B Cell Checkpoints in Autoimmune Rheumatic Diseases
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Primary Sjogren Syndrome: Focus on Innate Immune Cells and Inflammation
Review Primary Sjogren Syndrome: Focus on Innate Immune Cells and Inflammation Chiara Rizzo 1, Giulia Grasso 1, Giulia Maria Destro Castaniti 1, Francesco Ciccia 2 and Giuliana Guggino 1,* 1 Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, Piazza delle Cliniche 2, 90110 Palermo, Italy; [email protected] (C.R.); [email protected] (G.G.); [email protected] (G.M.D.C.) 2 Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-091-6552260 Received: 30 April 2020; Accepted: 29 May 2020; Published: 3 June 2020 Abstract: Primary Sjogren Syndrome (pSS) is a complex, multifactorial rheumatic disease that mainly targets salivary and lacrimal glands, inducing epithelitis. The cause behind the autoimmunity outbreak in pSS is still elusive; however, it seems related to an aberrant reaction to exogenous triggers such as viruses, combined with individual genetic pre-disposition. For a long time, autoantibodies were considered as the hallmarks of this disease; however, more recently the complex interplay between innate and adaptive immunity as well as the consequent inflammatory process have emerged as the main mechanisms of pSS pathogenesis. The present review will focus on innate cells and on the principal mechanisms of inflammation connected. In the first part, an overview of innate cells involved in pSS pathogenesis is provided, stressing in particular the role of Innate Lymphoid Cells (ILCs). Subsequently we have highlighted the main inflammatory pathways, including intra- and extra-cellular players. -
Role of IL-4 Receptor &Alpha
Role of IL-4 receptor a–positive CD41 T cells in chronic airway hyperresponsiveness Frank Kirstein, PhD, Natalie E. Nieuwenhuizen, PhD,* Jaisubash Jayakumar, PhD, William G. C. Horsnell, PhD, and Frank Brombacher, PhD Cape Town, South Africa, and Berlin, Germany Background: TH2 cells and their cytokines are associated with IL-17–producing T cells and, consequently, increased airway allergic asthma in human subjects and with mouse models of neutrophilia. allergic airway disease. IL-4 signaling through the IL-4 receptor Conclusion: IL-4–responsive T helper cells are dispensable for 1 a (IL-4Ra) chain on CD4 T cells leads to TH2 cell acute OVA-induced airway disease but crucial in maintaining differentiation in vitro, implying that IL-4Ra–responsive CD41 chronic asthmatic pathology. (J Allergy Clin Immunol T cells are critical for the induction of allergic asthma. However, 2016;137:1852-62.) mechanisms regulating acute and chronic allergen-specific T 2 H Key words: responses in vivo remain incompletely understood. TH2 cell, acute allergic airway disease, chronic asthma, Objective: This study defines the requirements for IL-4Ra– cytokine receptors, IL-4, IL-13, gene-deficient mice responsive CD41 T cells and the IL-4Ra ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the Allergic asthma is a chronic inflammatory disease of the airways onset and chronic phase of experimental allergic airway disease. characterized by an inappropriate immune response to harmless Methods: Development of acute and chronic ovalbumin environmental antigens. T 2 cells regulate adaptive immune 1 H (OVA)–induced allergic asthma was assessed weekly in CD4 T responses to allergens, and their presence correlates with disease 2 cell–specific IL-4Ra–deficient BALB/c mice (LckcreIL-4Ra /lox) symptoms in human subjects and mice.1 IL-4 plays a crucial role and respective control mice in the presence or absence of IL-4 in the in vitro and in vivo differentiation of TH2 cells, suggesting or IL-13. -
Autoimmunity and Organ Damage in Systemic Lupus Erythematosus
