DOCSLIB.ORG

Opsonization of Dendritic Cells Does Not Require Ic3b Apoptotic Cell

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Opsonization of Dendritic Cells Does Not Require Ic3b Apoptotic Cell Apoptotic Cell-Mediated Immunoregulation of Dendritic Cells Does Not Require iC3b Opsonization This information is current as Edward M. Behrens, Yue Ning, Nidal Muvarak, Philip W. of September 24, 2021. Zoltick, Alan W. Flake and Stefania Gallucci J Immunol 2008; 181:3018-3026; ; doi: 10.4049/jimmunol.181.5.3018 http://www.jimmunol.org/content/181/5/3018 Downloaded from References This article cites 42 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/181/5/3018.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 24, 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 Apoptotic Cell-Mediated Immunoregulation of Dendritic Cells Does Not Require iC3b Opsonization1 Edward M. Behrens,2*† Yue Ning,*† Nidal Muvarak,‡ Philip W. Zoltick,‡ Alan W. Flake,‡ and Stefania Gallucci*† A number of recent studies show that activation of CR3 on dendritic cells (DCs) suppresses TLR-induced TNF-␣ and IL-12 production and inhibits effective Ag presentation. Although the proposed physiologic role for these phenomena is immune sup- pression due to recognition of iC3b opsonized apoptotic cells by CR3, all of the aforementioned investigations used artificial means of activating CR3. We investigated whether iC3b opsonized apoptotic cells could induce the same changes reported with artificial ligands such as mAbs or iC3b-opsonized RBC. We explored the kinetics of iC3b opsonization in two models of murine cell apoptosis, ␥-irradiated thymocytes and cytokine deprivation of the IL-3 dependent cell line BaF3. Using a relatively homogenous population of early apoptotic cells (IL-3 deprived BaF3 cells), we show that iC3b opsonized apoptotic cells engage CR3, but this interaction is Downloaded from dispensable in mediating the anti-inflammatory effects of apoptotic cells. TLR-induced TNF-␣ and IL-12 production by bone marrow- derived DCs occurs heterogeneously, with apoptotic cells inhibiting only certain populations depending on the TLR agonist. In contrast, although apoptotic cells induced homogeneous IL-10 production by DCs, IL-10 was not necessary for the inhibition of TNF-␣ and IL-12. Furthermore, because the ability of iC3b opsonization to enhance phagocytosis of apoptotic cells has been controversial, we report that iC3b opsonization does not significantly affect apoptotic cell ingestion by DCs. We conclude that the apoptotic cell receptor system on DCs is sufficiently redundant such that the absence of CR3 engagement does not significantly affect the normal anti-inflammatory http://www.jimmunol.org/ processing of apoptotic cells. The Journal of Immunology, 2008, 181: 3018–3026. ying cells need to be carefully handled by the immune cific way for phagocytes to recognize dying cells and induce the ␣ ␤ system so as not to provoke an immune response against appropriate anti-inflammatory environment. The m 2 integrin D self-Ags. Apoptosis, the programmed mode of cell complement receptor 3 (CR3) recognizes apoptotic cells by death, is carefully orchestrated to be an anti-inflammatory event. binding to the serum protein iC3b bound to their surface. Op- Both the apoptotic cells themselves (1), as well as the cells clearing sonization of iC3b is thought to be driven in part by the specific away the apoptotic debris, contribute to this anti-inflammatory envi- exposure of phosphatidylserine molecules by apoptotic by guest on September 24, 2021 ronment (2). This anti-inflammatory environment comes in the form cells (4). of functional suppression of APCs via inhibition of proinflammatory Three recent genome-wide association studies have found that a cytokine production. This suppression prevents the immune system particular polymorphism of the gene encoding the ␣-chain of CR3, from initiating a response against the multiple neo-self-Ags created ITGAM, is associated with high risk to develop SLE (5–7). The during the apoptosis process. In the archetypal autoimmune disease molecular and functional mechanisms underlying this risk factor 3 systemic lupus erythematosus (SLE), an impaired clearance of apo- still remain to be discovered. ptotic cells, or their failure to induce tolerance to self Ags, are hy- We and others have shown that CR3 ligation suppresses inflam- pothesized as a pathogenic mechanism (3). matory cytokine production by dendritic cells (DCs). However, in There are many receptors for apoptotic cells, found in various each of these experimental systems, the ligand used to produce the combinations depending on cell type, which may provide a spe- CR3 effect has been