Host_Defense_Mechanisms_ofthe_Lung_RespI_5154_2023_BENSON_final.pptx

5155: Respiratory System I November 29th, 2023 10 - 11 AM Marc Benson, Ph.D. • • • • Office: 317 E-mail: [email protected] Phone: (575) 674-2317 Office hours: E-mail for appointment or stop by office Reading Material Mak et al. Primer to the Immune Response, Chapter 12 • Link: http://ezproxy.ad...

5155: Respiratory System I November 29th, 2023 10 - 11 AM Marc Benson, Ph.D. • • • • Office: 317 E-mail: [email protected] Phone: (575) 674-2317 Office hours: E-mail for appointment or stop by office Reading Material Mak et al. Primer to the Immune Response, Chapter 12 • Link: http://ezproxy.ad.bcomnm.org/login?url=https://www.clinicalkey.com/dura/browse/bookChapter/3-s2.0C20090622170 Davidson's Principles and Practice of Medicine, Twenty-Second Edition, Walker, Brian R., BSc MD FRCPE FRSE, © 2014, Elsevier Limited. All rights reserved Host Defense Mechanisms of the Lung Abbas et al. Cellular and Molecular Immunology, 10th ed. Chapter 14 • Link: https://ezproxy.ad.bcomnm.org/login?url=https://www.clinicalkey.com/dura/browse/bookChapter/3s2.0-C20190004463 1 Copyright Notice • All reproduction or use of copyrighted materials shall comply with provisions of applicable law. Individuals are responsible for maintaining copyright compliance in good faith and with each intended use. Please consult BCOM Policy B5041 and the copyright guidelines located on https://bcomnm.org/copyrightguidelines/ for detailed information • BCOM prohibits duplication, distribution, or use of copyrighted materials by students, faculty and staff unless a fair use or other exemption applies, or permission has been obtained from the work's rights holder (which may or may not be the author/creator) • Infringement of copyright law may be considered a violation of the College’s Code of Professional Conduct. Anyone found liable for civil and/or criminal copyright infringement may be responsible for any monetary damages suffered by the College due to such violation(s) of this policy or related law or regulation 2 Lecture Outline 1. 2. 3. 4. 5. 6. 7. Pre-Lecture Clicker Questions Objectives Immune tissue of the Respiratory Tract Innate Immune Response Adaptive Immune Response Post-Lecture Clicker Questions Sample Questions 3 Pre-Lecture Clicker Questions 4 Lecture Outline 1. 2. 3. 4. 5. 6. 7. Pre-Lecture Clicker Questions Objectives Immune tissue of the Respiratory Tract Innate Immune Response Adaptive Immune Response Post-Lecture Clicker Questions Sample Questions 5 Objectives 1. Compare and contrast the variety of cells, structures and secretions found in the respiratory tract that provide innate immune defense 2. Compare and contrast the host-defense roles of phagocytic cells resident in the respiratory tract with those found in other compartments 3. Describe the action of the mucociliary system in moving particulate matter away from the lungs 4. List the major components of the mucosal immune system and explain how it functions in the defense of the respiratory tract 5. Explain the function of secretory IgA and how a deficiency in IgA antibody would affect respiratory defenses 6. Describe the location(s) of immune tissue (diffuse, nodular, and tonsillar) within the various regions of the respiratory tree 6 Lecture Outline 1. 2. 3. 4. 5. 6. 7. Pre-Lecture Clicker Questions Objectives Immune tissue of the Respiratory Tract Innate Immune Response Adaptive Immune Response Post-Lecture Clicker Questions Sample Questions 7 Immune tissue of the Respiratory Tract Diffuse lymphoid tissue • Locations where lymphocytes congregate Nodular lymphoid tissue • Lymphocytes within a structure of reticular fibers • E.g. Tonsils (aggregate of nodules) Mak, Tak W., Primer to the Immune Response, Chapter 12, 269-292, Copyright © 2014 Elsevier Inc. All rights reserved. 8 Lecture Outline 1. 2. 3. 4. Pre-Lecture Clicker Questions Objectives Immune tissue of the Respiratory Tract Innate Immune Response • Cough • Lung Microbiome • Non-specific secreted factors • Mucociliary transport • Innate immune cells 5. Adaptive Immune Response 6. Post-Lecture Clicker Questions 7. Sample Questions 9 Systems Immunology OPP: Structure-Function Anatomy and function drives antigen sampling Antigen sampling determines immune functions in organ systems 10 Age-Related Changes to Immune Response Prevention of Respiratory Tract Infections • Hydration ¯ Immune cell activation ¯ Response to vaccines ¯ Mucociliary clearance ¯ Cough reflex • No smoking • Vaccines • Staff in close proximity to susceptible engage in proper infection