergone measurement of disability using the Expanded Disability Status Scale (EDSS).
Results
No statistically significant difference was found between MS patients and healthy controls (HC) in genotypic and allelic frequencies of HLA-G 14-bp INS/DEL polymorphism (P=0.305). No significant association was found between HLA-G 14-bp INS/DEL polymorphism genotypes and clinical characteristics or degree of disability of MS patients. The most frequent presenting symptoms of MS were motor symptoms. Fatigue was the most reported symptom along the course of MS disease.
Conclusion
Although it has been long known that HLA-G represents an important MS susceptibility locus, in this study, no significant relation could be detected between the 14-bp INS/DEL polymorphism genotype and MS susceptibility. MS risk susceptibility may be not linked to a single allele but may depend on the combination of different polymorphic genetic sites. In this study, the lack of genetic susceptibility may be attributed to ethnic factor.
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11
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Almeida RS, Ferreira MLB, Sonon P, Cordeiro MT, Sadissou I, Diniz GTN, Militão-Albuquerque MDFP, Franca RFDO, Donadi EA, Lucena-Silva N. Cytokines and Soluble HLA-G Levels in the Acute and Recovery Phases of Arbovirus-Infected Brazilian Patients Exhibiting Neurological Complications. Front Immunol 2021; 12:582935. [PMID: 33776990 PMCID: PMC7994272 DOI: 10.3389/fimmu.2021.582935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 01/08/2021] [Indexed: 12/19/2022] Open
Abstract
Severe neurological complications following arbovirus infections have been a major concern in seasonal outbreaks, as reported in the Northeast region of Brazil, where the same mosquito transmitted Zika (ZIKV), Dengue (DENV), and Chikungunya (CHIKV) viruses. In this study, we evaluated the levels of 36 soluble markers, including cytokines, chemokines, growth factors, and soluble HLA-G (Luminex and ELISA) in: i) serum and cerebrospinal fluid (CSF), during the acute phase and two years after the infection (recovery phase, only serum), ii) the relationship among all soluble molecules in serum and CSF, and iii) serum of infected patients without neurological complications, during the acute infection. Ten markers (sHLA-G, IL-10, IL-22, IL-8, MIP-1α, MIP-1β, MCP-1, HGF, VEGF, and IL-1RA) exhibited differential levels between the acute and recovery phases, with pronounced increases in MIP-1α (P<0.0001), MCP-1 (P<0.0001), HGF (P= 0.0001), and VEGF (P<0.0001) in the acute phase. Fourteen molecules (IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-13, IL-15, IL-17A, IFN-α, TNF, and G-CSF) exhibited distinct levels between arbovirus patients presenting or not neurological complications. IL-8, EGF, IL-6, and MCP-1 levels were increased in CSF, while RANTES and Eotaxin levels were higher in serum. Soluble serum (IL-22, RANTES, Eotaxin) and CSF (IL-8, EGF, IL-3) mediators may discriminate putative risks for neurological complications following arbovirus infections. Neurological complications were associated with the presence of a predominant inflammatory profile, whereas in non-complicated patients an anti-inflammatory profile may predominate. Mediators associated with neuroregeneration (EGF and IL-3) may be induced in response to neurological damage. Broad spectrum immune checkpoint molecules (sHLA-G) interact with cytokines, chemokines, and growth factors. The identification of soluble markers may be useful to monitor neurological complications and may aid in the development of novel therapies against neuroinflammation.
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Affiliation(s)
- Renata Santos Almeida
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | | | - Paulin Sonon
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil.,Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Marli Tenório Cordeiro
- Department of Virology and Experimental Therapy, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | - Ibrahim Sadissou
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - George Tadeu Nunes Diniz
- Department of Collective Health, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | | | | | | | - Norma Lucena-Silva
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
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12
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Ivan DC, Walthert S, Berve K, Steudler J, Locatelli G. Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System. Front Immunol 2021; 11:609921. [PMID: 33746939 PMCID: PMC7973121 DOI: 10.3389/fimmu.2020.609921] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/29/2020] [Indexed: 01/02/2023] Open
Abstract
The central nervous system (CNS) parenchyma is enclosed and protected by a multilayered system of cellular and acellular barriers, functionally separating glia and neurons from peripheral circulation and blood-borne immune cells. Populating these borders as dynamic observers, CNS-resident macrophages contribute to organ homeostasis. Upon autoimmune, traumatic or neurodegenerative inflammation, these phagocytes start playing additional roles as immune regulators contributing to disease evolution. At the same time, pathological CNS conditions drive the migration and recruitment of blood-borne monocyte-derived cells across distinct local gateways. This invasion process drastically increases border complexity and can lead to parenchymal infiltration of blood-borne phagocytes playing a direct role both in damage and in tissue repair. While recent studies and technical advancements have highlighted the extreme heterogeneity of these resident and CNS-invading cells, both the compartment-specific mechanism of invasion and the functional specification of intruding and resident cells remain unclear. This review illustrates the complexity of mononuclear phagocytes at CNS interfaces, indicating how further studies of CNS border dynamics are crucially needed to shed light on local and systemic regulation of CNS functions and dysfunctions.
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13
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Kumano S, Okushi Y, Fujimoto K, Adachi H, Furuichi K, Yokoyama H. Role and expression of non-classical human leukocyte antigen-G in renal transplanted allografts. Clin Exp Nephrol 2021; 25:428-438. [PMID: 33398603 DOI: 10.1007/s10157-020-01999-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/19/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND The non-classical class I molecule human leukocyte antigen-G (HLA-G) has great potential to modulate the immune response. However, the mechanism underlying HLA-G induction remains unknown. Therefore, this study aimed to determine the factors that induce HLA-G expression on proximal tubular epithelial cells (pTECs) in renal transplanted allografts in vivo and in vitro. METHODS This study included 40 adult Japanese patients with renal allografts (35 and five patients with kidneys from living and deceased donors, respectively) who survived for at least 1 year. We evaluated HLA-G1/5 expression using an immunofluorescence method and investigated the induction of HLA-G expression in primary cultured human pTECs by cytokines and immunosuppressants. RESULTS The HLA-G expression was identified in the perinuclear region or on the basement membrane of pTECs of renal biopsy tissue in 12 (30%) of 40 patients at 2-4 weeks and at 1 year following transplantation. A reduction of 30% in the estimated glomerular filtration rate was lower in the HLA-G-positive group than that of the negative group (p = 0.016). Cox proportional hazard models also demonstrated that HLA-G1/5 expression on pTECs was an independent predictor of improved renal allograft function (hazard ratio, 0.189; 95% CI 0.041-0.850, p = 0.030). Interferon-beta was the most powerful inducer of HLA-G expression in vitro, whereas the immunosuppressants everolimus, tacrolimus, cyclosporin, and dexamethasone did not induce any expression. CONCLUSION Unlike immunosuppressants, acquired HLA-G expression might confer long-term renal preservation effects in renal transplanted allografts.
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Affiliation(s)
- Sho Kumano
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
| | - Yuki Okushi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Keiji Fujimoto
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hiroki Adachi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Kengo Furuichi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
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14
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Priya R, Brutkiewicz RR. Brain astrocytes and microglia express functional MR1 molecules that present microbial antigens to mucosal-associated invariant T (MAIT) cells. J Neuroimmunol 2020; 349:577428. [PMID: 33096293 DOI: 10.1016/j.jneuroim.2020.577428] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 10/13/2020] [Accepted: 10/13/2020] [Indexed: 12/24/2022]
Abstract
It is unknown whether brain astrocytes and microglia have the capacity to present microbial antigens via the innate immune MR1/MAIT cell axis. We have detected MAIT cells in the normal mouse brain and found that both astrocytes and microglia are MR1+. When we stimulated brain astrocytes and microglia with E. coli, and then co-cultured them with MAIT cells, MR1 surface expression was upregulated and MAIT cells were activated in an antigen-dependent manner. Considering the association of MAIT cells with inflammatory conditions, including those in the CNS, the MR1/MAIT cell axis could be a novel therapeutic target in neuroinflammatory disorders.
