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4. innate immune system
- 1. INNATE IMMUNE SYSTEM PHYSIOLOGY: IMMUNO & HEME
- 3. BARRIERS TO INFECTION OVERVIEW ‣ The innate immune system has several first-line barriers to infection, preventing the entry and growth of pathogens ‣ It is also important to note that the following barriers work in parallel with various cellular and humoral agents (from both the innate and adaptive immune systems) to prevent colonization and infection ‣ Learning Goal ‣ To discuss the physical, physiological, chemical and biological barriers and clinical conditions that may result from their failure
- 4. BARRIERS TO INFECTION PHYSICAL BARRIERS ‣ These barriers provide a physical block against pathogens ‣ The largest barrier comprises the skin, which has a large surface area and covers most of the body’s external surfaces ‣ Superficially, the skin has multiple layers of dead, keratinized epithelium which is continuously sloughed off, facilitating the removal of any adherent microbes ‣ The mucous membranes of the respiratory, gastrointestinal and urinary tracts are also in contact with the external environment ‣ The outermost, epithelial layer is held together by tight junctions, making it robust enough to impede deeper pathogen access
- 5. BARRIERS TO INFECTION PHYSICAL BARRIERS ‣ Another physical barrier of the innate system is the bronchial cilia ‣ These cells form the mucociliary escalator, which allows the gradual removal of pathogens from the respiratory system ‣ Finally, some surfaces are constantly irrigated by various secretions ‣ The free flow and drainage of secretions are important in and of themselves in avoiding infections ‣ Tears, urine, saliva, bile, pancreatic secretions, mucus and sebaceous secretions help protect the surfaces they flow over from infection by reducing pathogenic attachment and duration of contact with bodily surfaces ‣ If the flow is obstructed, the static fluid becomes a nutritious site for infection by various microorganisms
- 9. BARRIERS TO INFECTION PHYSIOLOGICAL BARRIERS ‣ The physiological barriers of the body are processes that occur in response to pathogens to remove them from the system and vary depending on location and situation ‣ The main physiological barriers are: ‣ Diarrhoea ‣ Vomiting ‣ Coughing ‣ Sneezing
- 10. BARRIERS TO INFECTION CHEMICAL BARRIERS ‣ Broadly speaking, there are two main chemical barriers to infection ‣ Firstly, there are microenvironmental factors such as pH ‣ The relatively low pH in certain parts of the body prevents pathogen growth ‣ For example, the following areas of the body have an acidic pH: ‣ Skin – pH 5.5 ‣ Gastric acid – pH 1-3 ‣ Vagina – pH 4.4 ‣ These conditions create a hostile environment that pathogens struggle to thrive in and, especially in the case of gastric acid, can directly kill microorganisms by denaturing their proteins
- 11. BARRIERS TO INFECTION CHEMICAL BARRIERS ‣ There are also a variety of innate antimicrobial molecules throughout the body that can aid in the destruction of pathogens: ‣ IgA – present in tears, saliva and mucous membranes ‣ Lysozyme ‣ Has bactericidal properties ‣ Present in sebum, perspiration and urine ‣ Paneth cells in the crypts of the small intestine produce lysozymes as well as phospholipase A and defensins ‣ Mucus ‣ Has antiseptic peptides and works passively to prevent bacterial adhesion ‣ The viscous nature of mucous traps bacteria, which can then be actively cleared by the mucociliary escalator in the lung or peristalsis of the gut ‣ It is present in mucous membranes
- 12. BARRIERS TO INFECTION CHEMICAL BARRIERS ‣ Defensins ‣ Epithelial cells and cells of the innate immune system produce small proteins called defensins ‣ There are many types with various antimicrobial and antifungal properties ‣ However, the main two types found in vertebrates are alpha and beta-defensins ‣ Beta-defensins help epithelial surfaces to to resist microbial colonization ‣ They can kill microbes by creating channels and disrupting the microbial cell membrane ‣ Alpha defensins are found in macrophages, neutrophils and intestinal paneth cells ‣ Enzymes ‣ Eg. pepsin is an endopeptidase present in the gastrointestinal tract and can help kill bacteria through proteolysis