control 11 Respiratory Tract Epithelium • Respiratory tract mucosa is in direct contact with outside environment • Outside and inside environment separated by thin mucosal epithelial layer (compared to skin) • Must respond to pathogenic insult while minimizing damage to the respiratory epithelium • Must balance immune response with infection control • Exposed to: • Environmental debris • Toxic aerosols • Dust, molds, spores • Human-generated aerosols/droplets contaminated with pathogenic organisms 12 Innate Immune Response Cough • Major part of normal respiratory defense • High pressure expiration • Clearance of secretions (excessive mucus) • Foreign materials expelled • Voluntary (individuals can suppress) • Cortically controlled – inspiratory, compressive, expulsion phases • Involuntary (regulated by the vagal afferent nerve) • Irritant receptor stimulation • Chemicals, inflammatory mediators, mechanical stimuli • Often diminished in elderly • Material that is coughed up is either released into the environment or swallowed 13 Innate Immune Response Lung Microbiome Generally derived from the upper respiratory tract Most Common Genera •Prevotella •Streptococcus •Veillonella •Neisseria •Haemophilus •Fusobacterium Purpose: • To maintain immune tolerance • To prevent aberrant inflammation The lung microbiome: progress and promise, Samantha A. Whiteside, … , John E. McGinniss, Rona Published August 2, 2021 , J Clin Invest. 2021;131(15):e150473. https://doi.org/10.1172/JCI15047 14 Innate Immune Response Non-Specific Secreted Factors • Anti-microbial peptides (e.g., defensins) • Mucus • 90% H2O • 10% protein, carbohydrates, lipids • Mucin • Lysozyme and other enzymes • Lactoferrin • Collectins: • Surfactant protein A & D (SP-A, SP-D) • Soluble PRRs - bind and opsonize microbes • Secreted by Type II pneumocytes Leiva-Juárez, M M, Mucosal Immunology, Volume 11, Issue 1, 21-34. Copyright © 2018 © Society for Mucosal Immunology TA, lipotechtoic acid; DLP, diacylated lipopeptides; HβD, human β-defensin; NTHi, non-typeable Haemophillus influenza ; ODN, oligodeoxynucleotide; ROS, reactive oxygen species; SP, surfactant protein; TLR, Toll-like receptor; TEER, transepithelial electrical resistance. 15 Innate Immune Response Mucociliary transport • Mucociliary clearance is necessary to move captured material, including pathogens, out of lung • Primary method of removing contaminants from lung • Destruction of cilia impairs mucociliary clearance • Smoking (smoker’s lung) • Viral infection (Influenza) • Increased susceptibility to infection/disease Bustamante-Marin XM, Ostrowski LE. Cilia and Mucociliary Clearance. Cold Spring Harb Perspect Biol. 2017 Apr 3;9(4):a028241. doi: 10.1101/cshperspect.a028241. PMID: 27864314; PMCID: PMC5378048. 16 Innate Immune Response Cells - Epithelium Samuel J. Wadsworth, et al (2012). IL-13, Asthma and Glycosylation in Airway Epithelial Repair, Carbohydrates - Comprehensive Studies on Glycobiology and Glycotechnology, Prof. Chuan-Fa Chang (Ed.), InTech, DOI: 10.5772/51970. • • Epithelial cells form a tight barrier • Intercellular junctions • Especially tight and adherens junctions • Ciliated columnar cell • Mucociliary transport • Antimicrobial factors • Secretary cells • Mucin secretion Alveolar epithelium • Type II pneumocyte • Secrete surfactant proteins • Cytokine production • IL-1, IL-6, TNF-α 17 Innate Immune Response Cells - Macrophages Lungs have resident macrophages: • Interstitial • Alveolar spaces Normal Exposure to Non-Pathogenic Antigen Exposure to Pathogenic Antigen Resident macrophage functions include: • Recognize and dispose of inhaled microbes • Phagocytosis • Antigen presentation • Cytokine production • Clear pulmonary surfactant • Suppress aberrant inflammation Pulmonary Alveolar Proteinosis (rare) • Alveolar macrophage numbers reduced • Increased lipid-rich, proteinaceous material • Difficulty breathing • Macrophage play major role in clearing pulmonary surfactant Murray and Nadel's Textbook of Respiratory Medicine, Sixth Edition, Broaddus, V. Courtney, MD, Copyright © 2016, 2005 by Saunders, an imprint of Elsevier Inc. 18 Innate Immune Response Cells – Dendritic Cells Two types of dendritic cells: • Intraepithelial • Within the lamina propria DCs sample the lung environment Upon antigen recognition: • Migrate to draining lymph nodes • Present antigen to naïve T cells Dendritic cells in lamina propria Modified from G. Szalai Antigen sampling via intraepithelial dendritic cell 19 Lecture Outline 1. 2. 3. 4. 5. 6. 