artificial, either using a mAb against the ␣-chain (8, 9), or RBC that have been opsonized with iC3b (10). *Laboratory of Dendritic Cell Biology, Division of Rheumatology, Joseph Stokes, Jr. Although apoptotic cells have certainly been demonstrated to sup- Research Institute, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318; †Division of Rheumatology, Department of Pediatrics, University of Pennsylvania press DC inflammatory cytokine production (11), the physiological School of Medicine, Philadelphia, PA 19104-4318; ‡Department of Surgery, Chil- contribution of CR3/iC3b interactions toward this effect remains in dren’s Hospital of Philadelphia, Philadelphia, PA 19104-4318 question. Furthermore, there are multiple conflicting reports on the Received for publication February 29, 2008. Accepted for publication June 20, 2008. ability of CR3/iC3b interactions to enhance the phagocytosis and The costs of publication of this article were defrayed in part by the payment of page internalization of apoptotic cells (10, 12–14). Because apoptosis is charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. an asynchronous event, it is difficult to generate homogenous pop- ulations of apoptotic cells. Using an IL-3-dependent cell line, we 1 E.M.B. was supported by the National Institute of Health (NIH Grant T32- HD0043021) and an Arthritis Foundation Post-Doctoral Fellowship, and S.G. by the are able to generate a relatively homogenous population of apo- Lupus Foundation Southeastern Pennsylvania Chapter, Arthritis Foundation (Innova- ptotic cells that can be opsonized with serum proteins. Using this tive Grant). system, we show that although apoptotic cell coculture results in 2 Address correspondence and reprint requests to Dr. Edward M. Behrens, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, ARC 1102, Philadelphia, PA cytokine suppression, this effect does not require CR3/iC3b inter- 19104-4318. E-mail address: [email protected] actions. We furthermore present data that CR3/iC3b interactions 3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic do not contribute to the amount or kinetics of apoptotic cell phago- cell; FSC, forward scatter; MdFI, median fluorescence intensity; BMDC, bone mar- cytosis. Understanding the physiologic role of CR3 in apoptotic row derived DCs; CR3, complement receptor 3. cell processing will help us to evaluate its potential pharmacologic Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 utility. www.jimmunol.org The Journal of Immunology 3019 FIGURE 1. iC3b deposition occurs on both early and late apoptotic cells. A, An- nexin V/7-AAD staining of thymocytes after 16 h of culture post 500 rads of gamma ir- radiation. Small numbers represent percent- age of cells within each population. B, Thy- Downloaded from mocytes prepared as in A were incubated with no serum, wild type serum, or serum from C3-deficient mice for 30 min and stained for iC3b on their surface. Panels 1–4 refer to the populations 1–4 in A. Cells stained only with secondary Ab are shown to http://www.jimmunol.org/ establish baseline staining. Vertical lines are provided for reference to the median inten- sity of this baseline. C, Forward and side scatter profiles of the iC3b positive and iC3b negative populations from the early apopto- tic thymocytes (population 2). Small num- bers represent percentage of cells within each population. The forward and side scat- ter profile of the live thymocytes (population 1) is shown for comparison. D, Apoptotic by guest on September 24, 2021 BaF3 after 48 h of IL-3 deprivation stained as in A. E, Apoptotic BaF3 cells stained and plotted as in B. Results representative of two to three experiments. Materials and Methods ogy and FITC-anti-Rat IgG1 (BD Biosciences) was used as a secondary ␮ Mice and Abs Ab. IL-10 receptor blocking Ab 1B1.3A was used at 10 g/ml. C57BL/6, C57BL/6-Rag1Ϫ/Ϫ, and ITGAMϪ/Ϫ (deficient in CR3) mice Ϫ Ϫ were purchased from Jackson ImmunoResearch Laboratories. C3 / mice Bone marrow derived DC (BMDC) generation were generously provided by Dr. Wenchao Song (University of Pennsyl- vania, Philadelphia, PA). All mice were bred and maintained in accordance Bone marrow-derived DCs were generated as previously described (15). In Ϫ Ϫ with guidelines of the Institutional Animal Care and Use Committee of The brief, bone marrow precursors from Rag1 / mice were cultured for 6 days Children’s Hospital of Philadelphia, an American Association for the Ac- in complete IMDM containing 3.3 ng/ml GM-CSF (BD Biosciences). Gen- creditation of Laboratory Animal Care accredited facility. Anti-TNF-␣, erating DCs from RAG-KO BM does not require depletion of T- and B- IL-12, IL-10, and CR3 Abs were purchased from BD Biosciences.