- 13. BARRIERS TO INFECTION BIOLOGICAL BARRIERS ‣ The main biological barrier to pathogens is the normal flora found within the body ‣ These are non-pathogenic microbes found within strategic locations of the body, primarily those in contact with the external environment ‣ These are typically found in the: ‣ Nasopharynx ‣ Mouth and throat ‣ Skin ‣ GI tract ‣ Vagina
- 14. BARRIERS TO INFECTION BIOLOGICAL BARRIERS ‣ Normal flora consist of non-invasive commensal microorganisms that do not normally cause disease ‣ However, they outcompete pathogens for attachment sites and resources and may even produce antimicrobial chemicals ‣ For example, vaginal bacilli secrete antimicrobial peptides like lactic acid to inhibit pathogenic activity ‣ In addition to this, many also produce essential vitamins, such as Vitamin K and B12
- 15. BARRIERS TO INFECTION BIOLOGICAL BARRIERS ‣ Loss of normal microbiota is associated with the use of antibiotics, or excessive use of antiseptic solutions ‣ This can provide an opportunity for pathogenic bacteria to colonize the vacated tissues ‣ The use of systemic, broad-spectrum antibiotics such as penicillins/ cephalosporins lead to alterations in the normal bowel flora ‣ The treatment kills off the competing, commensal species ‣ This subsequently allows the outgrowth of pathogenic species such as Clostridium difficile which produce harmful toxins, resulting in intestinal inflammation and abdominal symptoms
- 25. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ What is the normal pH range for gastric acid? ‣ pH 1-3 ‣ pH 2-5 ‣ pH 7 ‣ pH 8-10
- 26. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ What is the normal pH range for gastric acid? ‣ pH 1-3 ‣ pH 2-5 ‣ pH 7 ‣ pH 8-10
- 27. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following is NOT one of the antimicrobial molecules that form a chemical barrier to infections? ‣ IgA ‣ IgE ‣ Lysozyme ‣ Pepsin
- 28. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following is NOT one of the antimicrobial molecules that form a chemical barrier to infections? ‣ IgA ‣ IgE ‣ Lysozyme ‣ Pepsin ‣ IgE is released by mast cells and basophils as a part of the allergic response
- 29. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ What is the empirical antibiotic class of choice for bacterial meningitis? ‣ Macrolides ‣ Tetracyclines ‣ Quinolones ‣ Cephalosporins
- 30. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ What is the empirical antibiotic class of choice for bacterial meningitis? ‣ Macrolides ‣ Tetracyclines ‣ Quinolones ‣ Cephalosporins
- 31. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following is NOT part of the normal flora of the stomach? ‣ Clostridium spp. ‣ Lactobacillus ‣ Streptococcus ‣ Staphylococcus
- 32. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following is NOT part of the normal flora of the stomach? ‣ Clostridium spp. ‣ Lactobacillus ‣ Streptococcus ‣ Staphylococcus
- 33. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following vitamins do normal flora within the body produce? ‣ Vitamin A ‣ Vitamin B12 ‣ Vitamin C ‣ Vitamin D
- 34. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following vitamins do normal flora within the body produce? ‣ Vitamin A ‣ Vitamin B12 ‣ Vitamin C ‣ Vitamin D
- 35. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ What type of barrier to infection is coughing? ‣ Physical ‣ Chemical ‣ Biological ‣ Physiological
- 36. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ What type of barrier to infection is coughing? ‣ Physical ‣ Chemical ‣ Biological ‣ Physiological
- 37. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following is a physical barrier to infection? ‣ Diarrhea ‣ Mucociliary escalator ‣ Gastric acid ‣ Normal flora
- 38. BARRIERS TO INFECTION REVIEW QUESTIONS ‣ Which of the following is a physical barrier to infection? ‣ Diarrhea ‣ Mucociliary escalator ‣ Gastric acid ‣ Normal flora