7. Pre-Lecture Clicker Questions Objectives Immune tissue of the Respiratory Tract Innate Immune Response Adaptive Immune Response Post-Lecture Clicker Questions Sample Questions 20 Innate Immune Response Recruitment of Immune Cells and Activation of Adaptive Immune Response • Recognition of microbial pathogens (PAMPs) and damaged host cells (DAMPs) by PRRs (TLR, NOD, etc.) • Immune cells recruited • Adaptive Immune response activation Whitsett JA and Alenghat T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol. 2014; 16: 27-35. 21 Adaptive Immune Response NALT M cell • Immune cells distributed in epithelium and lamina propria (efferent) • Afferent regions • Antigens recognized and induce immune response • Efferent regions • Memory cells activated • Antibody production • Cytotoxic T cell activity Follicle DC cell Principles of Mucosal Immunology & Society for Mucosal ImmunologyPhilip D Smith, Thomas T MacDonald, and Richard S Blumberg (eds.) Garland Science, New York, 2012 NALT (nasal-associated lymphoid tissue) • Lymphoid aggregates (afferent) • T cells • B cells (follicles) • M cells (epithelial cells that perform transcytosis) 22 Adaptive Immune Response IgA or IgG? Modified from Principles of Mucosal Immunology & Society for Mucosal ImmunologyPhilip D Smith, Thomas T MacDonald, and Richard S Blumberg (eds.) Garland Science, New York, 2012 APC and T cell interaction in follicle-associated epithelium APC and T cell interaction in draining lymph node 23 Effector Functions of Antibodies Summary IgM IgG IgA + ++ ++ IgE IgD Function Opsonization + Antibody-dependent cell-mediated cytotoxicity (ADCC) + + Mast Cell/Basophil Activation (allergy and helminth defense) Complement activation + Transport across epithelium + + ++ Some images Neutralization + Transport across placenta (neonatal immunity) + Mother’s milk B cell receptor (membrane-bound) + Mucosal Immunity + Which cytokine is responsible for the class switch to IgA? + ++ Accounts for >70% of immunoglobulin 24 Selective IgA Deficiency (SIgAD) • A primary humoral immunodeficiency • Most common primary immunodeficiency • Low IgA levels • Believed to be heterogenous mechanisms that lead to this deficiency • From your knowledge of immunology, what may lead to SIgAD • Patients usually asymptomatic (>2/3) – why? • If symptoms: • Respiratory tract infections • Giardia lamblia GI infection (why only this organism?) • Higher autoimmune disease (celiac, inflammatory bowel diseases, SLE, others) • In some patients with no IgA, anaphylactic reaction upon blood transfusion – why? 25 IgA/IgM:pIgR Transcytosis Basolateral Surface Apical Surface • IgA (and IgM) are associated with the J (joining) chain, a polypeptide responsible for multimerization and transport across membranes • The poly-Ig receptor (pIgR) recognizes the J chain in IgA and IgM on the basolateral side of the mucosal epithelial surface • Receptor mediated endocytosis induced to transport antibody across mucosal epithelial surface (transcytosis) • Released on apical (luminal) side of the mucosal epithelial surface Specialized Immunity at Epithelial Barriers and in Immune Privileged Tissues. Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 14, 313-336. Copyright © 2022 by Elsevier Inc. All rights reserved. 26 The Germinal Center Reaction Summary Germinal center (follicle becomes a secondary follicle) Germinal center structure: • Dark zone – rapidly proliferating B cells that undergo somatic hypermutation (affinity maturation) • Light zone – Follicular dendritic cells (no MHC) show antigen to B cells to test antigen binding of BCR. Tfh recognize MHCII-peptide complex and induce class switching and differentiation The germinal center reaction (CD40L:CD40-dependent) • B cells leave the dark zone to ‘test’ their mutagenized BCR on fDCs • If high affinity, then migrate back to dark zone for proliferation • If low affinity, then die by apoptosis • B cells interact with Tfh cells to class switch and differentiate into memory or plasma cells Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 14, 313-336. Copyright © 2022 by Elsevier Inc. All rights reserved. 27 Lecture Outline 1. 2. 3. 4. 5. 6. 7. Pre-Lecture Clicker Questions Objectives Immune tissue of the Respiratory Tract Innate Immune Response Adaptive Immune Response Post-Lecture Clicker Questions Sample Questions 28 Post-Lecture Clicker Questions 29 Lecture Outline 1. 2. 3. 4. 5. 6. 7. Pre-Lecture Clicker Questions Objectives Immune tissue of the Respiratory Tract Innate Immune Response Adaptive Immune Response Post-Lecture Clicker Questions Sample Questions • Learning Catalytics ID: 28473559 30 Thank You 31