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Affiliation(s)
- Raj Priya
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
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15
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Arns T, Antunes DA, Abella JR, Rigo MM, Kavraki LE, Giuliatti S, Donadi EA. Structural Modeling and Molecular Dynamics of the Immune Checkpoint Molecule HLA-G. Front Immunol 2020; 11:575076. [PMID: 33240264 PMCID: PMC7677236 DOI: 10.3389/fimmu.2020.575076] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 10/13/2020] [Indexed: 02/01/2023] Open
Abstract
HLA-G is considered to be an immune checkpoint molecule, a function that is closely linked to the structure and dynamics of the different HLA-G isoforms. Unfortunately, little is known about the structure and dynamics of these isoforms. For instance, there are only seven crystal structures of HLA-G molecules, being all related to a single isoform, and in some cases lacking important residues associated to the interaction with leukocyte receptors. In addition, they lack information on the dynamics of both membrane-bound HLA-G forms, and soluble forms. We took advantage of in silico strategies to disclose the dynamic behavior of selected HLA-G forms, including the membrane-bound HLA-G1 molecule, soluble HLA-G1 dimer, and HLA-G5 isoform. Both the membrane-bound HLA-G1 molecule and the soluble HLA-G1 dimer were quite stable. Residues involved in the interaction with ILT2 and ILT4 receptors (α3 domain) were very close to the lipid bilayer in the complete HLA-G1 molecule, which might limit accessibility. On the other hand, these residues can be completely exposed in the soluble HLA-G1 dimer, due to the free rotation of the disulfide bridge (Cys42/Cys42). In fact, we speculate that this free rotation of each protomer (i.e., the chains composing the dimer) could enable alternative binding modes for ILT2/ILT4 receptors, which in turn could be associated with greater affinity of the soluble HLA-G1 dimer. Structural analysis of the HLA-G5 isoform demonstrated higher stability for the complex containing the peptide and coupled β2-microglobulin, while structures lacking such domains were significantly unstable. This study reports for the first time structural conformations for the HLA-G5 isoform and the dynamic behavior of HLA-G1 molecules under simulated biological conditions. All modeled structures were made available through GitHub (https://github.com/KavrakiLab/), enabling their use as templates for modeling other alleles and isoforms, as well as for other computational analyses to investigate key molecular interactions.
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Affiliation(s)
- Thais Arns
- Department of Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Dinler A. Antunes
- Department of Computer Science, Rice University, Houston, TX, United States
| | - Jayvee R. Abella
- Department of Computer Science, Rice University, Houston, TX, United States
| | - Maurício M. Rigo
- Department of Computer Science, Rice University, Houston, TX, United States
| | - Lydia E. Kavraki
- Department of Computer Science, Rice University, Houston, TX, United States
| | - Silvana Giuliatti
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Eduardo A. Donadi
- Department of Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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16
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Contini P, Murdaca G, Puppo F, Negrini S. HLA-G Expressing Immune Cells in Immune Mediated Diseases. Front Immunol 2020; 11:1613. [PMID: 32983083 PMCID: PMC7484697 DOI: 10.3389/fimmu.2020.01613] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022] Open
Abstract
HLA-G is a HLA class Ib antigen that possesses immunomodulatory properties. HLA-G-expressing CD4+ and CD8+ T lymphocytes, NK cells, monocytes, and dendritic cells with immunoregulatory functions are present in small percentages of patients with physiologic conditions. Quantitative and qualitative derangements of HLA-G+ immune cells have been detected in several conditions in which the immune system plays an important role, such as infectious, neoplastic, and autoimmune diseases as well as in complications from transplants and pregnancy. These observations strongly support the hypothesis that HLA-G+ immune cells may be implicated in the complex mechanisms underlying the pathogenesis of these disorders.
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Affiliation(s)
| | | | - Francesco Puppo
- Department of Internal Medicine, University of Genoa, Genoa, Italy
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17
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Yang Y, Zhang Z. Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer's Disease. Front Aging Neurosci 2020; 12:110. [PMID: 32477095 PMCID: PMC7241259 DOI: 10.3389/fnagi.2020.00110] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 03/30/2020] [Indexed: 01/27/2023] Open
Abstract
Alzheimer’s disease (AD) has been a major health issue for more than one century since it was first reported in 1906. As one of the most common neurodegenerative diseases, AD is characterized by the presence of senile plaques and neurofibrillary tangles (NFTs) in the affected brain area. Microglia are the major regulators of neuroinflammation in the brain, and neuroinflammation has become recognized as the core pathophysiological process of various neurodegenerative diseases. In the central nervous system (CNS), microglia play a dual role in AD development. For one thing, they degrade amyloid β (Aβ) to resist its deposition; for another, microglia release pro-inflammatory and inflammatory factors, contributing to neuroinflammation as well as the spreading of Aβ and tau pathology. Wnt pathways are important regulators of cell fate and cell activities. The dysregulation of Wnt pathways is responsible for both abnormal tau phosphorylation and synaptic loss in AD. Recent studies have also confirmed the regulatory effect of Wnt signaling on microglial inflammation. Thus, the study of microglia, Wnt pathways, and their possible interactions may open up a new direction for understanding the mechanisms of neuroinflammation in AD. In this review, we summarize the functions of microglia and Wnt pathways and their roles in AD in order to provide new ideas for understanding the pathogenesis of AD.
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Affiliation(s)
- Yunying Yang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhentao Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
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18
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Huang YS, Ogbechi J, Clanchy FI, Williams RO, Stone TW. IDO and Kynurenine Metabolites in Peripheral and CNS Disorders. Front Immunol 2020; 11:388. [PMID: 32194572 PMCID: PMC7066259 DOI: 10.3389/fimmu.2020.00388] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 02/18/2020] [Indexed: 12/12/2022] Open
Abstract
The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.
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Affiliation(s)
- Yi-Shu Huang
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Joy Ogbechi
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Felix I Clanchy
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Richard O Williams
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Trevor W Stone
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
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19
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Ajith A, Portik-Dobos V, Horuzsko DD, Kapoor R, Mulloy LL, Horuzsko A. HLA-G and humanized mouse models as a novel therapeutic approach in transplantation. Hum Immunol 2020; 81:178-185. [PMID: 32093884 DOI: 10.1016/j.humimm.2020.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/15/2020] [Accepted: 02/17/2020] [Indexed: 01/12/2023]
Abstract
HLA-G is a nonclassical MHC-Class I molecule whose expression, along the feto-maternal barrier contributes towards tolerance of the semiallogeneic fetus during pregnancy. In light of its inhibitory properties, recent research has established HLA-G involvement in mechanisms responsible for directing allogeneic immune responses towards tolerance during allogeneic situations such as organ transplantation. Here, we critically review the data supporting the tolerogenic role of HLA-G in organ transplantation, the various factors influencing its expression, and the introduction of novel humanized mouse models that are one of the best approaches to assess the utility of HLA-G as a therapeutic tool in organ transplantation.
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Affiliation(s)
- Ashwin Ajith
- Georgia Cancer Canter, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Vera Portik-Dobos
- Georgia Cancer Canter, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Daniel D Horuzsko
- Philadelphia College of Osteopathic Medicine South Georgia, Moultrie, GA, USA
| | - Rajan Kapoor
- Division of Nephrology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Laura L Mulloy
- Division of Nephrology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Anatolij Horuzsko
- Georgia Cancer Canter, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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20
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Banerjee PP, Pang L, Soldan SS, Miah SM, Eisenberg A, Maru S, Waldman A, Smith EA, Rosenberg-Hasson Y, Hirschberg D, Smith A, Ablashi DV, Campbell KS, Orange JS. KIR2DL4-HLAG interaction at human NK cell-oligodendrocyte interfaces regulates IFN-γ-mediated effects. Mol Immunol 2019; 115:39-55. [PMID: 30482463 PMCID: PMC6543535 DOI: 10.1016/j.molimm.2018.09.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 09/11/2018] [Accepted: 09/30/2018] [Indexed: 12/12/2022]
Abstract
Interactions between germline-encoded natural killer (NK) cell receptors and their respective ligands on tumorigenic or virus-infected cells determine NK cell cytotoxic activity and/or cytokine secretion. NK cell cytokine responses can be augmented in and can potentially contribute to multiple sclerosis (MS), an inflammatory disease of the central nervous system focused upon the oligodendrocytes (OLs). To investigate mechanisms by which NK cells may contribute to MS pathogenesis, we developed an in vitro human model of OL-NK cell interaction. We found that activated, but not resting human NK cells form conjugates with, and mediate cytotoxicity against, human oligodendrocytes. NK cells, when in conjugate with OLs, rapidly synthesize and polarize IFN-γ toward the OLs. IFN-γ is capable of reducing myelin oligodendrocyte and myelin associated glycoproteins (MOG and MAG) content. This activity is independent of MHC class-I mediated inhibition via KIR2DL1, but dependent upon the interaction between NK cell-expressed KIR2DL4 and its oligodendrocyte-expressed ligand, HLA-G. NK cells from patients with MS express higher levels of IFN-γ following conjugation to OLs, more actively promote in vitro reduction of MOG and MAG and have higher frequencies of the KIR2DL4 positive population. These data collectively suggest a mechanism by which NK cells can promote pathogenic effects upon OLs.
