Immunology Lecture Second Line of Host Defense 2023 PDF

Immunology (Second Line of Host Defense) Prof. Ashraf M. Ahmed Department of Bacteriology, Faculty of Veterinary Medicine Kafrelsheikh University Egypt  Second Line of Host Defense 1. Fever 2. Inflammation 3. Phagocytosis 4....

Immunology (Second Line of Host Defense) Prof. Ashraf M. Ahmed Department of Bacteriology, Faculty of Veterinary Medicine Kafrelsheikh University Egypt  Second Line of Host Defense 1. Fever 2. Inflammation 3. Phagocytosis 4. Natural killer cells 5. Antimicrobial Substances: a. Complement b. Interferons c. Lysozymes d. Acute phase proteins 2 3  1. Fever Systemic non-specific response to infection. Pyrogen Exogenous LPS, pathogens, foreign cells, vaccines Endogenous Interleukin-1 (IL-1 and 6) & Tumor necrosis factor (TNF-α) Monocytes, neutrophils & macrophages Resets hypothalamus (in brain) thermostat to a higher setting Low-grade fever (38-38.5) effective defense against disease. 4 2.The Inflammatory Response When Pathogens get past skin and mucous membranes, and enter the Body, this Second Line of Defence comes into play, triggered by injury to tissues in the body and release of histamine which starts the a series of changes called the Inflammatory Response. Mast cells are the major producer of histamine, then basophils. 5 Pro-Inflammatory Cytokines Tumor necrosis factor (TNF-α) Interleukin-1 Interleukin-6 Interleukin-8 Chemokines Interferons 6  3. Phagocytosis Derived from the Greek words “Eat and cell”. Phagocytosis is carried out by white blood cells: monocytes (macrophages), neutrophils, and occasionally eosinophils plus dendritic cells. Neutrophils predominate early in infection. Fixed Macrophages (Histiocytes): Located in liver, nervous system, lungs, lymph nodes, bone marrow, and several other tissues. 7 Phagocytic Cells 8  Origin of Phagocytic Cells: Macrophages (Monocytes), Neutrophils, and Eosinophils 9  3. Phagocytosis Cellular Elements of Blood Cell Type # Cells/mm3 Function Erythrocytes (RBC) 4.8-5.4 million Transport O2 and CO2 Leukocytes (WBC) 5000-9000 Various I. Granulocytes: 1. Neutrophils (Microphage) (70% of WBC) Phagocytosis 2. Basophils (1%) Produce histamine 3. Eosinophils (4%) Toxins against parasites II. Agranulocytes: some phagocytosis 1. Monocytes (Macrophages) (5%) Phagocytosis 2. Lymphocytes (20%) Antibody production (B cells) Cell mediated immunity (T cells) Platelets 300,000 Blood clotting 10  Stages of Phagocytosis 1. Chemotaxis: Phagocytes are chemically attracted to site of infection by chemotactic factors released from microbes, damaged tissues and inflammatory cells. 2. Adherence: Phagocyte plasma membrane attaches to surface of pathogen or foreign material. Adherence can be inhibited by bacterial capsule Opsonization: Coating process with opsonins that facilitates attachment. – Opsonins include antibodies and complement proteins.  Stages of Phagocytosis 3. Ingestion (endocytosis): Plasma membrane of phagocytes extends projections (pseudopods) which engulf the microbe. Microbe is enclosed in a sac called phagosome. 4. Digestion: Inside the cell, phagosome fuses with lysosome to form a phagolysosome. Lysosomal enzymes kill most bacteria within 30 minutes and include: Lysozymes: Destroy cell wall peptidoglycan Lipases and Proteases RNAses and DNAses 5. Exocytosis: After digestion, residual body with Phagocytes are Attracted to Site of Infection by Chemotaxis 13 Stages of Phagocytosis  Neutrophil phagocytosing S. pyogenes, the cause of strep throat Human neutrophils are WBCs that arrive quickly at the site of a bacterial infection and whose primary function is to eat and kill bacteria. This neutrophil ingesting Streptococcus pyogenes was imaged in gray scale with phase contrast optics and colorized. 15  Macrophage Ingesting Yeast This human macrophage, like the neutrophil, is a professional "phagocyte" or eating cell (phago = "eating", cyte = "cell"). Here, it envelops cells of a yeast, Candida albicans. After ingestion, the white cell must kill the organisms by some means, such as the oxidative burst. 