- 39. CYTOKINES
- 40. CYTOKINES OVERVIEW ‣ Cytokines (literally “cell movement”) are a group of small proteins used in cell– signalling ‣ They are produced by a wide range of cells, including macrophages, lymphocytes, mast cells, endothelial cells and fibroblasts ‣ They are responsible for producing some of the cardinal signs of inflammation and influence both the innate and adaptive immune responses ‣ There are different types of cytokines including chemokines, interferons, interleukins, lymphokines and tumour necrosis factors ‣ Learning Goal ‣ To look at different classes of cytokine and their actions
- 41. CYTOKINES CHEMOKINES ‣ Chemokines induce chemotaxis (chemical-induced migration) in local cells ‣ Following the release of chemokines, local cells are attracted to these proteins and follow their concentration gradient to the source, where the concentration is highest ‣ The source is where the chemokines were originally released and where the cells attracted are most needed ‣ They are mainly produced by macrophages during infection, for example, Interleukin-8 (IL-8) recruits neutrophils to the site during the acute phase response
- 42. CYTOKINES CHEMOKINES ‣ Cells need chemokine receptors to respond to these cytokines ‣ Chemokine receptors are G protein-coupled receptors which activate phospholipase C, leading to the release of calcium from intracellular stores ‣ This, subsequently, gives rise to several downstream effects including, cytoskeletal changes, pseudopod formation and enhanced cell adhesion through integrins
- 43. CYTOKINES CHEMOKINE ACTIONS ‣ Chemokines can have many actions within tissues ‣ These can be: ‣ Pro-inflammatory –> recruiting immune cells to the site of infection or injury ‣ These chemokines are inducible ‣ Cells produce or upregulate pro-inflammatory chemokines in response to infection or trauma ‣ Chemokine secretion is stimulated by other pro-inflammatory cytokines (TNF α, IFN γ) or microbial products (lipopolysaccharide) ‣ Pro-inflammatory chemokines allow immune cells such as neutrophils and monocytes to exit the bone marrow and hone into affected tissues
- 44. CYTOKINES CHEMOKINE ACTIONS ‣ Homeostatic –> attracting cells required for angiogenesis and allowing for the growth of new blood vessels ‣ These chemokines are constitutively produced ‣ The body maintains basal levels without the need for a specific stimulus ‣ Eg. Stromal cells within the bone marrow secrete CXCL12 which binds to its receptor, CXCR4, and this helps to retain neutrophils in the bone marrow until they are mobilized into the circulation during infection ‣ Chemokines are involved in immune surveillance and allow T cells and dendritic cells to migrate and circulate through secondary lymphoid organs in search of potential pathogens ‣ Chemokines are also key to the development of lymph organs and positioning of cells within lymphoid tissues ‣ Eg. A specific subset of B cells- responsible for mounting T-independent responses and producing IgM against encapsulated bacteria – localize to the marginal zone in the spleen through CXCR7 ‣ Note: Some chemokines have both pro-inflammatory and homeostatic roles
- 46. CYTOKINES INTERFERONS ‣ Interferons are a type of cytokine released by host cells in response to pathogens (e.g. viruses and bacteria) and tumour cells ‣ They are grouped according to their complementary receptor ‣ There are three main groups: ‣ type I (interferon-α and interferon-β) ‣ type II (interferon-γ) ‣ type III (Interferon λ) ‣ Type III has similar actions to type I and type II
- 47. CYTOKINES INTERFERON ACTIONS ‣ These cytokines have a number of roles : ‣ Type-I Interferons ‣ Almost any body cell can produce type-I interferons, including fibroblasts, endothelial cells and macrophages ‣ Type I interferons such as Interferon-α and interferon-β interfere with viral replication and help the immune system fight viral infections ‣ They are expressed in response to microbial products ‣ Once secreted by the infected cell, they bind to the interferon receptors on the same cell and neighbouring cells ‣ This autocrine and paracrine signalling causes changes in gene expression within the cell ‣ As a result, this leads to the destruction of viral mRNA and prevents host and viral protein translation ‣ They also upregulate NK cell ligands and MHC I on the cell surface ‣ So that NK cells and cytotoxic T cells are more likely to detect and attack virus-infected cells