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Affiliation(s)
- P P Banerjee
- Baylor College of Medicine, 1 Baylor Plaza, Houston, TX-77030, USA; Center for Human Immunobiology, Texas Children's Hospital, 1102 Bates St, Houston, TX, 77030, USA.
| | - L Pang
- Center for Human Immunobiology, Texas Children's Hospital, 1102 Bates St, Houston, TX, 77030, USA
| | - S S Soldan
- The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA
| | - S M Miah
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - A Eisenberg
- The Children's Hospital of Philadelphia Research Institute, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - S Maru
- The Children's Hospital of Philadelphia Research Institute, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - A Waldman
- The Children's Hospital of Philadelphia Research Institute, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - E A Smith
- Baylor College of Medicine, 1 Baylor Plaza, Houston, TX-77030, USA; Center for Human Immunobiology, Texas Children's Hospital, 1102 Bates St, Houston, TX, 77030, USA
| | - Y Rosenberg-Hasson
- Human Immune Monitoring Center, Stanford School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA
| | - D Hirschberg
- Human Immune Monitoring Center, Stanford School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA
| | - A Smith
- Baylor College of Medicine, 1 Baylor Plaza, Houston, TX-77030, USA; Center for Human Immunobiology, Texas Children's Hospital, 1102 Bates St, Houston, TX, 77030, USA
| | - D V Ablashi
- Human Herpes Virus 6 Foundation, 1482 East Valley Road, Suite 619 Santa Barbara, CA 93108, USA
| | - K S Campbell
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - J S Orange
- Baylor College of Medicine, 1 Baylor Plaza, Houston, TX-77030, USA; Center for Human Immunobiology, Texas Children's Hospital, 1102 Bates St, Houston, TX, 77030, USA
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Toni Ho GG, Heinen F, Stieglitz F, Blasczyk R, Bade-Döding C. Dynamic Interaction between Immune Escape Mechanism and HLA-Ib Regulation. Immunogenetics 2019. [DOI: 10.5772/intechopen.80731] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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22
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The expression and clinical significance of different forms of LILRA3 in systemic lupus erythematosus. Clin Rheumatol 2019; 38:3099-3107. [PMID: 31209706 DOI: 10.1007/s10067-019-04624-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/22/2019] [Accepted: 05/27/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Our previous study has shown that functional leukocyte immunoglobulin-like receptors A3 (LILRA3) contributes to susceptibility and subphenotypes of systemic lupus erythematosus (SLE). However, the mechanism remains unclear. We aimed to evaluate the role of LILRA3 in SLE. METHODS One hundred twenty-six SLE patients and 48 healthy controls were recruited in this study. Functional studies were performed using intracellular flow cytometry and ELISA. RESULTS Both LILRA3 levels in serum and CD14+ monocytes were significantly elevated in SLE patients compared with healthy controls. Elevated LILRA3 level was found positively correlated with SLEDAI. Furthermore, more elevated LILRA3 levels were found in patients with higher SLEDAI, presence of lupus nephritis, and thrombocytopenia. CONCLUSIONS Both LILRA3 levels in serum and CD14+ monocytes significantly increased in SLE and positively correlated with disease activity and severity. The upregulation of LILRA3 expression may serve as a biomarker of disease activity and severity of SLE. KEY POINTS • LILRA3 contributes to susceptibility and subphenotypes of SLE; LILRA3 is elevated in SLE patients. • Increased LILRA3 correlated with disease activity and severity. • LILRA3 may serve as a biomarker of disease activity and severity of SLE.
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Abstract
SummaryHLA-G expression has been detected in early preimplantation embryos and it has been postulated that a relationship between embryonic expression of this factor and successful pregnancy may exist. Forty-six patients were prospectively selected from our centre 'Unidad de Reproducción Humana, Hospital Universitario de Canarias' for conducting this study. In all cases, metaphase II (MII) oocytes were fertilized using intracytoplasmic sperm injection 2-4 h after retrieval. Embryos were cultured individually in 20 µl droplets of G-1 medium (VitroLife) under oil at 37°C and a 6% CO2 environment. Fertilization was assessed at 18 h postinsemination and all oocytes fertilized were passed into a new culture plaque individually in 300 µl culture medium until day 3 of culture. The culture medium was examined for the expression and secretion of sHLA-G with a sandwich enzyme-linked immunosorbent assay kit (BioVendor, Heidelberg, Germany) according to the manufacturer's instructions. We found statistical significance between higher levels of sHLA-G secretion and pregnancy rate. When both groups were compared there was no difference in embryo quality of transferred embryos, but a significant difference in the number of oocytes and the embryo quality of the cohort existed that was greater in the pregnant group. A standardized sHLA-G assay with a specifically defined range and standard units provides a non-invasive method to identify the most competent embryos for transfer.
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Touil H, Kobert A, Lebeurrier N, Rieger A, Saikali P, Lambert C, Fawaz L, Moore CS, Prat A, Gommerman J, Antel JP, Itoyama Y, Nakashima I, Bar-Or A. Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis. J Neuroinflammation 2018; 15:114. [PMID: 29673365 PMCID: PMC5907187 DOI: 10.1186/s12974-018-1136-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 03/22/2018] [Indexed: 12/22/2022] Open
Abstract
Background The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated. Methods We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells. Results Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease. Conclusions Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease. Electronic supplementary material The online version of this article (10.1186/s12974-018-1136-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hanane Touil
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada.,Department of Neurology and Center for NeuroInflammation and Experimental Therapeutics (CNET), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Antonia Kobert
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada
| | - Nathalie Lebeurrier
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada
| | - Aja Rieger
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada
| | - Philippe Saikali
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada
| | - Caroline Lambert
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada
| | - Lama Fawaz
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada
| | - Craig S Moore
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada.,Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NF, Canada
| | - Alexandre Prat
- Université de Montréal Centre de Recherche du CHUM (CRCHUM) and Department of Neuroscience, Université de Montréal, 900 Saint Denis Street, Montreal, QC, H2X 0A9, Canada
| | - Jennifer Gommerman
- Department of Immunology, Medical Sciences Building, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Jack P Antel
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada
| | - Yasuto Itoyama
- Department of Neurology, School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Ichiro Nakashima
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada.,Department of Neurology, School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Amit Bar-Or
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada. .,Department of Neurology and Center for NeuroInflammation and Experimental Therapeutics (CNET), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Hopperton KE, Mohammad D, Trépanier MO, Giuliano V, Bazinet RP. Markers of microglia in post-mortem brain samples from patients with Alzheimer's disease: a systematic review. Mol Psychiatry 2018; 23:177-198. [PMID: 29230021 PMCID: PMC5794890 DOI: 10.1038/mp.2017.246] [Citation(s) in RCA: 354] [Impact Index Per Article: 50.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 08/15/2017] [Accepted: 09/14/2017] [Indexed: 02/07/2023]
Abstract
Neuroinflammation is proposed as one of the mechanisms by which Alzheimer's disease pathology, including amyloid-β plaques, leads to neuronal death and dysfunction. Increases in the expression of markers of microglia, the main neuroinmmune cell, are widely reported in brains from patients with Alzheimer's disease, but the literature has not yet been systematically reviewed to determine whether this is a consistent pathological feature. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to 23 February 2017. Papers were included if they quantitatively compared microglia markers in post-mortem brain samples from patients with Alzheimer's disease and aged controls without neurological disease. A total of 113 relevant articles were identified. Consistent increases in markers related to activation, such as major histocompatibility complex II (36/43 studies) and cluster of differentiation 68 (17/21 studies), were identified relative to nonneurological aged controls, whereas other common markers that stain both resting and activated microglia, such as ionized calcium-binding adaptor molecule 1 (10/20 studies) and cluster of differentiation 11b (2/5 studies), were not consistently elevated. Studies of ionized calcium-binding adaptor molecule 1 that used cell counts almost uniformly identified no difference relative to control, indicating that increases in activation occurred without an expansion of the total number of microglia. White matter and cerebellum appeared to be more resistant to these increases than other brain regions. Nine studies were identified that included high pathology controls, patients who remained free of dementia despite Alzheimer's disease pathology. The majority (5/9) of these studies reported higher levels of microglial markers in Alzheimer's disease relative to controls, suggesting that these increases are not solely a consequence of Alzheimer's disease pathology. These results show that increased markers of microglia are a consistent feature of Alzheimer's disease, though this seems to be driven primarily by increases in activation-associated markers, as opposed to markers of all microglia.
