1 the Immune System
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IFM Innate Immunity Infographic
UNDERSTANDING INNATE IMMUNITY INTRODUCTION The immune system is comprised of two arms that work together to protect the body – the innate and adaptive immune systems. INNATE ADAPTIVE γδ T Cell Dendritic B Cell Cell Macrophage Antibodies Natural Killer Lymphocites Neutrophil T Cell CD4+ CD8+ T Cell T Cell TIME 6 hours 12 hours 1 week INNATE IMMUNITY ADAPTIVE IMMUNITY Innate immunity is the body’s first The adaptive, or acquired, immune line of immunological response system is activated when the innate and reacts quickly to anything that immune system is not able to fully should not be present. address a threat, but responses are slow, taking up to a week to fully respond. Pathogen evades the innate Dendritic immune system T Cell Cell Through antigen Pathogen presentation, the dendritic cell informs T cells of the pathogen, which informs Macrophage B cells B Cell B cells create antibodies against the pathogen Macrophages engulf and destroy Antibodies label invading pathogens pathogens for destruction Scientists estimate innate immunity comprises approximately: The adaptive immune system develops of the immune memory of pathogen exposures, so that 80% system B and T cells can respond quickly to eliminate repeat invaders. IMMUNE SYSTEM AND DISEASE If the immune system consistently under-responds or over-responds, serious diseases can result. CANCER INFLAMMATION Innate system is TOO ACTIVE Innate system NOT ACTIVE ENOUGH Cancers grow and spread when tumor Certain diseases trigger the innate cells evade detection by the immune immune system to unnecessarily system. The innate immune system is respond and cause excessive inflammation. responsible for detecting cancer cells and This type of chronic inflammation is signaling to the adaptive immune system associated with autoimmune and for the destruction of the cancer cells. -
Environments of Haematopoiesis and B-Lymphopoiesis in Foetal Liver K
Environments of haematopoiesis and B-lymphopoiesis in foetal liver K. Kajikhina1, M. Tsuneto1,2, F. Melchers1 1Max Planck Fellow Research Group ABSTRACT potent myeloid/lymphoid progenitors on “Lymphocyte Development”, In human and murine embryonic de- (MPP), and their immediate progeny, Max Planck Institute for Infection velopment, haematopoiesis and B-lym- common myeloid progenitors (CMP) Biology, Berlin, Germany; phopoiesis show stepwise differentia- and common lymphoid progenitors 2Department of Stem Cell and Developmental Biology, Mie University tion from pluripotent haematopoietic (CLP) soon thereafter (10). The first Graduate School of Medicine, Tsu, Japan. stem cells and multipotent progenitors, T- or B-lymphoid lineage-directed pro- Katja Kajikhina over lineage-restricted lymphoid and genitors appear at E12.5-13.5, for T- Motokazu Tsuneto, PhD myeloid progenitors to B-lineage com- lymphocytes in the developing thymus Fritz Melchers, PhD mitted precursors and finally differenti- (11), for B-lymphocytes in foetal liver Please address correspondence to: ated pro/preB cells. This wave of dif- (12). Time in development, therefore, Fritz Melchers, ferentiation is spatially and temporally separates and orders these different Max Planck Fellow Research Group organised by the surrounding, mostly developmental haematopoietic stages. on “Lymphocyte Development”, non-haematopoietic cell niches. We re- Three-dimensional imaging of progen- Max Planck Institute for Infection Biology, view here recent developments and our itors and precursors indicates that stem Chariteplatz 1, current contributions on the research D-10117 Berlin, Germany. cells are mainly found inside the em- E-mail: [email protected] on blood cell development. bryonic blood vessel, and are attracted Received and accepted on August 28, 2015. -
An Essential Role of UBXN3B in B Lymphopoiesis Tingting Geng Et Al. This File Contains 9 Supplemental Figures and Legends