- 48. CYTOKINES INTERFERON ACTIONS ‣ Type-II interferons ‣ Interferon-γ is a type-II interferon ‣ NK cells, cytotoxic T cells and Th1 cells produce interferon-γ in response to IL-12 and IL-18 ‣ Interferon-γ activates macrophages and increases their ability to kill pathogens by enhancing pinocytosis and lysosome function ‣ Type-II interferons also upregulate MHC II expression ‣ This promotes antigen-presentation and effective phagocytosis ‣ Note: there is overlap between interferon-I and interferon-II actions but they are both important for anti-viral and anti-tumour responses
- 49. CYTOKINES INTERLEUKINS ‣ Interleukins are another type of cytokine produced by T-lymphocytes, monocytes and macrophages ‣ They have a wide range of functions, including: ‣ Promoting the production and differentiation of B and T lymphocytes ‣ Specifically, IL-1α/β, IL-4, IL-7 and IL-21 ‣ Activating neutrophils and natural killer cells – for example, IL-2, IL-8 and IL-12 ‣ Producing detectable signs ‣ Interleukin-6 (IL-6) increases body temperature (fever) which inhibits microbial growth ‣ IL-6, additionally, raises acute phase proteins such as C-reactive protein (CRP) which is associated with inflammation ‣ Promoting vascular permeability which causes swelling and allows faster recruitment of cells involved in immunity
- 50. CYTOKINES TUMOR NECROSIS FACTOR ‣ Tumour necrosis factor (TNF) is a cytokine mainly produced by macrophages when they encounter an endotoxin ‣ However, it can also be produced by other cells of the immune system including, mast cells, B cells and T cells ‣ TNF α and β have similar functions, including: ‣ Local induction of apoptosis ‣ Increasing local vascular permeability ‣ Neutrophil chemotaxis ‣ Stimulation of a pro-inflammatory state – for instance, by increasing CRP production in the liver and prostaglandin E2 production by macrophages (and TNF also induces fever) ‣ Suppression of appetite ‣ High concentrations of TNF can induce shock through the increase in vascular permeability and resulting drop in blood pressure ‣ On the other hand, chronic exposure to low levels leads to the syndrome of cachexia which is often seen in chronic infection and cancer
- 58. CYTOKINES REVIEW QUESTIONS ‣ What is the definition of chemotaxis? ‣ Directional movement of a phagocyte towards a chemical attractant ‣ Activation of resting phagocytes by inflammatory mediators ‣ Leucocytes assume marginal positions in blood vessels ‣ Production of collagenase by leucocytes to allow them to exit blood vessels
- 59. CYTOKINES REVIEW QUESTIONS ‣ What is the definition of chemotaxis? ‣ Directional movement of a phagocyte towards a chemical attractant ‣ Activation of resting phagocytes by inflammatory mediators ‣ Leucocytes assume marginal positions in blood vessels ‣ Production of collagenase by leucocytes to allow them to exit blood vessels ‣ The first option is the correct definition. "Activation of resting phagocytes by inflammatory mediators" describes the process of activation of phagocytes. "Leucocytes assume marginal positions in blood vessels" describes the process of margination and "Production of collagenase by leucocytes to allow them to exit blood vessels" describes the process of diapedesis.
- 60. CYTOKINES REVIEW QUESTIONS ‣ Which group of cytokines are responsible for increasing MHC class molecule expression? ‣ Chemokines ‣ Interferons ‣ Interleukins ‣ Tumour Necrosis Factor
- 61. CYTOKINES REVIEW QUESTIONS ‣ Which group of cytokines are responsible for increasing MHC class molecule expression? ‣ Chemokines ‣ Interferons ‣ Interleukins ‣ Tumour Necrosis Factor