REVIEW ARTICLE https://doi.org/10.1038/s41590-020-0677-6 Autoimmunity and organ damage in systemic lupus erythematosus George C. Tsokos ✉ Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune sys- tem contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigen- etic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique ‘interactome’, which will dictate specific treatment. t took almost 100 years to realize that lupus erythematosus, strongly to the heterogeneity of the disease. Several genes linked to which was initially thought to be a skin entity, is a systemic the immune response are regulated through long-distance chroma- Idisease that spares no organ and that an aberrant autoimmune tin interactions10,11. Studies addressing long-distance interactions response is involved in its pathogenesis. The involvement of vital between gene variants in SLE are still missing, but, with the advent organs and tissues such as the brain, blood and the kidney in most of new technologies, such studies will emerge. patients, the vast majority of whom are women of childbearing age, Better understanding of the epigenome is needed to under- impels efforts to develop diagnostic tools and effective therapeu- stand how it supplements the genetic contribution to the dis- tics. The prevalence ranges from 20 to 150 cases per 100,000 peo- ease. -
Inhibition of Midkine Alleviates Experimental Autoimmune Encephalomyelitis Through the Expansion of Regulatory T Cell Population
Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population Jinyan Wang*, Hideyuki Takeuchi*†, Yoshifumi Sonobe*, Shijie Jin*, Tetsuya Mizuno*, Shin Miyakawa‡, Masatoshi Fujiwara‡, Yoshikazu Nakamura§¶, Takuma Katoʈ, Hisako Muramatsu**, Takashi Muramatsu**††, and Akio Suzumura*† *Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; ‡RIBOMIC, Inc., 3-15-5-601 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan; §Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; ¶Core Research Evolutional Science and Technology, Japan Science and Technology Agency, Toyonaka, Osaka 560-8531, Japan; ʈDepartment of Bioregulation, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan; **Department of Biochemistry, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; and ††Department of Health Science, Faculty of Psychological and Physical Sciences, Aichi Gakuin University, Nisshin, Aichi 470-0195, Japan Edited by Ethan Shevach, National Institutes of Health, Bethesda, MD, and accepted by the Editorial Board January 20, 2008 (received for review October 12, 2007) CD4؉CD25؉ regulatory T (Treg) cells are crucial mediators of nity, and abnormalities in Treg cell function may contribute to the autoimmune tolerance. The factors that regulate Treg cells, how- development of -
Pathophysiology of Immune Thrombocytopenic Purpura: a Bird's-Eye View
Egypt J Pediatr Allergy Immunol 2014;12(2):49-61. Review article Pathophysiology of immune thrombocytopenic purpura: a bird's-eye view. Amira Abdel Moneam Adly Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt ABSTRACT and B lymphocytes (including T-helper, T- Immune thrombocytopenic purpura (ITP) is a cytotoxic, and T-regulatory lymphocytes) 6. common autoimmune disorder resulting in isolated The triggering event for ITP is unknown7, but thrombocytopenia. It is a bleeding disorder continued research is providing new insights into characterized by low platelet counts due to decreased the underlying immunopathogenic processes as well platelet production as well as increased platelet as the cellular and molecular mechanisms involved destruction by autoimmune mechanisms. ITP can in megakaryocytopoiesis and platelet turnover. present either alone (primary) or in the setting of other Although historically ITP-associated thrombo- conditions (secondary) such as infections or altered cytopenia was attributed solely to increased rates of immune states. ITP is associated with a loss of destruction of antibody- coated platelets, it has tolerance to platelet antigens and a phenotype of become evident that suboptimal platelet production accelerated platelet destruction and impaired platelet also plays a role 8. production. Although the etiology of ITP remains Bleeding is due to decreased platelet production unknown, complex dysregulation of the immune as well as accelerated platelet destruction mediated system is observed in ITP patients. Antiplatelet in part by autoantibody-based destruction antibodies mediate accelerated clearance from the mechanisms9. Most autoantibodies in ITP are circulation in large part via the reticuloendothelial isotype switched and harbor somatic mutations10, (monocytic phagocytic) system. -
Molecules with Specificity for Cd45 and Cd79 Moleküle Mit Cd45- Und Cd79-Spezifizität Molécules Présentant Une Spécificité Vis-À-Vis De Cd45 Et Cd79