An Essential Role of UBXN3B in B Lymphopoiesis Tingting Geng et al. This file contains 9 supplemental figures and legends. a Viral load (relative) load Viral Serum TNF-α b +/+ Serum IL-6 Ubxn3b Ubxn3b-/- Ubxn3b+/+ 100 100 ** Ubxn3b-/- ** 10 10 IL-6 IL-6 (pg/ml) GM-CSF (pg/ml) GM-CSF 1 1 0 3 8 14 35 0 3 8 14 35 Time post infection (Days) Time post infection (Days) Serum IL-10 Serum CXCL10 Ubxn3b+/+ Ubxn3b-/- 10000 1000 +/+ -/- * Ubxn3b Ubxn3b 1000 100 IFN-γ (pg/ml) CXCL10 (pg/ml) CXCL10 100 10 0 3 8 14 35 0 3 8 14 35 Time post infection (Days) Time post infection (Days) IL-1β IL-1β (pg/ml) Supplemental Fig.s1 UBXN3B is essential for controlling SARS-CoV-2 pathogenesis. Sex- and-age matched littermates were administered 2x105 plaque forming units (PFU) of SARS-CoV-2 intranasally. a) Quantitative RT-PCR (qPCR) quantification of SARS-CoV-2 loads in the lung at days 3 and 10 post infection (p.i). Each symbol= one mouse, the small horizontal line: the median of the result. *, p<0.05; **, p<0.01, ***, p<0.001 (non-parametric Mann-Whitney test) between Ubxn3b+/+ and Ubxn3b-/- littermates at each time point. Ubxn3b+/+ Ubxn3b-/- Live Live 78.0 83.6 CD45+ CD45+ UV UV CD45 94.1 CD45 90.9 FSC-A FSC-A FSC-A FSC-A Mac Mac 23.0 38.1 MHC II MHC II CD11b Eso CD11b Eso 5.81 7.44 CD19, MHCII subset F4_80, CD11b subset CD19, MHCII subset F4_80, CD11b subset Myeloid panel Myeloid 70.1 65.6 94.2 51.1 CD19 F4/80 CD19 F4/80 Neu DC Neu DC 4.87 1.02 16.2 2.24 CD11b, Ly-6G subset CD11b, Ly-6G subset 94.9 83.3 Ly-6G Ly-6G MHC II MHC II CD11b CD11c CD11b CD11c Live Live 82.3 76.5 CD45+ CD45+ 91.1 91.3 UV UV CD45 CD45 FSC-A FSC-A FSC-A FSC-A Q1 Q2 Q1 Q2 Q1 Q2 Q1 Q2 Lymphoid panel Lymphoid 20.1 0.29 54.1 1.17 4.27 0.060 39.2 2.55 CD4 CD4 CD19 CD19 Q4 Q3 Q4 Q3 Q4 Q3 Q4 Q3 47.0 32.6 7.21 37.5 67.7 28.0 7.27 51.0 CD3 CD8 CD3 CD8 Supplemental Fig.s2 Dysregulated immune compartmentalization in Ubxn3b-/- lung. -
Innate Immunity in the Lung: How Epithelial Cells Fight Against
Copyright #ERSJournals Ltd 2004 EurRespir J 2004;23: 327– 333 EuropeanRespiratory Journal DOI: 10.1183/09031936.03.00098803 ISSN0903-1936 Printedin UK –allrights reserved REVIEW Innateimmunity in the lung: how epithelialcells ght against respiratorypathogens R. Bals*,P.S. Hiemstra # Innateimmunity in the lung: how epithelial cells ® ghtagainst respiratory pathogens *Deptof Internal Medicine, Division of R Bals, P S Hiemstra #ERS JournalsLtd 2004 PulmonaryMedicine, Hospital of the Uni- versityof Marburg, Philipps-University, ABSTRACT: Thehuman lung is exposed to a largenumber of airborne pathogens as a # resultof the daily inhalation of 10,000 litres of air Theobservation that respiratory Marburg,Germany; Deptof Pulmonology, LeidenUniversity Medical Center, Leiden, infectionsare nevertheless rare is testimony to the presence of anef®cient host defence TheNetherlands systemat the mucosal surface of the lung Theairway epithelium is strategically positioned at the interface with the Correspondence:P S Hiemstra,Dept of environment,and thus plays a keyrole in this host defence system Recognition Pulmonology,Leiden University Medical systemsemployed by airwayepithelial cells to respond to microbialexposure include the Center, P O Box9600, 2300 RC Leiden, The actionof the toll-like receptors Netherlands Theairway epithelium responds to such exposure by increasing its production of Fax:31 715266927 mediatorssuch as cytokines, chemokines and antimicrobial peptides Recent® ndings E-mail: p s hiemstra@lumc nl indicatethe importance of these peptides -
Targeting Innate Immunity to Treat Cancer
cancers Editorial Targeting Innate Immunity to Treat Cancer Matthew Austin and Harriet Kluger * Yale Cancer Center, Yale School of Medicine, 333 Cedar St, WWW211B, New Haven, CT 06520, USA; [email protected] * Correspondence: [email protected] Received: 14 September 2020; Accepted: 16 September 2020; Published: 23 September 2020 In recent years, it has become clear that the immune system plays a critical role in rejecting malignant cells. Through the complex interplay between multiple cell types from both the adaptive and innate immune systems, immune cells are able to identify and destroy tumor cells. Multiple mechanisms of escape from immune surveillance have been characterized and are being harnessed for therapeutic benefit. Proposed mechanisms include, but are not limited to, alteration of surface antigens [1,2], down-regulation of necessary components for antigen presentation [3], secretion of anti-inflammatory cytokines by tumor cells or cells in the tumor micro-environment [4], and upregulation of expression of immune inhibitory molecules [5]. Drugs that target these immune-evasion mechanisms and successfully re-invigorate the immune response include inhibitors of PD-1, its ligand PDL-1, and CTLA-4, all of which have dramatically revolutionized cancer care [6–8]. Other classes of immune therapies that have been approved by the food and drug administration include CAR-T and natural killer (NK) cellular therapies [9], cytokine therapies [10], oncolytic viruses [11] and dendritic cell therapies, such as sipuleucel-T [12]. Immune checkpoint inhibitors, which are thought to primarily work by activation of cytotoxic T cells [13], are the most widely used; however, they are only active in a subset of cancer patients. -