- 62. CYTOKINES REVIEW QUESTIONS ‣ Which of these cell types produces interferon-γ? ‣ B cells ‣ Plasma cells ‣ Macrophages ‣ Th1 cells
- 63. CYTOKINES REVIEW QUESTIONS ‣ Which of these cell types produces interferon-γ? ‣ B cells ‣ Plasma cells ‣ Macrophages ‣ Th1 cells
- 64. CYTOKINES REVIEW QUESTIONS ‣ What is the role of IL-10? ‣ Production of acute phase proteins ‣ Inhibition of viral replication ‣ Inhibition of immune function ‣ Induces differentiation of CD4 T cells into Th2 cells
- 65. CYTOKINES REVIEW QUESTIONS ‣ What is the role of IL-10? ‣ Production of acute phase proteins ‣ Inhibition of viral replication ‣ Inhibition of immune function ‣ Induces differentiation of CD4 T cells into Th2 cells
- 66. CYTOKINES REVIEW QUESTIONS ‣ Which of the following conditions can be treated with interleukins? ‣ Ovarian cancer ‣ Melanoma ‣ Hepatitis B ‣ Chronic Granulomatous Disease
- 67. CYTOKINES REVIEW QUESTIONS ‣ Which of the following conditions can be treated with interleukins? ‣ Ovarian cancer ‣ Melanoma ‣ Hepatitis B ‣ Chronic Granulomatous Disease
- 68. CYTOKINES REVIEW QUESTIONS ‣ Which of the following cytokines does NOT induce fever during infection? ‣ Interferon-α ‣ TNF-α ‣ IL-6 ‣ IL-1
- 69. CYTOKINES REVIEW QUESTIONS ‣ Which of the following cytokines does NOT induce fever during infection? ‣ Interferon-α ‣ TNF-α ‣ IL-6 ‣ IL-1
- 70. CYTOKINES REVIEW QUESTIONS ‣ Which of the following cytokines is responsible for the syndrome of cachexia in chronic infection and cancer? ‣ Interferons ‣ Chemokines ‣ Tumour Necrosis Factor ‣ Interleukins
- 71. CYTOKINES REVIEW QUESTIONS ‣ Which of the following cytokines is responsible for the syndrome of cachexia in chronic infection and cancer? ‣ Interferons ‣ Chemokines ‣ Tumour Necrosis Factor ‣ Interleukins
- 72. CYTOKINES REVIEW QUESTIONS ‣ Which of the following cytokines does NOT play a role in inhibiting viral replication? ‣ Interferon-γ ‣ IL-12 ‣ Interferon-β ‣ Interferon-α
- 73. CYTOKINES REVIEW QUESTIONS ‣ Which of the following cytokines does NOT play a role in inhibiting viral replication? ‣ Interferon-γ ‣ IL-12 ‣ Interferon-β ‣ Interferon-α
- 74. CYTOKINES REVIEW QUESTIONS ‣ Which of the following is an example of a chemokine? ‣ IL-8 ‣ Interferon-α ‣ TNF-α ‣ IL-17
- 75. CYTOKINES REVIEW QUESTIONS ‣ Which of the following is an example of a chemokine? ‣ IL-8 ‣ Interferon-α ‣ TNF-α ‣ IL-17
- 77. INFECTION RECOGNITION MOLECULES OVERVIEW ‣ In order to establish themselves in the body, pathogens must first gain entry into the body by penetrating the first line of defence, including natural barriers such as the skin, tears, mucus, cilia and stomach acid ‣ After a pathogen has entered the body, it is vital for cells of the immune system to identify the pathogen as foreign and destroy it ‣ In the innate immune system, this involves interaction between Pathogen Associated Molecular Patterns (PAMPs) and Pattern Recognition Receptors (PRRs) ‣ In the adaptive immune system, this involves interaction between Major Histocompatibility Complexes (MHCs) and T cells ‣ Learning Goal ‣ To discuss how the immune system recognizes foreign cells through infection recognition molecules
- 78. INFECTION RECOGNITION MOLECULES PATTERN RECOGNITION RECEPTORS ‣ The innate immune system is rapid and non-specific, quickly phagocytosing foreign cells ‣ It uses Pattern Recognition Receptors (PRRs) to recognize pathogens ‣ Pattern Recognition Receptors are infection recognition receptors located on immune cells such as macrophages and dendritic cells ‣ They bind to Pathogen Associated Molecular Patterns (PAMPs) ‣ A PAMP is a specific arrangement of carbohydrates, lipids and nucleic acids on the surface of a pathogen that signals to a phagocyte that a cell is foreign ‣ Many different molecules can act as PAMPs, including peptidoglycans, endotoxin and flagellin
- 79. INFECTION RECOGNITION MOLECULES MEMBRANE-ASSOCIATED PRRS ‣ PRRs can be located on the cell surface, for extracellular infection recognition, or in the cytoplasm, to target intracellular pathogens such as viruses ‣ The main type of PRR is a Toll-like receptor (TLR), of which there are 11 types in humans, all recognizing different PAMPs ‣ Toll-like receptors are an example of a PRR located on the cell surface
