W2 Innate Immunity (Adebiyi) (2).pdf

ROSS UNIVERSITY SCHOOL OF MEDICINE Innate Immunity Raymond F Adebiyi Professor Immunology and Medical Microbiology Resources Required Book: Basic Immunology: Functions and Disorders of the Immune System. 5th ed. 2016 Abbas, AK, Lichtman, AH, & Pillai, S. Elsevier. St. Louis, MO. Chapter 2, pp 27-53...

ROSS UNIVERSITY SCHOOL OF MEDICINE Innate Immunity Raymond F Adebiyi Professor Immunology and Medical Microbiology Resources Required Book: Basic Immunology: Functions and Disorders of the Immune System. 5th ed. 2016 Abbas, AK, Lichtman, AH, & Pillai, S. Elsevier. St. Louis, MO. Chapter 2, pp 27-53 Suggested Reading: How the Immune System Works, 6th edition, 2019 Lauren Sompeyrac. Wiley-Blackwell, Lecture 2 Accessible through Canvas: Student Resources Resources  R2 Digital Library Immunology & Serology Recommended Book: Immunology at a Glance. 10th ed., 2013. Playfair, JHL, & Chain, BM. Wiley-Blackwell. Hoboken, NJ. Any Questions? [email protected] Office Hours https://atge.webex.com/meet/radebiyi Learning Objectives 1. Compare and contrast innate and adaptive immunity. 2. Discuss the natural barriers to infection. 3. List the cellular and non-cellular components of innate immunity and outline their contribution to host defense. 4. Discuss the principles involved in pathogen recognition by innate cells, e.g., phagocytes. List the types of receptors found on innate cells and explain how each functions. 5. Outline the process of neutrophil recruitment and activation. 6. List the major participants in the NF-B signal transduction pathway and explain how the process works. 7. Describe the process of intracellular killing by phagocytes, including the roles of specific enzymes and their products. 8. Explain how the innate system affects the adaptive system. 9. Discuss tests to demonstrate the efficacy (or detect defects) of innate immunity and give specific examples of tests and their application. Innate Immunity ▪ ▪ ▪ ▪ First line of defense Preformed (constitutive, natural, native) Rapid response Non-specific o o receptors encoded in the germ line identical receptors, not clonally distributed ▪ No memory ▪ Triggers the adaptive response. Areas of Operation of Innate Immunity 1. The Skin Main physical barrier Antimicrobial secretions (fatty acids, defensins in sweat; sebaceous gland secretions) Chemotactic secretions: TNF-, IL-8, etc. Antigen presentation by dendritic cells Tight junctions at all locations 2. The Respiratory Tract Mucus Ciliated epithelium o Cough-sneeze reflex Surfactants (collectins) o Secreted by type II pneumocytes o Lubrication of the alveoli o Binds pathogens for phagocytosis Alveolar macrophages 3. The Gastrointestinal Tract Stomach acidity Resident bacteria Epithelium Paneth cells – secrete -defensins, lysozyme and phospholipase-A 4. The Genitourinary Tract Flushing action of urine Urine acidity Vaginal secretions, lysozyme Tamm-Horsfall protein (THP; antimicrobial - immunomodulation…) Innate Defense Mechanisms The Cells of Innate Immunity -Cellular Innate Functions1. Epithelial cells 2. Phagocytes o o o Macrophages Neutrophils Dendritic cells 3. NK cells, intraepithelial lymphocytes Proteins of Innate Immunity -Humoral Innate Functions1. IFN-α, IFN-, IFN-λ, IFN- o Inhibition of viral replication o Activation of NK cells 2. Complement 3. Acute phase proteins o C-reactive protein o Mannan binding lectin 4. Defensins Type I IFNs: IFN- & IFN- Type II IFNs: IFN- Type III IFNs: IFN- Type I and type III IFNs have very similar functions and are primarily involved in antiviral defense. IFN- is also involved in defenses against intracellular pathogens, but it is associated more with cellular immunity. Cardinal Signs Redness – Rubor Increased blood flow – erythema Swelling – Tumor Leakage of plasma – local edema Warmth – Calor Increased blood flow, pyrogens Pain – Dolor Pressure on nerve endings, bradykinin, histamine Loss of function Histology: Lymphoid Tissue Leukocyte Migration Phagocyte Mobilization and the Inflammatory Response Phagocyte (inflammatory stimulus)  margination, pavementing (expression of selectins & integrins) leukocyte adhesion, CD18/ICAM-1  diapedesis  chemotaxis (IL-8, C5a, TNF-, PG-E2, IL-1) Clinical correlation: Leukocyte adhesion deficiency Innate Effector Functions Complement system Innate Effector Functions - Humoral Response - Phagocytic Killing Phagocyte Oxidative Burst Reactive Oxygen Species NBT (Nitro Blue Tetrazolium) measures killing capacity by ROS DHR (Dihydrorhodamine) measures ROS production myeloperoxidase Phagocyte oxidase Superoxide dismutase Deficiencies ▪ G6PD Clinical correlation: Chronic granulomatous disease ▪ NADPH oxidase (chronic granulomatous disease) ▪ MPO (absence is NOT clinically significant) CD8 α:β + CD8 : T cells Natural Killer Cells Special type of T cells – CD2+ / CD3 negative. 5-10% PBL; large, granular lymphocytes Express CD56, but not TCR.. Express KAR (Killer Activation Receptor) and KIR (Killer Inhibition Receptor). Activated by IL-12, IFN-, TNF-, IL-15 etc. Possess Fc receptor, FcRIII (CD16; ADCC). Inducible expression of FasL (cell cytotoxicity). Release perforin/granzyme (cell cytotoxicity). Release IFN- in response to IL-12 stimulation. NK Cell - Innate Killing Function - NK Cell - Adaptive Killing Function – Antibody Dependent Cellular Cytotoxicity (ADCC) virus Ag on infected cell  IgG binds to Ag  FcRIII (CD16) binds IgG  NK activation NK expression of FasL Release of granules (perforin/granzyme)  Caspase activated  Fas+ target destroyed Cell Death via Fas/FasL Apoptosis is an important part of immunity. o Kill infected cells by inducing apoptosis. o Eliminate self-reactive lymphocytes during development. o Get rid of effector T cells after infection is terminated. Apoptosis can be triggered through Fas. o Fas and FasL are induced during an immune response. o Binding of FasL to Fas induces apoptosis of Fas-expressing cell. Binding of FasL to Fas induces cell death in Fas-expressing cells. The End