Immune Cell Migration in Inflammation: Present and Future Therapeutic Targets
REVIEW DAMPENING INFLAMMATION Immune cell migration in inflammation: present and future therapeutic targets Andrew D Luster1, Ronen Alon2 & Ulrich H von Andrian3 The burgeoning field of leukocyte trafficking has created new and exciting opportunities in the clinic. Trafficking signals are being defined that finely control the movement of distinct subsets of immune cells into and out of specific tissues. Because the accumulation of leukocytes in tissues contributes to a wide variety of diseases, these ‘molecular codes’ have provided new targets for inhibiting tissue-specific inflammation, which have been confirmed in the clinic. However, immune cell migration is also critically important for the delivery of protective immune responses to tissues. http://www.nature.com/natureimmunology Thus, the challenge for the future will be to identify the trafficking molecules that will most specifically inhibit the key subsets of cells that drive disease processes without affecting the migration and function of leukocytes required for protective immunity. The past three decades have witnessed an explosion of knowledge in they deploy to migrate to target tissues? How do trafficking molecules immunology, which is being increasingly ‘translated’ into new thera- regulate effector cell recruitment in vessels and during subsequent trans- pies for seemingly unrelated human pathologies caused by excessive or endothelial and interstitial migration? Which trafficking molecules are misdirected inflammatory responses. Although such diseases can affect promising targets for safe and effective drug inhibition? Which migra- any part of the body, almost all inflammatory conditions are restricted tion-directed drugs might be effective in which disease(s) and why? to particular target organs or tissue components1–3. -
Qnas with Max D. Cooper and Jacques F. A. P. Miller
QNAS QnAswithMaxD.CooperandJacquesF.A.P.Miller QNAS Brian Doctrow, Science Writer Anyone who has ever contracted chicken pox can thank the adaptive immune system for future pro- tection against the disease. It is also thanks to this system that vaccines prevent diseases. The adaptive immune system provides organisms with a memory of past infections, enabling the body to quickly kill returning infections before they can do significant damage. Immunologists Jacques F. A. P. Miller and Max D. Cooper determined that adaptive immunity requires 2 distinct cell types that perform comple- mentary functions. Miller’s findings, published in the early 1960s in Lancet (1) and Proceedings of the Royal Society (2), showed that the ability to distinguish one’s own cells from foreign cells, a key feature of the adap- tive immune system, depends on lymphocytes, now known as T cells, matured in an organ called the thy- mus. Subsequently, Cooper reported in Nature (3) that Max Dale Cooper. Image courtesy of Georgia Research antibody production depends on a separate set of Alliance/Billy Howard. lymphocytes, dubbed B cells. The division of labor between T and B cells is a fundamental organizing principle of the adaptive immune system, the discov- did cancer research. I started working on leukemia and ery of which laid the groundwork for modern immu- this gave me an interest in lymphocytes. nology and made possible many subsequent medical advances, including monoclonal antibody produc- Cooper: I became interested through patients that I tion, vaccine development, and checkpoint inhibi- was taking care of: Children that had deficient immune tion therapies for cancer. -
Cells, Tissues and Organs of the Immune System