Load more

Recommended publications
  • The Case for Lupus Nephritis
    Journal of Clinical Medicine Review Expanding the Role of Complement Therapies: The Case for Lupus Nephritis Nicholas L. Li * , Daniel J. Birmingham and Brad H. Rovin Department of Internal Medicine, Division of Nephrology, The Ohio State University, Columbus, OH 43210, USA; [email protected] (D.J.B.); [email protected] (B.H.R.) * Correspondence: [email protected]; Tel.: +1-614-293-4997; Fax: +1-614-293-3073 Abstract: The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled inflammation and organ damage, especially to the kidney. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance, autoantibody production, and immune complex deposition in tissues including the kidney, with inflammatory consequences. Effective clearance of immune complexes and cellular waste by early complement components protects against the development of lupus nephritis, while uncontrolled activation of complement, especially the alternative pathway, promotes kidney damage in SLE. Therefore, complement plays a dual role in the pathogenesis of lupus nephritis. Improved understanding of the contribution of the various complement pathways to the development of kidney disease in SLE has created an opportunity to target the complement system with novel therapies to improve outcomes in lupus nephritis. In this review, we explore the interactions between complement and the kidney in SLE and their implications for the treatment of lupus nephritis. Keywords: lupus nephritis; complement; systemic lupus erythematosus; glomerulonephritis Citation: Li, N.L.; Birmingham, D.J.; Rovin, B.H.
    [Show full text]
  • 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
    [Show full text]
  • Complement Herbert L
    Host Defense 2011 Complement Herbert L. Mathews, Ph.D. COMPLEMENT Date: 4/11/11 Reading Assignment: Janeway’s Immunobiology, 7th Edition, pp. 54-55, 61-82, 406- 409, 514-515. Figures: (Unless otherwise noted) Janeway’s Immunobiology, 7th Edition, Murphy et al., Garland Publishing. KEY CONCEPTS AND LEARNING OBJECTIVES You will be able to describe the mechanism and consequences of the activation of the complement system. To attain the goals for these lectures you will be able to: a. List the components of the complement system. b. Describe the three activation pathways for complement. c. Explain the consequences of complement activation. d. Describe the consequence of complement deficiency. Page 1 Host Defense 2011 Complement Herbert L. Mathews, Ph.D. CONTENT SUMMARY Introduction Nomenclature Activation of Complement The classical pathway The mannan-binding lectin pathway The alternative pathway Biological Consequence of Complement Activation Cell lysis and viral neutralization Opsonization Clearance of Immune Complexes Inflammation Regulation of Complement Activation Human Complement Component Deficiencies Page 2 Host Defense 2011 Complement Herbert L. Mathews, Ph.D. Introduction The complement system is a group of more than 30 plasma and membrane proteins that play a critical role in host defense. When activated, complement components interact in a highly regulated fashion to generate products that: Recruit inflammatory cells (promoting inflammation). Opsonize microbial pathogens and immune complexes (facilitating antigen clearance). Kill microbial pathogens (via a lytic mechanism known as the membrane attack complex). Generate an inflammatory response. Complement activation takes place on antigenic surfaces. However, the activation of complement generates several soluble fragments that have important biologic activity.
    [Show full text]
  • Primary Immunodeficiency Disorders
    ALLERGY AND IMMUNOLOGY 00954543 /98 $8.00 + .OO PRIMARY IMMUNODEFICIENCY DISORDERS Robert J. Mamlok, MD Immunodeficiency is a common thought among both patients and physicians when confronted with what is perceived as an excessive num- ber, duration, or severity of infections. Because of this, the starting point for evaluating patients for suspected immunodeficiency is based on what constitutes ”too many infections.” It generally is agreed that children with normal immune systems may have an average of 6 to 8 respiratory tract infections per year for the first decade of life. Even after a pattern of ab- normal infection is established, questions of secondary immunodeficiency should first be raised. The relatively uncommon primary immunodefi- ciency diseases are statistically dwarfed by secondary causes of recurrent infection, such as malnutrition, respiratory allergy, chronic cardiovascular, pulmonary, and renal disease, and environmental factors. On the other hand, a dizzying spiral of progress in our understanding of the genetics and immunology of primary immunodeficiency disease has resulted in improved diagnostic and therapeutic tools. Twenty-five newly recognized immunologic disease genes have been cloned in the last 5 ~ears.2~It has become arguably more important than ever for us to recognize the clinical and laboratory features of these relatively uncommon, but increasingly treatable, disorders. CLASSIFICATION The immune system has been classically divided into four separate arms: The B-cell system responsible for antibody formation, the T-cell sys- From the Division of Pediatric Allergy and Immunology, Texas Tech University Health Sci- ences Center, Lubbock, Texas PRIMARY CARE VOLUME 25 NUMBER 4 DECEMBER 1998 739 740 MAMLOK tem responsible for immune cellular regulation, the phagocytic (poly- morphonuclear and mononuclear) system and the complement (opsonic) system.