- 81. INFECTION RECOGNITION MOLECULES MEMBRANE-ASSOCIATED PRRS ‣ There are multiple other types of PRR, including mannose receptors, but these exist in fewer numbers ‣ Unlike components of the adaptive immune system, PRRs are not specific to individual pathogens, but to groups of pathogens ‣ Thus, they do not possess cellular memory
- 82. INFECTION RECOGNITION MOLECULES SECRETED PRRS ‣ In addition to the PRRs associated with cell membranes discussed above, a number of PRRs are produced during the acute phase response and released into the bloodstream ‣ One of these is Mannose-binding lectin (MBL) ‣ This is an acute phase protein produced by the liver and is an example of a collectin ‣ Collectins are proteins present in solution throughout the body with collagen-like domains and sugar-binding (lectin) domains
- 83. INFECTION RECOGNITION MOLECULES SECRETED PRRS ‣ These are able to bind to surface sugars on pathogens, known as opsonisation, making them easier targets for phagocytosis ‣ Another PRR produced by the liver as an acute phase protein is C- Reactive Protein (CRP) ‣ This binds to a molecule known as phosphocholine in microbial polysaccharides ‣ Once bound the pathogen has been opsonized for phagocytosis and complement is activated ‣ Raised CRP levels in the blood is commonly used as a marker of infection and inflammation
- 84. INFECTION RECOGNITION MOLECULES MAJOR HISTOCOMPATIBILITY COMPLEXES ‣ The adaptive immune system becomes active after the first few foreign cells have been phagocytosed ‣ Lymphocytes mount a specific immune response by recognizing antigens on the surface on antigen-presenting cells such as macrophages ‣ Once a pathogen has been phagocytosed, the macrophage or dendritic cell digests the pathogen and presents a small peptide (the antigen) on its surface ‣ The antigen is presented as part of a receptor that is located on the surface of antigen-presenting cells ‣ This receptor is known as a Major Histocompatibility Complex (MHC) and forms an important role in stimulating the adaptive, pathogen-specific immune system
- 85. INFECTION RECOGNITION MOLECULES MAJOR HISTOCOMPATIBILITY COMPLEXES ‣ There are two types of MHC molecules, each of which have different roles ‣ MHC Class I ‣ Present peptides from intracellular pathogens ‣ Bind to and stimulate T-cytotoxic cells only ‣ MHC Class II ‣ Present peptides from extracellular pathogens ‣ Bind to and stimulate T-helper cells (CD4 cells)
- 86. INFECTION RECOGNITION MOLECULES MAJOR HISTOCOMPATIBILITY COMPLEXES ‣ In humans, MHCs are called Human Leukocyte Antigens (HLAs) ‣ HLAs corresponding to MHC Class I include HLA A, B and C ‣ These are involved in presenting antigens from intracellular pathogens ‣ HLAs corresponding to MHC Class II include HLA D, which has several subtypes such as HLA DP, DQ and DR, among others ‣ These are involved in presenting antigens from extracellular pathogens
- 88. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ Where is C-Reactive Protein produced? ‣ The spleen ‣ The bone marrow ‣ The liver ‣ The appendix
- 89. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ Where is C-Reactive Protein produced? ‣ The spleen ‣ The bone marrow ‣ The liver ‣ The appendix
- 90. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ What is the term for the part of a pathogen’s surface that signals it is foreign to a phagocyte? ‣ Pattern Recognition Receptors ‣ Pathogen Associated Molecule Patterns ‣ Toll-like Receptors ‣ Acute Phase Proteins
- 91. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ What is the term for the part of a pathogen’s surface that signals it is foreign to a phagocyte? ‣ Pattern Recognition Receptors ‣ Pathogen Associated Molecule Patterns ‣ Toll-like Receptors ‣ Acute Phase Proteins ‣ Pattern recognition receptors interact with pathogen associated molecule patterns on the surface of pathogens - this signals that they are foreign to phagocytes.