Immune Cells and Organs Bonnie Hylander, Ph.D. Aug 29, 2014 Dept of Immunology [email protected] Immune system Purpose/function? • First line of defense= epithelial integrity= skin, mucosal surfaces • Defense against pathogens – Inside cells= kill the infected cell (Viruses) – Systemic= kill- Bacteria, Fungi, Parasites • Two phases of response – Handle the acute infection, keep it from spreading – Prevent future infections We didn’t know…. • What triggers innate immunity- • What mediates communication between innate and adaptive immunity- Bruce A. Beutler Jules A. Hoffmann Ralph M. Steinman Jules A. Hoffmann Bruce A. Beutler Ralph M. Steinman 1996 (fruit flies) 1998 (mice) 1973 Discovered receptor proteins that can Discovered dendritic recognize bacteria and other microorganisms cells “the conductors of as they enter the body, and activate the first the immune system”. line of defense in the immune system, known DC’s activate T-cells as innate immunity. The Immune System “Although the lymphoid system consists of various separate tissues and organs, it functions as a single entity. This is mainly because its principal cellular constituents, lymphocytes, are intrinsically mobile and continuously recirculate in large number between the blood and the lymph by way of the secondary lymphoid tissues… where antigens and antigen-presenting cells are selectively localized.” -Masayuki, Nat Rev Immuno. May 2004 Not all who wander are lost….. Tolkien Lord of the Rings …..some are searching Overview of the Immune System Immune System • Cells – Innate response- several cell types – Adaptive (specific) response- lymphocytes • Organs – Primary where lymphocytes develop/mature – Secondary where mature lymphocytes and antigen presenting cells interact to initiate a specific immune response • Circulatory system- blood • Lymphatic system- lymph Cells= Leukocytes= white blood cells Plasma- with anticoagulant Granulocytes Serum- after coagulation 1. -
Inflammation and Introduction to Wound Healing
Inflammation and Introduction to Wound Healing Alan D. Proia, M.D., Ph.D. February 14, 2011 Proia©/DUMC 1 Objectives Understand basic concepts of acute, chronic, and granulomatous inflammation Recognize key leukocytes participating in inflammatory responses Distinguish acute, chronic, and granulomatous inflammation Proia©/DUMC 2 What is Inflammation? Response to injury (including infection) Reaction of blood vessels leads to: » Accumulation of fluid and leukocytes in extravascular tissues Destroys, dilutes, or walls off the injurious agent Initiates the repair process Proia©/DUMC 4 What is Inflammation? Fundamentally a protective response May be potentially harmful » Hypersensitivity reactions to insect bites, drugs, contrast media in radiology » Chronic diseases: arthritis, atherosclerosis » Disfiguring scars, visceral adhesions Proia©/DUMC 5 What is Inflammation? Components of inflammatory response » Vascular reaction » Cellular reaction How: Chemical mediators » Derived from plasma proteins » Derived from cells inside and outside of blood vessels Proia©/DUMC 6 Historical Highlights Celsus, a first century A.D. Roman, listed four cardinal signs of acute inflammation: » Rubor (erythema [redness]): vasodilatation, increased blood flow » Tumor (swelling): extravascular accumulation of fluid » Calor (heat): vasodilatation, increased blood flow » Dolor (pain) Proia©/DUMC 7 Types of Inflammation Acute inflammation Chronic inflammation » Short duration » Longer duration » Edema » Lymphocytes & » Mainly neutrophils macrophages -
Migration Dynamics in Leukocyte Transendothelial Endothelial Actin-Binding Proteins and Actin
Th eJournal of Brief Reviews Immunology Endothelial Actin-Binding Proteins and Actin Dynamics in Leukocyte Transendothelial Migration Michael Schnoor The endothelium is the first barrier that leukocytes have Ag-1 and macrophage-1 Ag or the b1-integrin very late Ag-4 to overcome during recruitment to sites of inflamed tis- on leukocytes mediate firm adhesion. Subsequently, leukocytes sues. The leukocyte extravasation cascade is a complex reach the site of transmigration by intraluminal crawling. Leu- multistep process that requires the activation of various kocytes can crawl as much as 60 mm in a macrophage-1 Ag/ adhesion molecules and signaling pathways, as well as ac- ICAM-1–dependent fashion before they transmigrate (2). tin remodeling, in both leukocytes and endothelial