    [Show full text]
  • Ic3b Catalog Number: A115 Sizes Available: 250 Μg/Vial Concentration
    Name: iC3b Catalog Number: A115 Sizes Available: 250 µg/vial Concentration: 1.0 mg/mL (see Certificate of Analysis for actual concentration) Form: Frozen liquid Purity: >90% by SDS-PAGE Buffer: 10 mM sodium phosphate, 145 mM NaCl, pH 7.2 Extinction Coeff. A280 nm = 1.03 at 1.0 mg/mL Molecular Weight: 176,000 Da (3 chains) Preservative: None, 0.22 µm filtered Storage: -70oC or below. Avoid freeze/thaw. Source: Normal human serum (shown by certified tests to be negative for HBsAg and for antibodies to HCV, HIV-1 and HIV-II). Precautions: Use normal precautions for handling human blood products. Origin: Manufactured in the USA. General Description iC3b (inactivated C3b) is derived from C3b. Conversion of C3b to iC3b destroys almost all of the functional binding sites present on C3b. C3b itself is produced by all three pathways of complement (Law, S.K.A. and Reid, K.B.M. (1995)) when native C3 is cleaved releasing C3a. iC3b is prepared by cleavage of C3b by factor I in the presence of factor H. Cleavage by factors H and I occurs rapidly when the C3b is free in solution and is slower when it is attached to a surface. Other cofactors for factor I also permit cleavage if C3b to iC3b and these include the two membrane proteins CR1 (CD35) and MCP (CD46). Factor I can cleave C3b in two places in the alpha chain and if both sites are cleaved a small fragment (C3f, 2,000 Da) is released. If the C3b precursor was attached to a surface, the iC3b remains on that surface.
    [Show full text]
  • European Society for Immunodeficiencies (ESID)
    Journal of Clinical Immunology https://doi.org/10.1007/s10875-020-00754-1 ORIGINAL ARTICLE European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management Nicholas Brodszki1 & Ashley Frazer-Abel2 & Anete S. Grumach3 & Michael Kirschfink4 & Jiri Litzman5 & Elena Perez6 & Mikko R. J. Seppänen7 & Kathleen E. Sullivan8 & Stephen Jolles9 Received: 5 June 2019 /Accepted: 20 January 2020 # The Author(s) 2020 Abstract This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disor- ders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning. Keywords Complement .
    [Show full text]
  • Anti-Human/Anti-Mouse C3/C3b/Ic3b FITC-Conjugated
    data sheet anti-human/anti-mouse C3/C3b/iC3b FITC-conjugated FITC- conjugated monoclonal antibody 10C7 to human/mouse C3/C3b/iC3b Cat-No: 21157033 500 µl Clone: 10C7 Specificity: The anti-human/mouse Complement Component C3 monoclonal antibody (Clone: 10C7) reacts with human and mouse C3 as well as the breakdown products C3b and iC3b. C3 is the most abundant complement protein in serum. C3 and its cleavage products, C3a and C3b, play a central role in the complement activation cascade.C3b forms an integral part of the C3 and C5 convertases as it promotes complement activation and the subsequent formation of the membrane attack complex. C3a possesses anaphlatoxic as well as various immunoregulatory properties. Also, C3 has been implicated in developmental and non-imflammatory process such as hematopoiesis, skeletal and vascular development and reproduction. Clone 6C9 and Clone:10C7 recognize different epitopes of the C3/C3b/iC3b molecules and do not cross- compete. Isotype subclass: Mouse IgG1 Form: The purified antibody is conjugated with Fluoresceinisothiocyanate (FITC) under optimum conditions. The reagent is adjusted for direct use. No reconstitution is necessary. Physical state: Liquid Buffer/Additives/Preservative: PBS containing 1 % BSA and 0.09 % sodium azide (pH 7.2) Expiration date: The reagent is stable until the expiry date stated on the vial label Storage conditions: Store at 4°C. Do not freeze. Avoid prolonged exposure to light. Application: Flow Cytometry Warning: Sodium azide is harmful if swallowed (R22). Keep out of reach of children (S2). Keep away from food, drink and animal feeding stuff (S13). Wear suitable protective clothing (S36).