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Affiliation(s)
- K E Hopperton
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - D Mohammad
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada,Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - M O Trépanier
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - V Giuliano
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - R P Bazinet
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada,Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, FitzGerald Building, 150 College Street, Room 306, Toronto, ON M5S 3E2, Canada. E-mail:
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Cavalcanti A, Almeida R, Mesquita Z, Duarte ALBP, Donadi EA, Lucena-Silva N. Gene polymorphism and HLA-G expression in patients with childhood-onset systemic lupus erythematosus: A pilot study. HLA 2017; 90:219-227. [DOI: 10.1111/tan.13084] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 06/11/2017] [Accepted: 06/15/2017] [Indexed: 11/28/2022]
Affiliation(s)
- A. Cavalcanti
- Pediatric Rheumatology Unit; Federal University of Pernambuco; Recife Brazil
- Department of Immunology, Aggeu Magalhães Research Center; Oswaldo Cruz Foundation; Recife Brazil
| | - R. Almeida
- Department of Immunology, Aggeu Magalhães Research Center; Oswaldo Cruz Foundation; Recife Brazil
| | - Z. Mesquita
- Pediatric Rheumatology Unit; Institute of Integrative Medicine Professor Fernando Figueira; Recife Brazil
| | - A. L. B. P. Duarte
- Pediatric Rheumatology Unit; Federal University of Pernambuco; Recife Brazil
| | - E. A. Donadi
- Department of Clinical Medicine; São Paulo University; Ribeirão Preto Brazil
| | - N. Lucena-Silva
- Department of Immunology, Aggeu Magalhães Research Center; Oswaldo Cruz Foundation; Recife Brazil
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Zhang J, Mai S, Chen HM, Kang K, Li XC, Chen SH, Pan PY. Leukocyte immunoglobulin-like receptors in human diseases: an overview of their distribution, function, and potential application for immunotherapies. J Leukoc Biol 2017; 102:351-360. [PMID: 28351852 DOI: 10.1189/jlb.5mr1216-534r] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 02/24/2017] [Accepted: 03/08/2017] [Indexed: 01/03/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs), a population of immature myeloid cells expanded and accumulated in tumor-bearing mice and in patients with cancer, have been shown to mediate immune suppression and to promote tumor progression, thereby, posing a major hurdle to the success of immune-activating cancer therapies. MDSCs, like their healthy counterparts, such as monocytes/macrophages and granulocytes, express an array of costimulatory and coinhibitory molecules as well as myeloid activators and inhibitory receptors, such as leukocyte immunoglobulin-like receptors (LILR) A and B. This review summarizes current findings on the LILR family members in various diseases, their potential roles in the pathogenesis, and possible strategies to revert or enhance the suppressive function of MDSCs for the benefit of patients by targeting LILRs.
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Affiliation(s)
- Jilu Zhang
- Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Sunny Mai
- Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Hui-Ming Chen
- Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Kyeongah Kang
- Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Xian Chang Li
- Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, Texas, USA.,Department of Surgery, Weill Cornell Medical College, Cornell University, New York, New York, USA
| | - Shu-Hsia Chen
- Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA.,Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, New York, USA; and.,Department of General Surgery, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Ping-Ying Pan
- Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA; .,Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, New York, USA; and
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Ben Fredj N, Sakly K, Bortolotti D, Aissi M, Frih-Ayed M, Rotola A, Caselli E, Cura F, Sakly N, Aouni M, Di Luca D, Rizzo R. The association between functional HLA-G 14bp insertion/deletion and +3142 C>G polymorphisms and susceptibility to multiple sclerosis. Immunol Lett 2016; 180:24-30. [DOI: 10.1016/j.imlet.2016.10.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/16/2016] [Accepted: 10/18/2016] [Indexed: 11/30/2022]
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Tzang BS, Chiang SY, Chan HC, Liu CH, Hsu TC. Human parvovirus B19 antibodies induce altered membrane protein expression and apoptosis of BeWo trophoblasts. Mol Med Rep 2016; 14:4399-4406. [PMID: 27748859 DOI: 10.3892/mmr.2016.5787] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 09/13/2016] [Indexed: 11/06/2022] Open
Abstract
Human parvovirus B19 (B19) is harmful during pregnancy since it can be vertically transmitted to the developing fetus. In addition, the anti‑B19 antibodies induced by B19 infection are believed to have a cytopathic role in B19 transmission; however, knowledge regarding the effects of anti‑B19 antibodies during pregnancy is limited. To investigate the possible roles of anti‑B19 antibodies during pregnancy, the present study examined the effects of anti‑B19‑VP1 unique region (VP1u), anti‑B19‑VP2 and anti‑B19‑nonstructural protein 1 (NS1) immunoglobulin G (IgG) antibodies on BeWo trophoblasts. Briefly, BeWo trophoblasts were incubated with purified IgG against B19‑VP1u, B19‑VP2 and B19‑NS1. Subsequently, the expression of surface proteins and apoptotic molecules were assessed in BeWo trophoblasts using flow cytometry, ELISA and western blotting. The expression levels of human leukocyte antigen (HLA)‑G were significantly increased on BeWo trophoblasts treated with rabbit anti‑B19‑VP1u IgG, and were unchanged in those treated with rabbit anti‑B19‑NS1 and anti‑B19‑VP2 IgG, as compared with the control group. Furthermore, the expression levels of globoside (P blood group antigen) and cluster of differentiation (CD)29 (β1 integrin) were significantly increased in BeWo trophoblasts treated with rabbit anti‑B19‑NS1 and anti‑B19‑VP2 IgG, whereas only CD29 was also significantly increased in cells treated with anti‑B19‑VP1u IgG. In addition, the number of cells at sub‑G1 phase; caspase‑3 activity; and the expression of intrinsic and extrinsic apoptotic molecules, including Fas‑associated death domain protein, activated caspase‑8, activated caspase‑3, B‑cell lymphoma 2‑associated X protein, cytochrome c, apoptotic peptidase activating factor 1 and activated caspase‑9, were significantly increased in BeWo trophoblasts treated with anti‑B19‑VP1u and anti‑B19‑NS1 IgG. In conclusion, the present study demonstrated that antibodies against B19 may have a crucial role in pathological processes during pregnancy. These findings may help to elucidate the mechanisms underlying transmission of the B19 virus during pregnancy.
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Affiliation(s)
- Bor-Show Tzang
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Szu-Yi Chiang
- Division of Neurology, Department of Internal Medicine, Chi Mei Medical Center, Liouying 73663, Taiwan, R.O.C
| | - Hsu-Chin Chan
- Department of Biochemistry, School of Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Chung-Hsien Liu
- Department of Obstetrics and Gynecology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C
| | - Tsai-Ching Hsu
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
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Gineau L, Courtin D, Camara M, Ilboudo H, Jamonneau V, Dias FC, Tokplonou L, Milet J, Mendonça PB, Castelli EC, Camara O, Camara M, Favier B, Rouas-Freiss N, Moreau P, Donadi EA, Bucheton B, Sabbagh A, Garcia A. Human Leukocyte Antigen-G: A Promising Prognostic Marker of Disease Progression to Improve the Control of Human African Trypanosomiasis. Clin Infect Dis 2016; 63:1189-1197. [PMID: 27470243 DOI: 10.1093/cid/ciw505] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 07/21/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense can be diagnosed in the early hemolymphatic stage (stage 1 [S1]) or meningoencephalitic stage (stage 2 [S2]). Importantly, individuals harbouring high and specific antibody responses to Tbg antigens but negative parasitology are also diagnosed in the field (seropositive [SERO]). Whereas some develop the disease in the months following their initial diagnosis (SERO/HAT), others remain parasitologically negative for long periods (SERO) and are apparently able to control infection. Human leucocyte antigen (HLA)-G, an immunosuppressive molecule, could play a critical role in this variability of progression between infection and disease. METHODS Soluble HLA-G (sHLA-G) was measured in plasma for patients in the SERO (n = 65), SERO/HAT (n = 14), or HAT (n = 268) group and in cerebrospinal fluid for patients in S1 (n = 55), early S2 (n = 93), or late S2 (n = 110). Associations between these different statuses and the soluble level or genetic polymorphisms of HLA-G were explored. RESULTS Plasma sHLA-G levels were significantly higher in HAT (P = 6 × 10-7) and SERO/HAT (P = .007) than SERO patients. No difference was observed between the SERO/HAT and HAT groups. Within the HAT group, specific haplotypes (HG010102 and HG0103) displayed increased frequencies in S1 (P = .013) and late S2 (P = .036), respectively. CONCLUSIONS These results strongly suggest the involvement of HLA-G in HAT disease progression. Importantly, high plasma sHLA-G levels in SERO patients could be predictive of subsequent disease development and could represent a serological marker to help guide therapeutic decision making. Further studies are necessary to assess the predictive nature of HLA-G and to estimate both sensitivity and specificity.