cells. Transmigration (also known as diapedesis) occurs either trans- Endothelial adhesion molecules, such as E-selectin or cellularly or paracellularly, with the majority of transmigration ICAM-1, are connected to the actin cytoskeleton via events being across paracellular junctions both in vivo and actin-binding proteins (ABPs). Although the contribu- in vitro (3, 4). Finally, leukocytes have to cross pericytes and tion of receptor–ligand interactions to leukocyte extrav- the basement membrane (BM) to conclude extravasation. This asation has been studied extensively, the contribution of occurs through gaps in the pericyte layer that coincide with endothelial ABPs to the regulation of leukocyte adhe- regions of the BM that contain less extracellular matrix proteins sion and transendothelial migration remains poorly un- and, therefore, pose a thinner barrier for the transmigrating derstood. This review focuses on recently published leukocyte (5, 6). All of these steps require cell movement and evidence that endothelial ABPs, such as cortactin, myo- actin cytoskeletal remodeling in both cell types involved. -
Instant Notes: Immunology, Second Edition
Immunology Second Edition The INSTANT NOTES series Series Editor: B.D. Hames School of Biochemistry and Molecular Biology, University of Leeds, Leeds, UK Animal Biology 2nd edition Biochemistry 2nd edition Bioinformatics Chemistry for Biologists 2nd edition Developmental Biology Ecology 2nd edition Immunology 2nd edition Genetics 2nd edition Microbiology 2nd edition Molecular Biology 2nd edition Neuroscience Plant Biology Chemistry series Consulting Editor: Howard Stanbury Analytical Chemistry Inorganic Chemistry 2nd edition Medicinal Chemistry Organic Chemistry 2nd edition Physical Chemistry Psychology series Sub-series Editor: Hugh Wagner Dept of Psychology, University of Central Lancashire, Preston, UK Psychology Cognitive Psychology Forthcoming title Physiological Psychology Immunology Second Edition P.M. Lydyard Department of Immunology and Molecular Pathology, Royal Free and University College Medical School, University College London, London, UK A. Whelan Department of Immunology, Trinity College and St James’ Hospital, Dublin, Ireland and M.W. Fanger Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA © Garland Science/BIOS Scientific Publishers Limited, 2004 First published 2000 This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” Second edition published 2004 All rights reserved. No part of this book may be reproduced or -
Granulocyte Transfusions in Haematopoietic Cell Transplants and Leukaemia: the Phoenix Or Beating a Dead Horse?
www.nature.com/bmt EDITORIAL Granulocyte transfusions in haematopoietic cell transplants and leukaemia: the phoenix or beating a dead horse? © The Author(s), under exclusive licence to Springer Nature Limited 2021 Bone Marrow Transplantation (2021) 56:2046–2049; https://doi.org/10.1038/s41409-021-01399-3 You should make a point of trying every experience once, excepting incest and folk-dancing. (and perhaps granulocyte transfusions?) Sir Arnold Bax Why is it some things which are so intuitive and seem easily proved continue engendering controversy and debate (Fig. 1). The example at hand is granulocyte transfusions. It has been known for >50 years infection risk increases precipitously in people when their blood granulocyte concentration is <0.5 × 10E + 9/L [1, 2] (Fig. 2). Whether, given the development of more effective systemic and oral non-absorbable antibiotics and anti-fungal drugs, often given prophylactically 0.5 × 10E + 9/L remains the threshold for increased infection risk or whether the threshold is closer 0–0.2 × 10E + 9/L is unknown. It is also possible there is no blood granulocyte nadir requiring granulocyte transfusions or where a benefit of granulocyte transfusions can be convincingly proved. Regardless, the seemingly simple remedy to decreased Fig. 1 Centre for the Study of Rationality. Hebrew Univ. Jerusalem. blood granulocytes is to transfuse granulocytes from normals or, formally, from persons with chronic myeloid leukaemia (CML). Amino™ (now renamed CelltrifugeTM)orbyfiltration leukapheresis Why should granulocyte transfusions be different than RBC and in persons with granulocytopenia and gram-negative sepsis. platelet transfusions which are convincingly safe and effective.