(19) *EP003169704B1* (11) EP 3 169 704 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 16/28 (2006.01) 29.07.2020 Bulletin 2020/31 (86) International application number: (21) Application number: 15738655.8 PCT/EP2015/066368 (22) Date of filing: 16.07.2015 (87) International publication number: WO 2016/009029 (21.01.2016 Gazette 2016/03) (54) MOLECULES WITH SPECIFICITY FOR CD45 AND CD79 MOLEKÜLE MIT CD45- UND CD79-SPEZIFIZITÄT MOLÉCULES PRÉSENTANT UNE SPÉCIFICITÉ VIS-À-VIS DE CD45 ET CD79 (84) Designated Contracting States: • WRIGHT, Michael John AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Slough GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Berkshire SL1 3WE (GB) PL PT RO RS SE SI SK SM TR • TYSON, Kerry Designated Extension States: Slough BA ME Berkshire SL1 3WE (GB) Designated Validation States: MA (74) Representative: UCB Intellectual Property c/o UCB Celltech (30) Priority: 16.07.2014 GB 201412659 IP Department 208 Bath Road (43) Date of publication of application: Slough, Berkshire SL1 3WE (GB) 24.05.2017 Bulletin 2017/21 (56) References cited: (73) Proprietor: UCB Biopharma SRL WO-A1-2011/025904 WO-A1-2013/085893 1070 Brussels (BE) • GOLD ET AL.: "The B Cell Antigen Receptor (72) Inventors: Activates the AKT/Glycogegn Synthase Kinase-3 • FINNEY, Helene Margaret Signalling Pathway via Phosphatydilinositol Slough 3-Kinase", J. IMMUNOLOGY, vol. 163, 1999, Berkshire SL1 3WE (GB) pages 1894-1905, XP002745175, • RAPECKI, Stephen Edward Slough Berkshire SL1 3WE (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. -
B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells
cells Review B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells Carlo G. Bonasia 1 , Wayel H. Abdulahad 1,2 , Abraham Rutgers 1, Peter Heeringa 2 and Nicolaas A. Bos 1,* 1 Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, 9713 Groningen, GZ, The Netherlands; [email protected] (C.G.B.); [email protected] (W.H.A.); [email protected] (A.R.) 2 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 Groningen, GZ, The Netherlands; [email protected] * Correspondence: [email protected] Abstract: Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. Citation: Bonasia, C.G.; Abdulahad, W.H.; Rutgers, A.; Heeringa, P.; Bos, In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive N.A. B Cell Activation and Escape of B cells in autoimmune diseases. Tolerance Checkpoints: Recent Insights from Studying Autoreactive Keywords: autoimmune diseases; B cells; autoreactive B cells; tolerance B Cells. Cells 2021, 10, 1190. https:// doi.org/10.3390/cells10051190 Academic Editor: Juan Pablo de 1. -
List of Genes Used in Cell Type Enrichment Analysis
List of genes used in cell type enrichment analysis Metagene Cell type Immunity ADAM28 Activated B cell Adaptive CD180 Activated B cell Adaptive CD79B Activated B cell Adaptive BLK Activated B cell Adaptive CD19 Activated B cell Adaptive MS4A1 Activated B cell Adaptive TNFRSF17 Activated B cell Adaptive IGHM Activated B cell Adaptive GNG7 Activated B cell Adaptive MICAL3 Activated B cell Adaptive SPIB Activated B cell Adaptive HLA-DOB Activated B cell Adaptive IGKC Activated B cell Adaptive PNOC Activated B cell Adaptive FCRL2 Activated B cell Adaptive BACH2 Activated B cell Adaptive CR2 Activated B cell Adaptive TCL1A Activated B cell Adaptive AKNA Activated B cell Adaptive ARHGAP25 Activated B cell Adaptive CCL21 Activated B cell Adaptive CD27 Activated B cell Adaptive CD38 Activated B cell Adaptive CLEC17A Activated B cell Adaptive CLEC9A Activated B cell Adaptive CLECL1 Activated B cell Adaptive AIM2 Activated CD4 T cell Adaptive BIRC3 Activated CD4 T cell Adaptive BRIP1 Activated CD4 T cell Adaptive CCL20 Activated CD4 T cell Adaptive CCL4 Activated CD4 T cell Adaptive CCL5 Activated CD4 T cell Adaptive CCNB1 Activated CD4 T cell Adaptive CCR7 Activated CD4 T cell Adaptive DUSP2 Activated CD4 T cell Adaptive ESCO2 Activated CD4 T cell Adaptive ETS1 Activated CD4 T cell Adaptive EXO1 Activated CD4 T cell Adaptive EXOC6 Activated CD4 T cell Adaptive IARS Activated CD4 T cell Adaptive ITK Activated CD4 T cell Adaptive KIF11 Activated CD4 T cell Adaptive KNTC1 Activated CD4 T cell Adaptive NUF2 Activated CD4 T cell Adaptive PRC1 Activated -
Immunomodulation and Generation of Tolerogenic Dendritic Cells by Probiotic Bacteria in Patients with Inflammatory Bowel Disease