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Affiliation(s)
- Laure Gineau
- Institut de Recherche pour le Développement, UMR216 MERIT, Mère et Enfant face aux Infections Tropicales Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité
| | - David Courtin
- Institut de Recherche pour le Développement, UMR216 MERIT, Mère et Enfant face aux Infections Tropicales Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité
| | - Mamadou Camara
- Ministère de la Santé et de l'Hygiène Publique, Programme National de Lutte contre la Trypanosomose Humaine Africaine, Conakry, Guinea
| | - Hamidou Ilboudo
- Centre International de Recherche-Développement sur l'Elevage en Zones Subhumides, Unité de Recherches sur les Bases Biologiques de la Lutte Intégrée, Bobo-Dioulasso, Burkina Faso
| | - Vincent Jamonneau
- Centre International de Recherche-Développement sur l'Elevage en Zones Subhumides, Unité de Recherches sur les Bases Biologiques de la Lutte Intégrée, Bobo-Dioulasso, Burkina Faso Institut de Recherche Pour le Développement, Campus International de Baillarguet, Montpellier, France
| | - Fabricio C Dias
- Division of Clinical Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto
| | - Leonidas Tokplonou
- Institut de Recherche Pour le Développement, UMR 216, Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance, Faculté des Sciences de la Santé, Cotonou, Bénin
| | - Jacqueline Milet
- Institut de Recherche pour le Développement, UMR216 MERIT, Mère et Enfant face aux Infections Tropicales Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité
| | - Priscila B Mendonça
- Division of Clinical Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto
| | - Erick C Castelli
- Department de Pathology, School of Medicine, UNESP-Universidade Estadual Paulista, Botucatu, São Paulo, Brazil
| | - Oumou Camara
- Ministère de la Santé et de l'Hygiène Publique, Programme National de Lutte contre la Trypanosomose Humaine Africaine, Conakry, Guinea
| | - Mariam Camara
- Ministère de la Santé et de l'Hygiène Publique, Programme National de Lutte contre la Trypanosomose Humaine Africaine, Conakry, Guinea
| | - Benoit Favier
- Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis Université Paris Diderot, Sorbonne Paris Cité, UMRE5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis
| | - Nathalie Rouas-Freiss
- Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis Université Paris Diderot, Sorbonne Paris Cité, UMRE5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis
| | - Philippe Moreau
- Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis Université Paris Diderot, Sorbonne Paris Cité, UMRE5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis
| | - Eduardo A Donadi
- Division of Clinical Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto
| | - Bruno Bucheton
- Ministère de la Santé et de l'Hygiène Publique, Programme National de Lutte contre la Trypanosomose Humaine Africaine, Conakry, Guinea Institut de Recherche Pour le Développement, Campus International de Baillarguet, Montpellier, France
| | - Audrey Sabbagh
- Institut de Recherche pour le Développement, UMR216 MERIT, Mère et Enfant face aux Infections Tropicales Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité
| | - André Garcia
- Institut de Recherche pour le Développement, UMR216 MERIT, Mère et Enfant face aux Infections Tropicales Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité Institut de Recherche Pour le Développement, UMR 216, Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance, Faculté des Sciences de la Santé, Cotonou, Bénin
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Gerasimou P, Skordis N, Picolos M, Spyridonidis A, Costeas P. HLA-G 14-bp polymorphism affects the age of onset in Type I Diabetes Mellitus. Int J Immunogenet 2016; 43:135-42. [PMID: 27080982 DOI: 10.1111/iji.12259] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 02/02/2016] [Accepted: 03/10/2016] [Indexed: 02/06/2023]
Abstract
Type I diabetes mellitus (T1DM) is an organ-specific autoimmune disorder affecting the insulin-producing pancreatic cells. T1DM genetic association studies have so far revealed the involvement of more than 40 loci, with particularly strong associations for the human leucocyte antigens (HLA). Further to the well-established HLA class II associations, the immunomodulatory elements in the telomeric major histocompatibility complex locus, specifically nonclassical HLA class I, were also associated with T1DM, either in conferring susceptibility or by contributing to the overall pathogenesis. This study investigates the involvement of a 14-bp deletion polymorphism (rs371194629) at the 3' untranslated region of HLA-G in the context of T1DM and age of onset. The frequency of the polymorphism was determined in unrelated T1DM Cypriot patients and findings that emerge from this study show a strong association between the HLA-G 14-bp polymorphism and T1DM with respect to the age of onset. Specifically, the deletion/deletion (DEL/DEL) genotype was found to be associated with an early age of onset (P = 0.001), while the presence of the insertion allele (INS) was associated to a later age of onset (P = 0.0001), portraying a possible dominant effect over the deletion allele, a role in delaying disease onset and an overall involvement of HLA-G in the pathogenesis of type I diabetes mellitus.
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Affiliation(s)
- P Gerasimou
- Karaiskakio Foundation, Nicosia, Cyprus.,Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
| | - N Skordis
- Division of Paediatric Endocrinology, Paedi Centre for Specialized Paediatrics, Nicosia, Cyprus
| | - M Picolos
- Alithia Endocrinology Centre, Nicosia, Cyprus
| | - A Spyridonidis
- Division of Hematology/BMT Unit, University Hospital of Patras (PGNP), Rio, Greece
| | - P Costeas
- Karaiskakio Foundation, Nicosia, Cyprus
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Fan X, Wang Y, Zhang C, Liu X, Qian Z, Jiang T. Human leukocyte antigen-G overexpression predicts poor clinical outcomes in low-grade gliomas. J Neuroimmunol 2016; 294:27-31. [PMID: 27138095 DOI: 10.1016/j.jneuroim.2016.03.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 02/24/2016] [Accepted: 03/23/2016] [Indexed: 01/01/2023]
Abstract
Overexpression of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex class-I molecule associated with immunosuppression, has been reported in various human malignancies. In the present study, we examined the role of HLA-G in gliomas. Clinical characteristics, mRNA expression microarrays and follow-up data pertaining to 293 patients with histologically confirmed gliomas were analyzed. The expression levels of HLA-G were compared between different grades of gliomas and correlated with progression-free survival (PFS) and overall survival (OS) to evaluate its prognostic value. We found that HLA-G was overexpressed in gliomas as compared to that in normal brain tissue samples (-1.288±0.265). The highest expression levels were in glioblastomas (GBMs), anaplastic gliomas (AGs) and low-grade gliomas (LGGs), in that order (0.328±0.778, 0.176±0.881, -0.388±0.686, respectively). Significant inter-group differences were observed between low-grade and high-grade glioma tissues (p<0.001 and p<0.001, t-test, AGs and GBMs, respectively). More astrocytoma patients exhibited increased HLA-G expression as compared to other LGG patients (p=0.004, Chi-square test). Significant differences were observed with respect to PFS and OS (p=0.009 and 0.032, log-rank test, for PFS and OS, respectively) between the high- and low-expression subgroups in patients with LGGs. On Cox regression analysis, overexpression of HLA-G appeared to be an independent predictor of clinical outcomes (p=0.007 and 0.026, for PFS and OS, respectively). Our results suggest that HLA-G expression may serve as a potential biomarker for predicting aggressive tumor grades of gliomas and for histological subtype of LGGs. Elevated HLA-G expression could serve as an independent predictor of poor clinical outcomes in patients with low-grade gliomas.
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Affiliation(s)
- Xing Fan
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yinyan Wang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chuanbao Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Xing Liu
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zenghui Qian
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Tao Jiang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Clinical Oncology, Beijing Academy of Critical Illness in Brain, Beijing 100069, China.
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Fainardi E, Bortolotti D, Bolzani S, Castellazzi M, Tamborino C, Roversi G, Baldi E, Caniatti ML, Casetta I, Gentili V, Granieri E, Rizzo R, the ERMES study group, Granieri E, Castellazzi M, Casetta I, Tola MR, Fainardi E, Dallocchio F, Bellini T, Rizzo R, Rotola A, Di Luca D, Seraceni S, Contini C, Sabbioni S, Negrini M, Tognon M, Antonelli T, Groppo E, Gentile M, Baldi E, Caniatti ML, Ceruti S, Manfrinato MR, Trentini A, Bortolotti D, Miotto E, Ferracin M, Mazzoni E, Pietrobon S, Masini I, Rotondo JC, Martini F, Baruzzi A, Roberto D’Alessandro R, Michelucci R, Salvi F, Stecchi S, Scandellari C, Terzano G, Granella F, Nichelli P, Sola P, Ferraro D, Vitetta F, Simone AM, Bedin R, Marcello N, Motti L, Montepietra S, Guidetti D, Immovilli P, Montanari E, Pesci I, Guareschi A, Greco G, Santangelo M, Mauro AM, Malagù S, Rasi F, Spadoni M, Galeotti M, Fiorani L, Neri W, Ravasio A, Pasquinelli M, Gutman S, Monaldini C. Cerebrospinal fluid amounts of HLA-G in dimeric form are strongly associated to patients with MRI inactive multiple sclerosis. Mult Scler 2016; 22:245-249. [PMID: 26084349 DOI: 10.1177/1352458515590647] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 05/13/2015] [Indexed: 07/24/2024]
Abstract
Background: The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis. Methods: CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing–remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls. Results: CSF amounts of 78kDa HLA-G dimers were more frequent in RRMS than in inflammatory ( p<0.01) and non-inflammatory controls ( p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS ( p<0.00001). Conclusion: Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS.
