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Oral Tolerance: Therapeutic Implications for Autoimmune Diseases
Clinical & Developmental Immunology, June–December 2006; 13(2–4): 143–157 Oral tolerance: Therapeutic implications for autoimmune diseases ANA M. C. FARIA1 & HOWARD L. WEINER2 1Departamento de Bioquı´mica e Imunologia, Instituto de Cieˆncias Biolo´gicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil, and 2Harvard Medical School, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA Abstract Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-b) regulatory T cells (Tregs) plus CD4þCD25þ regulatory cells and LAPþT cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-b, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. -
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. -
The Distribution of Immune Cells in the Uveal Tract of the Normal Eye
THE DISTRIBUTION OF IMMUNE CELLS IN THE UVEAL TRACT OF THE NORMAL EYE PAUL G. McMENAMIN Perth, Western Australia SUMMARY function of these cells in the normal iris, ciliary body Inflammatory and immune-mediated diseases of the and choroid. The role of such cell types in ocular eye are not purely the consequence of infiltrating inflammation, which will be discussed by other inflammatory cells but may be initiated or propagated authors in this issue, is not the major focus of this by immune cells which are resident or trafficking review; however, a few issues will be briefly through the normal eye. The uveal tract in particular considered where appropriate. is the major site of many such cells, including resident tissue macro phages, dendritic cells and mast cells. This MACRO PHAGES review considers the distribution and location of these and other cells in the iris, ciliary body and choroid in Mononuclear phagocytes arise from bone marrow the normal eye. The uveal tract contains rich networks precursors and after a brief journey in the blood as of both resident macrophages and MHe class 11+ monocytes immigrate into tissues to become macro dendritic cells. The latter appear strategically located to phages. In their mature form they are widely act as sentinels for capturing and sampling blood-borne distributed throughout the body. Macrophages are and intraocular antigens. Large numbers of mast cells professional phagocytes and play a pivotal role as are present in the choroid of most species but are effector cells in cell-mediated immunity and inflam virtually absent from the anterior uvea in many mation.1 In addition, due to their active secretion of a laboratory animals; however, the human iris does range of important biologically active molecules such contain mast cells. -
Pathway in the Thymus by a CD24-Dependent Autoreactive T
Autoreactive T Cells Escape Clonal Deletion in the Thymus by a CD24-Dependent Pathway This information is current as Joseph W. Carl, Jr., Jin-Qing Liu, Pramod S. Joshi, Hani Y. of September 27, 2021. El-Omrani, Lijie Yin, Xincheng Zheng, Caroline C. Whitacre, Yang Liu and Xue-Feng Bai J Immunol 2008; 181:320-328; ; doi: 10.4049/jimmunol.181.1.320 http://www.jimmunol.org/content/181/1/320 Downloaded from References This article cites 54 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/181/1/320.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Autoreactive T Cells Escape Clonal Deletion in the Thymus by a CD24-Dependent Pathway1 Joseph W. Carl, Jr.,* Jin-Qing Liu,* Pramod S. -
Eosinophil Extracellular Traps and Inflammatory Pathologies—Untangling the Web!
REVIEW published: 26 November 2018 doi: 10.3389/fimmu.2018.02763 Eosinophil Extracellular Traps and Inflammatory Pathologies—Untangling the Web! Manali Mukherjee 1*, Paige Lacy 2 and Shigeharu Ueki 3 1 Department of Medicine, McMaster University and St Joseph’s Healthcare, Hamilton, ON, Canada, 2 Department of Medicine, Alberta Respiratory Centre, University of Alberta, Edmonton, AB, Canada, 3 Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan Eosinophils are an enigmatic white blood cell, whose immune functions are still under intense investigation. Classically, the eosinophil was considered to fulfill a protective role against parasitic infections, primarily large multicellular helminths. Although eosinophils are predominantly associated with parasite infections, evidence of a role for eosinophils in mediating immunity against bacterial, viral, and fungal infections has been recently reported. Among the mechanisms by which eosinophils are proposed to exert their protective effects is the production of DNA-based extracellular traps (ETs). Remarkably, Edited by: DNA serves a role that extends beyond its biochemical function in encoding RNA and Moncef Zouali, protein sequences; it is also a highly effective substance for entrapment of bacteria Institut National de la Santé et de la and other extracellular pathogens, and serves as valuable scaffolding for antimicrobial Recherche Médicale (INSERM), France mediators such as granule proteins from immune cells. Extracellular -
Natural Killer T Cells Are Required for the Development of a Superantigen-Driven T Helper Type 2 Immune Response in Mice