International Journal of Molecular Sciences Article Immunomodulation and Generation of Tolerogenic Dendritic Cells by Probiotic Bacteria in Patients with Inflammatory Bowel Disease 1, 2, 1 Shaghayegh Baradaran Ghavami y, Abbas Yadegar y , Hamid Asadzadeh Aghdaei , Dario Sorrentino 3,4,*, Maryam Farmani 1 , Adil Shamim Mir 5, Masoumeh Azimirad 2 , Hedieh Balaii 6, Shabnam Shahrokh 6 and Mohammad Reza Zali 6 1 Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; [email protected] (S.B.G.); [email protected] (H.A.A.); [email protected] (M.F.) 2 Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; [email protected] (A.Y.); [email protected] (M.A.) 3 IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA 4 Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, 33100 Udine, Italy 5 Department of Internal Medicine, Roanoke Memorial Hospital, Carilion Clinic, VA 24014, USA; [email protected] 6 Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; [email protected] (H.B.); [email protected] (S.S.); [email protected] (M.R.Z.) * Correspondence: [email protected] These authors equally contributed to this study. y Received: 7 August 2020; Accepted: 27 August 2020; Published: 29 August 2020 Abstract: In inflammatory bowel diseases (IBD), the therapeutic benefit and mucosal healing from specific probiotics may relate to the modulation of dendritic cells (DCs). -
Galectin-4 Interaction with CD14 Triggers the Differentiation of Monocytes Into Macrophage-Like Cells Via the MAPK Signaling Pathway
Immune Netw. 2019 Jun;19(3):e17 https://doi.org/10.4110/in.2019.19.e17 pISSN 1598-2629·eISSN 2092-6685 Original Article Galectin-4 Interaction with CD14 Triggers the Differentiation of Monocytes into Macrophage-like Cells via the MAPK Signaling Pathway So-Hee Hong 1,2,3,4,5, Jun-Seop Shin 1,2,3,5, Hyunwoo Chung 1,2,4,5, Chung-Gyu Park 1,2,3,4,5,* 1Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul 03080, Korea 2Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul 03080, Korea 3Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea 4Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea 5Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea Received: Jan 28, 2019 ABSTRACT Revised: May 13, 2019 Accepted: May 19, 2019 Galectin-4 (Gal-4) is a β-galactoside-binding protein mostly expressed in the gastrointestinal *Correspondence to tract of animals. Although intensive functional studies have been done for other galectin Chung-Gyu Park isoforms, the immunoregulatory function of Gal-4 still remains ambiguous. Here, we Department of Microbiology and Immunology, Seoul National University College of Medicine, demonstrated that Gal-4 could bind to CD14 on monocytes and induce their differentiation 103 Daehak-ro, Jongno-gu, Seoul 03080, into macrophage-like cells through the MAPK signaling pathway. Gal-4 induced the phenotypic Korea. changes on monocytes by altering the expression of various surface molecules, and induced E-mail: [email protected] functional changes such as increased cytokine production and matrix metalloproteinase expression and reduced phagocytic capacity. -
New Biological Therapies: Introduction to the Basis of the Risk of Infection
New biological therapies: introduction to the basis of the risk of infection Mario FERNÁNDEZ RUIZ, MD, PhD Unit of Infectious Diseases Hospital Universitario “12 de Octubre”, Madrid ESCMIDInstituto de Investigación eLibraryHospital “12 de Octubre” (i+12) © by author Transparency Declaration Over the last 24 months I have received honoraria for talks on behalf of • Astellas Pharma • Gillead Sciences • Roche • Sanofi • Qiagen Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Paul Ehrlich (1854-1915) • “side-chain” theory (1897) • receptor-ligand concept (1900) • “magic bullet” theory • foundation for specific chemotherapy (1906) • Nobel Prize in Physiology and Medicine (1908) (together with Metchnikoff) Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author 1981: B-1 antibody (tositumomab) anti-CD20 monoclonal antibody 1997: FDA approval of rituximab for the treatment of relapsed or refractory CD20-positive NHL 2001: FDA approval of imatinib for the treatment of chronic myelogenous leukemia Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Functional classification of targeted (biological) agents • Agents targeting soluble immune effector molecules • Agents targeting cell surface receptors -
Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.