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Affiliation(s)
- Enrico Fainardi
- Department of Neurosciences and Rehabilitation, Neuroradilogy Unit, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, Ferrara, Italy
| | - Daria Bortolotti
- Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, Ferrara, Italy
| | - Silvia Bolzani
- Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, Ferrara, Italy
| | - Massimiliano Castellazzi
- Department of Biomedical and Specialist Surgical Sciences, Section of Neurology, University of Ferrara, Ferrara, Italy
| | - Carmine Tamborino
- Department of Biomedical and Specialist Surgical Sciences, Section of Neurology, University of Ferrara, Ferrara, Italy
| | - Gloria Roversi
- Department of Biomedical and Specialist Surgical Sciences, Section of Neurology, University of Ferrara, Ferrara, Italy
| | - Eleonora Baldi
- Department of Neurosciences and Rehabilitation, Neurology Unit, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, Ferrara, Italy
| | - Maria Luisa Caniatti
- Department of Neurosciences and Rehabilitation, Neurology Unit, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, Ferrara, Italy
| | - Ilaria Casetta
- Department of Biomedical and Specialist Surgical Sciences, Section of Neurology, University of Ferrara, Ferrara, Italy
| | - Valentina Gentili
- Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, Ferrara, Italy
| | - Enrico Granieri
- Department of Biomedical and Specialist Surgical Sciences, Section of Neurology, University of Ferrara, Ferrara, Italy
| | - Roberta Rizzo
- Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, Ferrara, Italy
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Pankratz S, Ruck T, Meuth SG, Wiendl H. CD4(+)HLA-G(+) regulatory T cells: Molecular signature and pathophysiological relevance. Hum Immunol 2016; 77:727-33. [PMID: 26826445 DOI: 10.1016/j.humimm.2016.01.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 01/20/2016] [Indexed: 12/21/2022]
Abstract
The regulation of potentially harmful immune responses by regulatory T (Treg) cells is essential for maintaining peripheral immune tolerance and homeostasis. Especially CD4(+) Treg cells have been regarded as pivotal regulators of autoreactive and inflammatory responses as well as inducers of immune tolerance by using a variety of immune suppressive mechanisms. Besides the well-known classical CD4(+)CD25(+)FoxP3(+) Treg cells, CD4(+) T cells expressing the immune tolerizing molecule human leukocyte antigen G (HLA-G) have been recently described as another potent thymus-derived Treg (tTreg) cell subset. Albeit both tTreg subsets share common molecular characteristics, the mechanisms of their immunosuppressive function differ fundamentally. Dysfunction and numerical abnormalities of classical CD4(+) tTreg cells have been implicated in the pathogenesis of several immune-mediated diseases such as multiple sclerosis (MS). Clearly, a deeper understanding of the various CD4(+) tTreg subsets and also the underlying mechanisms of impaired immune tolerance in these disorders are essential for the development of potential therapeutic strategies. This review focuses on the current knowledge on defining features and functioning of HLA-G(+)CD4(+) tTreg cells as well as their emerging role in various pathologies with special emphasis on the pathogenesis of MS. Furthermore, future research possibilities together with potential therapeutic applications are discussed.
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Affiliation(s)
- Susann Pankratz
- Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.
| | - Tobias Ruck
- Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.
| | - Sven G Meuth
- Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.
| | - Heinz Wiendl
- Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.
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35
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Waschbisch A, Schröder S, Schraudner D, Sammet L, Weksler B, Melms A, Pfeifenbring S, Stadelmann C, Schwab S, Linker RA. Pivotal Role for CD16+ Monocytes in Immune Surveillance of the Central Nervous System. THE JOURNAL OF IMMUNOLOGY 2016; 196:1558-67. [PMID: 26746191 DOI: 10.4049/jimmunol.1501960] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 11/29/2015] [Indexed: 01/28/2023]
Abstract
Monocytes represent a heterogeneous population of primary immune effector cells. At least three different subsets can be distinguished based on expression of the low-affinity FcγRIII: CD14(++)CD16 -: classical monocytes, CD14(++)CD16(+) intermediate monocytes, and CD14(+)CD16 ++: non-classical monocytes. Whereas CD16 -: classical monocytes are considered key players in multiple sclerosis (MS), little is known on CD16(+) monocytes and how they contribute to the disease. In this study, we examined the frequency and phenotype of monocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF), and brain biopsy material derived from MS patients and controls. Furthermore, we addressed a possible monocyte dysfunction in MS and analyzed migratory properties of monocyte subsets using human brain microvascular endothelial cells. Our ex vivo studies demonstrated that CD16(+) monocyte subpopulations are functional but numerically reduced in the peripheral blood of MS patients. CD16(+) monocytes with an intermediate-like phenotype were found to be enriched in CSF and dominated the CSF monocyte population under noninflammatory conditions. In contrast, an inversed CD16(+) to CD16 -: CSF monocyte ratio was observed in MS patients with relapsing-remitting disease. Newly infiltrating, hematogenous CD16(+) monocytes were detected in a perivascular location within active MS lesions, and CD16(+) monocytes facilitated CD4(+) T cell trafficking in a blood -: brain barrier model. Our findings support an important role of CD16(+) monocytes in the steady-state immune surveillance of the CNS and suggest that CD16(+) monocytes shift to sites of inflammation and contribute to the breakdown of the blood-brain barrier in CNS autoimmune diseases.
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Affiliation(s)
- Anne Waschbisch
- Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Sina Schröder
- Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Dana Schraudner
- Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Laura Sammet
- Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Babette Weksler
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY 10065; and
| | - Arthur Melms
- Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Sabine Pfeifenbring
- Department of Neuropathology, University Medical Center, Georg August University Göttingen, 37075 Göttingen, Germany
| | - Christine Stadelmann
- Department of Neuropathology, University Medical Center, Georg August University Göttingen, 37075 Göttingen, Germany
| | - Stefan Schwab
- Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Ralf A Linker
- Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
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36
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An investigation into the association between HLA-G 14bp insertion/deletion polymorphism and multiple sclerosis susceptibility. J Neuroimmunol 2016; 290:115-8. [DOI: 10.1016/j.jneuroim.2015.11.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 11/11/2015] [Accepted: 11/23/2015] [Indexed: 11/18/2022]
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Alves BM, Prellwitz IM, Siqueira JD, Meyrelles ÂR, Bergmann A, Seuánez HN, Machado ES, Soares MA, Soares EA. The effect of human leukocyte antigen G alleles on human papillomavirus infection and persistence in a cohort of HIV-positive pregnant women from Brazil. INFECTION GENETICS AND EVOLUTION 2015; 34:339-43. [PMID: 26134300 DOI: 10.1016/j.meegid.2015.06.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 06/25/2015] [Accepted: 06/28/2015] [Indexed: 01/01/2023]
Abstract
Patients with compromised immune systems have more severe intraepithelial lesions and more rapid disease progression, in addition to increased risk for cervical cancer. Persistent infection by the human papillomavirus (HPV) is a necessary step in that process. By inducing expression of inhibitory ligands of natural killer cells, like HLA-G, HPV avoids the elimination of infected cells. Recent studies have investigated polymorphisms in HLA-G that may be associated with susceptibility to HPV infection and persistence. One hundred-forty HIV(+) pregnant women from Brazil had a DNA fragment comprising HLA-G exons 2-4 PCR-amplified, cloned, sequenced and analyzed for allele determination. Altogether, 22 alleles comprising 52 different genotypes were found. Four novel HLA-G alleles were characterized. We have not observed association of specific HLA-G alleles with HPV infection, but found a protective effect of the G:01:01:02 allele against the occurrence of intraepithelial lesions. In addition to describing new HLA-G alleles and defining new reference sequences, our data provide a better understanding of the impact of HLA-G alleles on HPV-related disease.