    [Show full text]
  • Superoxide Anion Generation in Human Milk Macrophages: Opsonin-Dependent Versus Opsonin-Independent Stimulation Compared with Blood Monocytes
    0031-3998/01/4903-0435 PEDIATRIC RESEARCH Vol. 49, No. 3, 2001 Copyright © 2001 International Pediatric Research Foundation, Inc. Printed in U.S.A. Superoxide Anion Generation in Human Milk Macrophages: Opsonin-Dependent Versus Opsonin-Independent Stimulation Compared with Blood Monocytes RÜDIGER ADAM, FRANK KUCZERA, HENRIK KÖHLER, AND HORST SCHROTEN Zentrum für Kinderheilkunde, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany ABSTRACT Macrophages are believed to play an important role within the found when unopsonized zymosan was used. After addition of - immunoprotective effects of human breast milk. It was the cytochalasin B, equal inhibition of O2 generation was observed purpose of this study to evaluate the capability of human milk regardless of the cell type or stimulus used. Thus, MM⌽ are ⌽ - macrophages (MM ) to generate superoxide anions (O2 )in stimulated to a greater extent by serum-independent mechanisms comparison with peripheral blood monocytes (BMo) after stim- than BMo. As opsonins like complement or IgG are rare in the ulation with opsonized and unopsonized zymosan. Potential in- colostrum and the neonatal intestinal environment, such a differ- hibitors of attachment and phagocytosis such as mannose and entiation toward serum-independent phagocytic abilities could cytochalasin B were used. Expression of the mannose receptor on play an important role for protective functions of human MM⌽. MM⌽ was demonstrated by staining with MAb. BMo generated Possible involvement of the mannose receptor and the ␤-glucan - ⌽ Ϯ Ϯ - more O2 than MM (417 79 versus 216 15 nmol O2 /mg receptor in this specialization are discussed. (Pediatr Res 49: protein, p Ͻ 0.05) after stimulation with opsonized zymosan.
    [Show full text]
  • AND DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA George Garratty, Phd, Frcpath
    PATHOPHYSIOLOGY OF AUTO- AND DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA George Garratty, PhD, FRCPath. Scientific Director American Red Cross Blood Services Southern California Region and Clinical Professor of Pathology University of California, Los Angeles [email protected] HEMOLYTIC ANEMIA Reduction of the average red blood cell life span to less than the normal range of 100- 120 days BEST TESTS TO DEFINE HEMOLYTIC ANEMIA • Hemoglobin/hematocrit • Blood film (bone marrow) • Reticulocyte count (corrected) • Hemoglobin in plasma (urine) • Bilirubin (indirect) • LDH • Haptoglobin • 51Cr RBC survival HEMOGLOBINEMIA • If hemoglobinuria is noted, make sure it is not hematuria (RBCs present). Immune-mediated hemoglobinuria must be accompanied by hemoglobinemia (i.e., hemoglobinemia alone possible, but not hemoglobinuria alone). • Hemoglobinemia can also be due to extravascular destruction [i.e., macrophage interactions (fragmentation and/or cytotoxicity)]. CLASSIFICATION OF THE HEMOLYTIC ANEMIAS ABNORMALITIES Intracellular Membrane Extracellular Hereditary Enzymes Spherocytosis Lipids (G6PD) Hemoglobin Elliptocytosis Lecithin (SCD) Stomatocytosis Acquired Environmental PNH Immune (lead) Lipids Mechanical Microangiopathic Burns Infection Hypersplenism CLASSIFICATION OF IMMUNE HEMOLYTIC ANEMIA • Alloimmune –Hemolytic transfusion reaction –Hemolytic disease of the fetus / newborn • Autoimmune (AIHA) – “Warm” – “Cold” a) cold agglutinin syndrome (CAS) b) paroxysmal cold hemoglobinuria (PCH) –Mixed / combined (warm + cold) • Drug-induced IMMUNE
    [Show full text]
  • Immunodeficiency Selected Topics in Clinical Immunology
    Department of Clinical Chemistry Immunodeficiency Selected Topics in Clinical Immunology Michaela Fux, PhD [email protected] University Institute of Clinical Chemistry M. Fux 1 Department of Clinical Chemistry Defects in MATURATION and/or ACTIVATION of the immune system Immunodeficiency Physiological Primary Secondary • Chemical • Infancy • Adaptive • Physical • Pregnancy • Innate • Malnutrition • Age • Combined • Chronic infections University Institute of Clinical Chemistry M. Fux 2 2 Definition of Primary Immunodeficiency • INTRINSIC defects in MATURATION and/or ACTIVATION of the immune system • Opposed to secondary immunodeficiency which are caused by EXTRINSIC stimuli (e.g. medication, chronic infections, malnutrition) 3 Primary Immunodeficiency: May