- 92. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ What is the role of opsonization? ‣ Direct killing of pathogens ‣ Making pathogens easier targets for phagocytosis ‣ Antigen presentation ‣ Production of interferon
- 93. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ What is the role of opsonization? ‣ Direct killing of pathogens ‣ Making pathogens easier targets for phagocytosis ‣ Antigen presentation ‣ Production of interferon ‣ Opsonisation makes pathogens easier targets for phagocytosis, particularly in the case of encapsulated bacteria.
- 94. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ Which cells do MHC class II molecules stimulate? ‣ T helper cells ‣ Cytotoxic T cells ‣ Plasma cells ‣ B memory cells
- 95. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ Which cells do MHC class II molecules stimulate? ‣ T helper cells ‣ Cytotoxic T cells ‣ Plasma cells ‣ B memory cells
- 96. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ How many types of Toll-like receptor are there in humans? ‣ 2 ‣ 5 ‣ 9 ‣ 11
- 97. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ How many types of Toll-like receptor are there in humans? ‣ 2 ‣ 5 ‣ 9 ‣ 11
- 98. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ Which MHC class molecules do cytotoxic T cells interact with? ‣ MHC class II ‣ MHC class V ‣ MHC class I ‣ MHC class IV
- 99. INFECTION RECOGNITION MOLECULES REVIEW QUESTIONS ‣ Which MHC class molecules do cytotoxic T cells interact with? ‣ MHC class II ‣ MHC class V ‣ MHC class I ‣ MHC class IV
- 100. PHAGOCYTOSIS
- 101. PHAGOCYTOSIS OVERVIEW ‣ Phagocytosis is a type of endocytosis whereby a cell engulfs a particle to form an internal compartment called a phagosome ‣ The cell rearranges its membrane to surround the particle that is to be phagocytosed and internalises it ‣ Within the phagosome that then forms the particle can be degraded ‣ In the immune system, it is a major mechanism that the body uses to remove potentially pathogenic material ‣ Learning Goal ‣ To briefly review the process of phagocytosis, highlight major phagocytes in the immune system and discuss the clinical relevance of phagocytosis
- 102. PHAGOCYTOSIS PHAGOCYTIC CELLS OF THE IMMUNE SYSTEM ‣ Many cells are capable of phagocytosis, but several types of immune cells are particularly specialized in this role ‣ Neutrophils – these are abundant in the blood and important in acute inflammation, as they are the first immune cells to arrive at the site of infection ‣ Macrophages – tissue resident cells that are key as a first defence mechanism and in initiating the adaptive immune response ‣ Dendritic cells – these cycle through the bloodstream, tissues and lymphoid organs, sampling potential pathogens and acting as a major link between the innate and adaptive immune systems
- 103. PHAGOCYTOSIS STAGES OF PHAGOCYTOSIS - ACTIVATION ‣ Resting phagocytes become activated by inflammatory mediators (e.g. bacterial proteins, capsules, peptidoglycan, prostaglandins, complement proteins) ‣ The result is that they gain the ability to leave the capillaries and enter the tissues towards the site of infection (chemotaxis) ‣ Phagocytes switch to a higher energy level ‣ This usually involves rearrangement of the cell cytoskeleton and swelling of the cell (caused by calcium and sodium ion influx) ‣ Phagocytes also produce pattern recognition receptors (PRRs) which recognize and bind to pathogen-associated molecular patterns (PAMPs) ‣ PAMPs are components of pathogens and can include molecules like peptidoglycan and lipopolysaccharide (LPS)
- 104. PHAGOCYTOSIS STAGES OF PHAGOCYTOSIS - CHEMOTAXIS ‣ This is the directional movement of the phagocyte towards a chemical attractant (chemotaxin) ‣ Chemotaxins include bacterial products (e.g. endotoxin), injured tissues, complement proteins (C3a, C4a, C5a) and chemical substances produced by leukocytes (leukotrienes) ‣ The process of chemotaxis is usually coupled with activation