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Affiliation(s)
- Brunna M Alves
- Programa de Oncovirologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Isabel M Prellwitz
- Programa de Oncovirologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Juliana D Siqueira
- Programa de Oncovirologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Ângela R Meyrelles
- Instituto de Ginecologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Anke Bergmann
- Programa de Epidemiologia Clínica, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Héctor N Seuánez
- Programa de Genética, Instituto Nacional de Câncer, Rio de Janeiro, Brazil; Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Elizabeth S Machado
- Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcelo A Soares
- Programa de Oncovirologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil; Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Esmeralda A Soares
- Programa de Oncovirologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
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38
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Airas L. Hormonal and gender-related immune changes in multiple sclerosis. Acta Neurol Scand 2015; 132:62-70. [PMID: 26046561 DOI: 10.1111/ane.12433] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2015] [Indexed: 01/10/2023]
Abstract
Similarly to many other autoimmune diseases, multiple sclerosis (MS) is more common among women than men, and its incidence among women is rising. There are also qualitative differences in the disease course between men and women, with male patients experiencing increased disease progression, brain atrophy, and cognitive impairment. During pregnancy, women with MS typically have a greatly reduced relapse rate, whereas very soon after the delivery, the disease activity returns, often even at a higher level than seen in the prepregnancy year. The reasons for the increased postpartum activity are not entirely clear, but factors such as the abrupt decrease in estrogen levels immediately after the delivery and the loss of the immunosuppressive state of pregnancy are likely of importance. There is compelling evidence that estrogen, progesterone, and testosterone control MS pathology by influencing immune responses and by contributing to repair mechanisms in the nervous system. Hormones may thus offer important insights into MS disease prevention and treatment. In this review, the possible reasons for the sex bias in autoimmune diseases will be discussed. The pregnancy-related alterations in MS, including the effect of pregnancy on disease activity, long-term disability accumulation, and prevalence will be reviewed, as well as the hormonal and immunological mechanisms potentially underlying these changes. Finally, the present thinking on the effect of hormones on the changing incidence of MS will be elucidated.
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Affiliation(s)
- L. Airas
- Division of Clinical Neurosciences; Turku University Hospital; Turku Finland
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39
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Schmitt J, Eckardt S, Schlegel PG, Sirén AL, Bruttel VS, McLaughlin KJ, Wischhusen J, Müller AM. Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing. Mol Med 2015; 21:185-96. [PMID: 25811991 DOI: 10.2119/molmed.2014.00188] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 03/23/2015] [Indexed: 12/26/2022] Open
Abstract
Parent-of-origin imprints have been implicated in the regulation of neural differentiation and brain development. Previously we have shown that, despite the lack of a paternal genome, human parthenogenetic (PG) embryonic stem cells (hESCs) can form proliferating neural stem cells (NSCs) that are capable of differentiation into physiologically functional neurons while maintaining allele-specific expression of imprinted genes. Since biparental ("normal") hESC-derived NSCs (N NSCs) are targeted by immune cells, we characterized the immunogenicity of PG NSCs. Flow cytometry and immunocytochemistry revealed that both N NSCs and PG NSCs exhibited surface expression of human leukocyte antigen (HLA) class I but not HLA-DR molecules. Functional analyses using an in vitro mixed lymphocyte reaction assay resulted in less proliferation of peripheral blood mononuclear cells (PBMC) with PG compared with N NSCs. In addition, natural killer (NK) cells cytolyzed PG less than N NSCs. At a molecular level, expression analyses of immune regulatory factors revealed higher HLA-G levels in PG compared with N NSCs. In line with this finding, MIR152, which represses HLA-G expression, is less transcribed in PG compared with N cells. Blockage of HLA-G receptors ILT2 and KIR2DL4 on natural killer cell leukemia (NKL) cells increased cytolysis of PG NSCs. Together this indicates that PG NSCs have unique immunological properties due to elevated HLA-G expression.
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Affiliation(s)
- Jessica Schmitt
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, Würzburg, Germany
| | - Sigrid Eckardt
- Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America
| | - Paul G Schlegel
- University Children's Hospital Würzburg, Pediatric Hematology/Oncology, Würzburg, Germany
| | - Anna-Leena Sirén
- Department of Neurosurgery, Section for Experimental Tumor Immunology, University of Würzburg, Würzburg, Germany
| | - Valentin S Bruttel
- University of Würzburg Medical School, Department of Obstetrics and Gynecology, Section for Experimental Tumor Immunology, University of Würzburg, Würzburg, Germany
| | - K John McLaughlin
- Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America
| | - Jörg Wischhusen
- University of Würzburg Medical School, Department of Obstetrics and Gynecology, Section for Experimental Tumor Immunology, University of Würzburg, Würzburg, Germany
| | - Albrecht M Müller
- Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, Würzburg, Germany
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40
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Jiang F, Zhao H, Wang L, Guo X, Wang X, Yin G, Hu Y, Li Y, Yao Y. Role of HLA-G1 in trophoblast cell proliferation, adhesion and invasion. Biochem Biophys Res Commun 2015; 458:154-60. [DOI: 10.1016/j.bbrc.2015.01.085] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 01/18/2015] [Indexed: 01/21/2023]
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41
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Rizzo R, Bortolotti D, Bolzani S, Fainardi E. HLA-G Molecules in Autoimmune Diseases and Infections. Front Immunol 2014; 5:592. [PMID: 25477881 PMCID: PMC4235267 DOI: 10.3389/fimmu.2014.00592] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 11/04/2014] [Indexed: 01/22/2023] Open
Abstract
Human leukocyte antigen (HLA)-G molecule, a non-classical HLA-Ib molecule, is less polymorphic when compared to classical HLA class I molecules. Human leukocyte antigen-G (HLA-G) was first detected on cytotrophoblast cells at the feto-maternal interface but its expression is prevalent during viral infections and several autoimmune diseases. HLA-G gene is characterized by polymorphisms at the 3' un-translated region and 5' upstream regulatory region that regulate its expression and are associated with autoimmune diseases and viral infection susceptibility, creating an unbalanced and pathologic environment. This review focuses on the role of HLA-G genetic polymorphisms, mRNA, and protein expression in autoimmune conditions and viral infections.
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Affiliation(s)
- Roberta Rizzo
- Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Daria Bortolotti
- Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Silvia Bolzani
- Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Enrico Fainardi
- Neuroradiology Unit, Department of Neurosciences and Rehabilitation, Azienda Ospedaliera-Universitaria Arcispedale S. Anna, Ferrara, Italy
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42
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Teklemariam T, Zhao L, Hantash BM. Heterologous expression of mutated HLA-G1 reduces alloreactivity of human dermal fibroblasts. Regen Med 2014; 9:775-84. [DOI: 10.2217/rme.14.58] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To engineer a stable HLA-G molecule and evaluate its immunomodulatory properties in transgenic human dermal fibroblasts (HDFs). Materials & methods: A mutated HLA-G1 (mHLA-G1) molecule was generated by modifying the endoplasmic reticulum retrieval motif and 3′-untranslated region miRNA-binding sites of HLA-G1. Immunomodulatory properties of transgenic HDF-mHLA-G1 were evaluated in vitro. Results: Stable mHLA-G1 expressing HDF cells were successfully generated and flow cytometry analysis revealed that mHLA-G1 efficiently localized to the cell surface. Natural killer cell-mediated cytolysis of HDF-mHLA-G1/green fluorescent protein (GFP) was reduced by 73% compared with HDF-GDP. HDF-mHLA-G1/GFP decreased phytohemagglutinin-activated peripheral blood mononuclear cell proliferation by 30% versus HDF-GFP. Conclusion: We are the first to successfully create a human fibroblast source with reduced alloreactivity using a novel mHLA-G1 construct. This approach may be extended to other cell types including human embryonic stem cells for use in allogeneic transplantation for cell-based regenerative medicine applications.
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Affiliation(s)
| | | | - Basil M Hantash
- Escape Therapeutics, Inc., San Jose, CA, USA
- Elixir Institute of Regenerative Medicine, Inc., San Jose, CA, USA
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43
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Teklemariam T, Purandare B, Zhao L, Hantash BM. Inhibition of DNA methylation enhances HLA-G expression in human mesenchymal stem cells. Biochem Biophys Res Commun 2014; 452:753-9. [PMID: 25204503 DOI: 10.1016/j.bbrc.2014.08.152] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 08/28/2014] [Indexed: 01/08/2023]
Abstract
Mesenchymal stem cells (MSCs) are immunosuppressive multipotent cells under investigation for potential therapeutic applications in regenerative medicine and prevention of graft-versus-host disease. Human leukocyte antigen (HLA)-G contributes to the immunomodulatory properties of MSCs. HLA-G expression in MSCs is very low and diminishes during in vitro expansion. Epigenetic regulation activates HLA-G expression in some cancer cell lines but not in MSCs. In the present study, adipose- and bone marrow-derived MSCs were exposed to the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) and histone deacetylase inhibitor valproic acid (VPA) and HLA-G mRNA levels assessed using semi-quantitative reverse-transcription PCR. Exposure to 5-aza-dC resulted in HLA-G1 and -G3 upregulation in both early and late passage MSCs. VPA treatment did not induce HLA-G expression in both bone marrow and adipose derived MSCs. Our results provide the first evidence that HLA-G3 could be expressed in MSCs and that methylation-mediated repression is partly responsible for the observed low levels of HLA-G expression in MSCs. Our findings provide insight that treatment of MSCs with specific epigenetic regulatory modulators may improve their immunoregulatory capability for therapeutic applications.