Affect the Innate and/or the Adaptive Immunity Darnoff et al. 2004 Nat Rev Cancer 4 Classification of Primary Immunodeficiency Specific Non-specific Well-defined Congenital Defects Predominantly Syndromes of of Phagocyte Antibody Deficiency Immunodeficiency Numbers, Function or Both Autoinflammatory Disorders Complement Deficiency Immune Dysregulation Combined Innate Immunity Immunodeficiency 5 Distribution of PID Categories in Switzerland Marschall et al. 2015 Clin Exp Immunol 6 Think Zebra Immune Deficiency Foundation, USA 7 10 Warning Signs of Primary Immunodeficiency • Four ore more new ear infections within 1 year for children, two ore more in 1 year for adults • Two or more serious sinus infections within 1 year • Two or more bouts of pneumonia within 1 year for children, and
    [Show full text]
  • Chapter 13 History Complement Components Complement Pathways
    History • Jules Border in 1890’s discovered complement Chapter 13 • Paul Ehrlich coined the term “complement” • “The activity of blood serum that Complement completes the action of antibody” • Now: “Set of serum proteins that act in a cascade fashion to increase the immune response” The Functions of Complement Complement Components Complement Pathways • Over 20 serum proteins •1) Classical Pathway – activated by • Cascade fashion antigen-antibody interaction. Best Ab for • Components designated: C1 – C9 complement activation: IgM, IgG1, IgG2 • Proteolysis results in: Large fragments “b” •2) Alternative pathway – activated by and smaller fragments “a” Æ C3a, C5b C3b binding to microbial cell surfaces • The only exception is C2, where C2a is •3) Lectin pathway – binding of the lectin the large fragment and C2b is the smaller mannose-binding lectin to the surface of fragment and diffuses away pathogens. 1 Structure of C1 C1qr2s2 -C1q - Binding of C1 complex to Ab leads to activation of C1r and - 2 molecules of C1r C1s - 2 molecules of C1s - Substrate for C1s is C4 and C2 Amplification Step C1complex (C1s) hydrolysis C4, resulting in C4a and C4b. C4b binds to the cell surface C1 complex (c1s) hydrolysis C2 resulting in C2b (small) and C2a which binds to C4b on the cell surface to form the C3 convertase (C4b2a) 2 - C3 in serum undergoes spontaneous hydrolysis Æ C3a, C3b - The half life of these products is very short, except… - C3b can bind to host and bacterial cell surfaces - Mammals have high levels of sialic acid Æ inactivation • ALTERNATIVE
    [Show full text]
  • ZOOLOGY – IMMUNOLOGY Unit 1St 1.1 Introduction to Basic Concepts in Immunology
    1 6th SEMESTER ZOO616DA: ZOOLOGY – IMMUNOLOGY Unit 1st 1.1 introduction to basic concepts in immunology Immunology is the science that is concerned with immune response to foreign challenges. Immunity (derived from Latin term immunis, meaning exempt), is the ability of an organism to resist infections by pathogens or state of protection against foreign organisms or substances. The array of cells, tissues and organs which carry out this activity constitute the immune system. The immune system is remarkably versatile defence system that has evolved to protect animals from invading pathogenic microorganisms and cancer. It is able to generate an enormous variety of cells and molecules capable of specifically recognizing and eliminating an apparently limitless variety of foreign invaders. These cells and molecules act together in a dynamic network whose complexity rivals that of the nervous system. Functionally, an immune response can be divided into two related activities—recognition and response. Immune recognition is remarkable for its specificity. The immune system is able to recognize subtle chemical differences that distinguish one foreign pathogen from another. Furthermore, the system is able to discriminate between foreign molecules and the body’s own cells and proteins. Once a foreign organism has been recognized, the immune system recruits a variety of cells and molecules to mount an appropriate response, called an effector response, to eliminate or neutralize the organism. In this way the system is able to convert the initial recognition event into a variety of effector responses, each uniquely suited for eliminating a particular type of pathogen. Later exposure to the same foreign organism induces a memory response, characterized by a more rapid and heightened immune reaction that serves to eliminate the pathogen and prevent disease.
    [Show full text]