IMMUNOLOGY ORIGINAL ARTICLE Natural killer T cells are required for the development of a superantigen-driven T helper type 2 immune response in mice Auro Nomizo,1 Edilberto Postol,2 Summary Raquel de Alencar,2 Fabı´ola We show, here, that one single injection or weekly injections of staphylo- Cardillo2 and Jose´ Mengel2 coccal enterotoxin B (SEB), starting in 1-day-old newborn mice, induced 1Department of Clinical Analysis, Toxicology a powerful immune response with a T helper type 2 (Th2) pattern, as and Bromatology, Faculty of Pharmaceutical Sciences of Ribeira˜o Preto, University of Sa˜o judged by the isotype and cytokine profile, with the production of large Paulo, Ribeira˜o Preto, and 2Department of amounts of SEB-specific immunoglobulin G1 (IgG1), detectable levels of Immunology, Institute of Biomedical Sciences, SEB-specific IgE and increased production of interleukin-4 by spleen cells. University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil These protocols also induced an increase in the levels of total IgE in the serum. Memory of SEB was transferred to secondary recipients by using total spleen cells from primed animals. The secondary humoral response in transferred mice was diminished if spleen cells from SEB-treated mice were previously depleted of CD3+ or Vb8+ T cells or NK1.1+ cells. In vivo depletion of NK1.1+ cells in adult mice resulted in a marked reduction in the SEB-specific antibody response in both the primary and secondary doi:10.1111/j.1365-2567.2005.02215.x immune responses. Additionally, purified NK1.1+ T cells were able to per- Received 11 April 2005; revised 23 May 2005; form SEB-specific helper B-cell actions in vitro and in vivo. -
Tolerance to Allergens: How It Develops and How It Can Be Induced
Session 2101 Plenary: Immunotherapy: Mechanism, Outcomes and Markers Tolerance to Allergens: How it Develops and How it Can be Induced Cezmi A. Akdis, MD Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland Corresponding author: Cezmi A. Akdis, MD Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos Address E-mail: [email protected] Tel.: + 41 81 4100848 Fax: + 41 81 4100840 Acknowledgments: The authors' laboratories are supported by the Swiss National Foundation grant 320030_132899 and Christine Kühne Center for Allergy Research and Education (CK-CARE). ABSTRACT The induction of immune tolerance and specific immune suppression are essential processes in the control of immune responses. Allergen immunotherapy induces early desensitization and peripheral T cell tolerance to allergens associated with development of Treg and Breg cells, and downregulation of several allergic and inflammatory aspects of effector subsets of T cells, B cells, basophils, mast cells and eosinophils. Similar molecular and cellular mechanisms have been observed in subcutaneous and sublingual AIT as well as natural tolerance to high doses of allergen exposure. In allergic disease, the balance between allergen-specific Treg and disease-promoting T helper 2 cells (Th2) appears to be decisive in the development of an allergic versus a non-disease promoting or “healthy” immune response against allergen. Treg specific for common environmental allergens represent the dominant subset in healthy individuals arguing for a state of natural tolerance to allergen in these individuals. In contrast, there is a high frequency of allergen-specific Th2 cells in allergic individuals. Treg function appears to be impaired in active allergic disease. -
B Lymphocytes in Neuromyelitis Optica
VIEWS & REVIEWS B lymphocytes in neuromyelitis optica Jeffrey L. Bennett, MD, ABSTRACT PhD Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the CNS that predomi- ’ Kevin C. O Connor, PhD nantly affects the spinal cord and optic nerves. A majority (approximately 75%) of patients with Amit Bar-Or, MD, FRCP NMO are seropositive for autoantibodies against the astrocyte water channel aquaporin-4 Scott S. Zamvil, MD, (AQP4). These autoantibodies are predominantly IgG1, and considerable evidence supports their PhD pathogenicity, presumably by binding to AQP4 on CNS astrocytes, resulting in astrocyte injury Bernhard Hemmer, MD and inflammation. Convergent clinical and laboratory-based investigations have indicated that Thomas F. Tedder, PhD B cells play a fundamental role in NMO immunopathology. Multiple mechanisms have been H.-Christian von hypothesized: AQP4 autoantibody production, enhanced proinflammatory B cell and plasmablast Büdingen, MD activity, aberrant B cell tolerance checkpoints, diminished B cell regulatory function, and loss of Olaf Stuve, MD, PhD B cell anergy. Accordingly, many current off-label therapies for NMO deplete B cells or modulate Michael R. Yeaman, PhD their activity. Understanding the role and mechanisms whereby B cells contribute to initiation, Terry J. Smith, MD maintenance, and propagation of disease activity is important to advancing our understanding Christine Stadelmann, of NMO pathogenesis and developing effective disease-specific therapies. Neurol Neuroimmunol MD Neuroinflamm 2015;2:e104; -
Proapoptotic Protein Bim Is Differentially Required During Thymic Clonal Deletion to Ubiquitous Versus Tissue-Restricted Antigens
Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens Alexander Y. W. Suen and Troy A. Baldwin1 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada T6G 2S2 Edited by Michael J. Bevan, University of Washington, Seattle, WA, and approved December 8, 2011 (received for review September 8, 2011) Positive and negative selection of thymocytes in the thymus are positively selected by high-affinity antigen encounter in the thy- critical for the development of a mature and self-tolerant T-cell mus (6). One such example are T-regulatory (Treg) cells, which repertoire. The proapoptotic Bcl-2 family member Bim is important are believed to require high-affinity interactions to develop in the for negative selection by inducing apoptosis in thymocytes receiv- medulla (7). It remains unknown what drives this distinction ing a strong signal through their antigen receptor. However, in the between negative selection and Treg development, although case of ubiquitous self-antigens (UbA), Bim is not required for the secondary signals, such as TGF-β, may play a role in overcoming clonal deletion of self-reactive thymocytes, suggesting the exis- cell death (8). tence of nonapoptotic clonal deletion mechanisms. Unlike UbA, Although it is unclear how the same TCR can transduce a sig- clonal deletion to tissue-restricted antigens (TRAs) requires posi- nal for positive or negative selection, differential mitogen-acti- tive selection and CCR7-mediated migration to the medulla. This vated protein kinase signaling appears to play a role, ultimately led us to hypothesize that Bim is required for the latter. -
Prenatal Allospecific NK Cell Tolerance Hinges on Instructive
Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development This information is current as of September 23, 2021. Amir M. Alhajjat, Beverly S. Strong, Amanda E. Lee, Lucas E. Turner, Ram K. Wadhwani, John R. Ortaldo, Jonathan W. Heusel and Aimen F. Shaaban J Immunol 2015; 195:1506-1516; Prepublished online 1 July 2015; Downloaded from doi: 10.4049/jimmunol.1500463 http://www.jimmunol.org/content/195/4/1506 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/07/01/jimmunol.150046 Material 3.DCSupplemental References This article cites 45 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/195/4/1506.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development Amir M. -
T-Cell Tolerance by Prof. Anand Prakash
PROF. ANAND PRAKASH Department of Biotechnology Mahatma Gandhi Central University Motihari Bihar • Immature T-Cells enter in the thymus after differentiating in the bone marrow. • These T-cells undergo maturation and develop TCRs through Somatic Recombination. Bone Marrow Precursors of the T-Cells enter from Bone marrow to THYMUS thymus T Cell Maturation starts Expression of TCR s • DEVELOPMENT OF T-CELL RECEPTORS (TCRs) Some of T-Cells in the thymus develop receptors which are useless with no antigen specificity and while others develop TCRs with • specificity for self antigens and non-self antigens. Thymocytes having TCRs with low affinity for auto antigens, displayed in the MHC class I and II, undergo positive selection and further differentiate to become part of adaptive immunity, whereas the one with non-functional receptors die off because of • negligence. Clonal deletion of T-cells with useless TCRs and high affinity receptors along with clonal diversion for development of “Treg”, are the major processes operative in the thymus towards elimination or regulation of self-reactive T cells. INSIDE THE THYMUS THE T-CELLS UNDERGO AN ELABORATE SCREENING PROCEDURE3 THROUGH FOLLOWING MECHANISMS • • • T CELLS RECOGNIZE ANTIGEN DERIVED PEPTIDES PRESENTED BY MHC MOLECULES MHC Class II MHC Class I Antigen Infected or Presenting Tumour Cell Cell CD8 Peptide CD4 CD4+ CD8+ Helper Cell Cytotoxic T Cell T Cell Receptor T Cell Receptor T CELLS RECOGNIZE ANTIGEN DERIVED PEPTIDES PRESENTED BY MHC MOLECULES Inside Thymus THYMIC T -CELL FATE IS DETERMINED BY STRENGTH OF TCR-MHC/PEPTIDE INTERACTION Thymic MHC stromal Cell Thymic T Cell TCR + CD4 CD8 • NEGATIVE SELECTION Negative selection occurs at the Double positive stage in the thymic cortex, or at the Single Positive stage in the thymic medulla. -
Regulation of Eosinophilia and Allergic Airway Inflammation by The
Regulation of eosinophilia and allergic airway PNAS PLUS inflammation by the glycan-binding protein galectin-1 Xiao Na Gea, Sung Gil Haa, Yana G. Greenberga, Amrita Raoa, Idil Bastana, Ada G. Blidnerb, Savita P. Raoa, Gabriel A. Rabinovichb,c,1, and P. Sriramaraoa,d,1,2 aDepartment of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108; bLaboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina; cFacultad de Ciencias Exactas y d Naturales, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina; and Department of Medicine, University of Minnesota, Minneapolis, SEE COMMENTARY MN 55455 Edited by Jorge Geffner, UBA-CONICET, Buenos Aires, Argentina, and accepted by Editorial Board Member Lawrence Steinman June 13, 2016 (received for review February 4, 2016) Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflamma- morphonuclear cells (PMNs), macrophages, dendritic cells tory activities, functions as a proresolving mediator in autoimmune (DCs), activated T cells, stromal cells, endothelial cells, and and chronic inflammatory disorders. However, its role in allergic epithelial cells (5, 6). At a cellular level, Gal-1 may act either airway inflammation has not yet been elucidated. We evaluated the intracellularly or extracellularly, and is profoundly involved in effects of Gal-1 on eosinophil function and its role in a mouse model resolving acute and chronic inflammation by affecting processes of allergic asthma. Allergen exposureresultedinairwayrecruitment such as immune cell adhesion, migration, activation, signaling, of Gal-1–expressing inflammatory cells, including eosinophils, as well proliferation, differentiation, and apoptosis (5, 7). Increasing evi- as increased Gal-1 in extracellular spaces in the lungs.