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Affiliation(s)
| | | | - Longmei Zhao
- Escape Therapeutics, Inc., San Jose, CA, United States
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44
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Vergara VM, Ulloa A, Calhoun VD, Boutte D, Chen J, Liu J. A three-way parallel ICA approach to analyze links among genetics, brain structure and brain function. Neuroimage 2014; 98:386-94. [PMID: 24795156 DOI: 10.1016/j.neuroimage.2014.04.060] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 03/20/2014] [Accepted: 04/20/2014] [Indexed: 01/11/2023] Open
Abstract
Multi-modal data analysis techniques, such as the Parallel Independent Component Analysis (pICA), are essential in neuroscience, medical imaging and genetic studies. The pICA algorithm allows the simultaneous decomposition of up to two data modalities achieving better performance than separate ICA decompositions and enabling the discovery of links between modalities. However, advances in data acquisition techniques facilitate the collection of more than two data modalities from each subject. Examples of commonly measured modalities include genetic information, structural magnetic resonance imaging (MRI) and functional MRI. In order to take full advantage of the available data, this work extends the pICA approach to incorporate three modalities in one comprehensive analysis. Simulations demonstrate the three-way pICA performance in identifying pairwise links between modalities and estimating independent components which more closely resemble the true sources than components found by pICA or separate ICA analyses. In addition, the three-way pICA algorithm is applied to real experimental data obtained from a study that investigate genetic effects on alcohol dependence. Considered data modalities include functional MRI (contrast images during alcohol exposure paradigm), gray matter concentration images from structural MRI and genetic single nucleotide polymorphism (SNP). The three-way pICA approach identified links between a SNP component (pointing to brain function and mental disorder associated genes, including BDNF, GRIN2B and NRG1), a functional component related to increased activation in the precuneus area, and a gray matter component comprising part of the default mode network and the caudate. Although such findings need further verification, the simulation and in-vivo results validate the three-way pICA algorithm presented here as a useful tool in biomedical data fusion applications.
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Affiliation(s)
- Victor M Vergara
- The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM 87106, USA.
| | - Alvaro Ulloa
- The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM 87106, USA; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM 87131, USA
| | - Vince D Calhoun
- The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM 87106, USA; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM 87131, USA
| | - David Boutte
- The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM 87106, USA
| | - Jiayu Chen
- The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM 87106, USA
| | - Jingyu Liu
- The Mind Research Network and Lovelace Biomedical and Environmental Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM 87106, USA; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM 87131, USA
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45
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Bortolotti D, Gentili V, Rotola A, Cassai E, Rizzo R, Luca DD. Impact of HLA-G analysis in prevention, diagnosis and treatment of pathological conditions. World J Methodol 2014; 4:11-25. [PMID: 25237627 PMCID: PMC4145573 DOI: 10.5662/wjm.v4.i1.11] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 12/28/2013] [Accepted: 01/16/2014] [Indexed: 02/06/2023] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule that differs from classical HLA class I molecules by low polymorphism and tissue distribution. HLA-G is a tolerogenic molecule with an immune-modulatory and anti-inflammatory function on both innate and adaptative immunity. This peculiar characteristic of HLA-G has led to investigations of its role in pathological conditions in order to define possible uses in diagnosis, prevention and treatment. In recent years, HLA-G has been shown to have an important implication in different inflammatory and autoimmune diseases, pregnancy complications, tumor development and aggressiveness, and susceptibility to viral infections. In fact, HLA-G molecules have been reported to alternate at both genetic and protein level in different disease situations, supporting its crucial role in pathological conditions. Specific pathologies show altered levels of soluble (s)HLA-G and different HLA-G gene polymorphisms seem to correlate with disease. This review aims to update scientific knowledge on the contribution of HLA-G in managing pathological conditions.
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Association between an HLA-G 14 bp insertion/deletion polymorphism and non-segmental vitiligo in the Korean population. Arch Dermatol Res 2014; 306:577-82. [DOI: 10.1007/s00403-014-1459-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 02/11/2014] [Accepted: 02/18/2014] [Indexed: 01/14/2023]
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Naji A, Menier C, Morandi F, Agaugué S, Maki G, Ferretti E, Bruel S, Pistoia V, Carosella ED, Rouas-Freiss N. Binding of HLA-G to ITIM-Bearing Ig-like Transcript 2 Receptor Suppresses B Cell Responses. THE JOURNAL OF IMMUNOLOGY 2014; 192:1536-46. [DOI: 10.4049/jimmunol.1300438] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Comparison of IFN-β inducible gene expression in primary-progressive and relapsing-remitting multiple sclerosis. J Neuroimmunol 2013; 265:68-74. [DOI: 10.1016/j.jneuroim.2013.10.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 10/11/2013] [Accepted: 10/16/2013] [Indexed: 11/18/2022]
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Doridot L, Miralles F, Barbaux S, Vaiman D. Trophoblasts, invasion, and microRNA. Front Genet 2013; 4:248. [PMID: 24312123 PMCID: PMC3836020 DOI: 10.3389/fgene.2013.00248] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 10/30/2013] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) have recently become essential actors in various fields of physiology and medicine, especially as easily accessible circulating biomarkers, or as modulators of cell differentiation. To this respect, terminal differentiation of trophoblasts (the characteristic cells of the placenta in Therian mammals) into syncytiotrophoblast, villous trophoblast, or extravillous trophoblast constitutes a good example of such a choice, where miRNAs have recently been shown to play an important role. The aim of this review is to provide a snapshot of what is known today in placentation mechanisms that are mediated by miRNA, under the angles of materno–fetal immune dialog regulation, trophoblast differentiation, and angiogenesis at the materno–fetal interface. Also, two aspects of regulation of these issues will be highlighted: the part played by oxygen concentration and the specific function of imprinted genes in the developing placenta.
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Affiliation(s)
- Ludivine Doridot
- Institut Cochin, INSERM U1016-CNRS UMR8104, Université Paris Descartes Paris, France
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Morandi F, Venturi C, Rizzo R, Castellazzi M, Baldi E, Caniatti ML, Tola MR, Granieri E, Fainardi E, Uccelli A, Pistoia V. Intrathecal soluble HLA-E correlates with disease activity in patients with multiple sclerosis and may cooperate with soluble HLA-G in the resolution of neuroinflammation. J Neuroimmune Pharmacol 2013; 8:944-55. [PMID: 23625177 DOI: 10.1007/s11481-013-9459-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 04/04/2013] [Indexed: 11/29/2022]
Abstract
Expression and function of the immunoregulatory molecule HLA-E was investigated in patients with relapsing-remitting (RR) multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) soluble (s)HLA-E and -G levels were measured by ELISA in 80 RRMS patients. Controls were patients with other inflammatory neurological disorders (OIND, n = 81) and noninflammatory neurological disorders (NIND, n = 86). Serum sHLA-E concentrations were higher in RRMS than in NIND patients only. CSF sHLA-E concentrations were higher in RRMS than controls. Increased CSF sHLA-E levels were detected in MRI inactive and clinically stable RRMS patients. sHLA-E intrathecal synthesis (ITS) was higher in RRMS than controls, and the number of patients with sHLA-E ITS above cut-off was higher i) in MS than controls, and ii) in clinically stable than clinically active MS patients. sHLA-E CSF levels and ITS correlated with i) the same sHLA-G parameters, and ii) disease duration. HLA-E expression and co-expression with CD markers were investigated in MS plaques from three different cases by immunohistochemistry and confocal microscopy, respectively. Infiltrating T lymphocytes and macrophages, as well as resident microglial cells and astrocytes expressed HLA-E. CSF samples from MS patients were finally tested for inhibitory activity of in vitro CTL and NK cell mediated cytotoxicity. sHLA-E⁺ were more effective than sHLA-E⁻ CSF samples in such inhibition. Maximum inhibition was achieved with sHLA-E⁺/sHLA-G⁺ CSF samples In conclusion, increased sHLA-E CSF levels may play an immunomodulatory role in MS, contributing to the inhibition of intrathecal inflammatory response. The potential of sHLA-E as biomarker of MS activity warrants further investigation.
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Affiliation(s)
- Fabio Morandi
- Laboratory of Oncology, Instituto Giannina Gaslini, Via Gaslini 1, 16148 Genoa, Italy.
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