16 Chemotactic Factors of Phagocytosis 1. Main chemotactic substances for neutrophils: cytokine (chemokine) and interleukin-8 (IL-8) 2. For monocytes: monocyte chemotactic protein-1 (MCP-1) 3. For macrophage: macrophage inflammatory protein-1α and 1β (MIP-1α and MIP-1β) 4. Complement products 17 5. Cytokines released by tissue macrophages Summary of Intracellular Killing Pathways Intracellular Killing Oxygen Oxygen Dependent Independent Myleoperoxidase Myleoperoxidase Dependent Independent 18  Oxygen-Independent Killing in the Phagolysosome Effector Molecule Function Cationic proteins (cathepsin) Damage to microbial membranes Lysozymes Hydrolyses mucopeptides in the cell wall Lactoferrin Deprives pathogens of iron Hydrolytic enzymes (proteases) Digests killed organisms 19  4. Natural Killer (NK) Cells  Also known as large granular lymphocytes (LGL)  Kill virus-infected or tumor cells  Secrete cytokines such as IFNγ and TNFα  Activated by IL2 and IFN-γ to become Lymphokine Activated Killer (LAK) cells 20  5.a. Complement Complement system: is a large group of serum proteins (about 30 types) that participate in the lysis of foreign cells, inflammation, and phagocytosis. Its lytic activity destroyed when heated at 56 ºC for 30 min. Participate in both innate and adaptive immunity. Produced by hepatocytes (mainly), monocytes and epithelial cells of the gastrointestinal and genitourinary tracts. Constitutes 5% (by weight) of the serum globulin  5.a. Complement Many components are proenzymes (zymogens), which are functionally inactive until proteolytic cleavage, which removes an inhibitory fragment and exposes the active site. Nomenclature: Its name means that it assists ‘complements’ the lytic function of antibodies. The first component of complement is named C1 (etc.) other components are designated by capital letters and names: Factor B, Properidin. When cleaved: fragments of complement components are designated by small letters (e.g. C3a and C3b)  Complement Pathways Three pathways for activation: 1. Classical: most specific (antibody dependent activation, binds C1) 2. Lectin binding: some specificity (mannose binding protein, binds C4) 3. Alternative: most primitive (non-specific, auto-activation of C3) Complement Pathways CLASSICAL LECTIN ALTERNATIVE PATHWAY PATHWAY PATHWAY antibody antibody dependent independent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY Complement Pathways  Mannose-binding Lectin (MBL) Pathway MBL binds to carbohydrates (to be specific, D-mannose and L-fucose residues) found on the surfaces of many pathogens, for example: 1. Bacteria such as Salmonella and streptococci 2. Yeasts such as Candida albicans. 3. Viruses such as HIVand influenza A 4. Parasites such as Leishmania Consequences of Complement Activation 1. Cytolysis: Due to the formation of a membrane attack complex (MAC) which produces lesions in microbial membranes. 2. Inflammation: Complement components (C3a) trigger the release of histamine, which increases vascular permeability. 3. Opsonization: Complement components (C3b) bind to microbial surface and promote phagocytosis. 4. Inactivation of Complement: Regulatory proteins limit damage to host cells that may be caused by complement.  5.b. Interferons Antiviral proteins that interfere with viral replication. Important in acute and short-term infections. Host specific, but not virus specific. Types of interferons: Type I: 1. a (Leukocyte): produced by lymphocytes & macrophages 2. b (Fibroblast): produced by fibroblasts & epithelial cells Type II: g (Immune): produced by T cells and NK cells  Mechanism of Interferons 30  5.c. Lysozyme It is an antimicrobial enzyme that forms part of the innate immune system. Lysozyme is a glycoside hydrolase that catalyzes the hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in peptidoglycan, which is the major component of Gram- positive bacterial cell wall causing lysis of the bacteria. Lysozyme is abundant in secretions including tears, saliva, human milk, and mucus. It is also present in cytoplasmic granules of the macrophages and neutrophils. 5.c. Lysozyme 32 https://maxfacts.uk/help/oral-hygiene/saliva-and-teeth-mucosa  5.d. Acute-Phase Proteins Acute-phase proteins (APPs) are a class of proteins whose plasma concentrations increase (positive acute- phase proteins) in response to inflammation. The local inflammatory cells (neutrophil and macrophages) secrete a number of cytokines (interleukins IL1, IL6, IL8 and TNF-α) into bloodstream. The liver responds by producing many acute-phase proteins (such as C-reactive protein) which involve in: 1. Fever 2. Acceleration of peripheral circulating neutrophils 3. Repair tissue damage 5.d. Acute-Phase Proteins 34 Innate Immunity Vs. Adaptive Immunity Criterion Innate immune system Adaptive immune system It is created in response to It is already present in the body. Presence exposure to a foreign substance. Pathogen and antigen Specificity Response is non-specific specific response Slow (1-2 Response Rapid (hours) weeks) Potency Limited and Lower potency High potency can remember the specific Memory No immunological memory pathogens which have encountered before. It is composed of physical and It is composed of B cells chemical barriers, phagocytic and T cells. Types leukocytes, dendritic cells, (Cell-mediated and natural killer cells, and plasma humoral immunity) proteins.