- 106. PHAGOCYTOSIS STAGES OF PHAGOCYTOSIS - MARGINATION, ROLLING AND ADHESION ‣ In margination, leucocytes assume marginal positions in the blood vessels ‣ They stick to the walls of the venules and roll along them until they become firmly attached to the vessel wall (adhesion) ‣ At this point, they begin to move out of the vessel
- 108. PHAGOCYTOSIS STAGES OF PHAGOCYTOSIS - DIAPEDESIS ‣ This refers to the process of the leucocytes ‘digging’ their way out of the venules ‣ They produce the enzyme collagenase which digests the basement membrane at their attachment point; allowing them to escape
- 109. PHAGOCYTOSIS STAGES OF PHAGOCYTOSIS - RECOGNITION-ATTACHMENT ‣ This can either be due to the innate recognition of PAMPs by the phagocyte through its PRRs (unenhanced attachment) or the phagocyte can attach itself to the microbe through antibody molecules (IgG) or complement proteins (C3b, C4b) ‣ This is known as enhanced attachment, and it is much more specific and efficient than unenhanced attachment
- 110. PHAGOCYTOSIS STAGES OF PHAGOCYTOSIS - PHAGOCYTOSIS ‣ After attachment, the phagocyte internalizes the microbe into a phagosome ‣ The phagosome then fuses with a lysosome to form a phagolysosome ‣ Lysosomes contain digestive enzymes which can destroy the internalized material ‣ Pathogen killing can occur in one of two ways: ‣ The oxygen dependent pathway (oxidative burst) involves the generation of reactive oxygen species (ROS) such as the superoxide radical and hydrogen peroxide ‣ These highly reactive radical molecules react with proteins, lipids and other biological molecules to kill the pathogen
- 111. PHAGOCYTOSIS STAGES OF PHAGOCYTOSIS - PHAGOCYTOSIS ‣ Superoxide radicals are initially produced (via the enzyme NADPH oxidase) and subsequently converted to hydrogen peroxide by the enzyme superoxide dismutase. ‣ Superoxide radicals can also react with the hydrogen peroxide to form powerful hydroxyl radicals which assist in killing the invading pathogen ‣ The oxygen independent pathway involves the destruction of the pathogen via lysosomal enzymes such as proteases, phospholipases, nucleases and lysozyme ‣ These enzymes help in destroying the pathogen primarily by breaking down its cell membrane ‣ This a less effective mechanism when compared to the oxygen dependent pathway
- 113. PHAGOCYTOSIS CLINICAL RELEVANCE – CHRONIC GRANULOMATOUS DISEASE (CGD) ‣ This is a group of inherited diseases caused by a NADPH oxidase deficiency ‣ NADPH oxidase is a key enzyme required to produce reactive oxygen species, particularly the superoxide radical ‣ The result of this is ineffective phagocytosis, as patients are less able to phagocytose via the oxygen dependent pathway (oxidative burst) ‣ This leads to persistent inflammation and granuloma formation in many organs as well as persistent infections ‣ Patients typically suffer from recurrent pneumonia, skin abscesses, arthritis and cellulitis and osteomyelitis ‣ This is often picked up during childhood ‣ Management is usually via antibiotic therapy and immunomodulation
- 114. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which of the following phagocytes has the shortest lifespan? ‣ Neutrophils ‣ Macrophages ‣ Microglia ‣ Dendritic cells
- 115. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which of the following phagocytes has the shortest lifespan? ‣ Neutrophils ‣ Macrophages ‣ Microglia ‣ Dendritic cells ‣ Neutrophils have a short lifespan of only 2-3 days as they are mainly involved in the acute phase response to infection.
- 116. PHAGOCYTOSIS REVIEW QUESTIONS ‣ What is the term for the process by which dendritic cells sample pathogens they encounter? ‣ Phagocytosis ‣ Degranulation ‣ Macropinocytosis ‣ Lysis
- 117. PHAGOCYTOSIS REVIEW QUESTIONS ‣ What is the term for the process by which dendritic cells sample pathogens they encounter? ‣ Phagocytosis ‣ Degranulation ‣ Macropinocytosis ‣ Lysis
- 118. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which of the following is NOT a stage of phagocytosis? ‣ Margination ‣ Chemotaxis ‣ Rolling ‣ Immunomodulation
- 119. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which of the following is NOT a stage of phagocytosis? ‣ Margination ‣ Chemotaxis ‣ Rolling ‣ Immunomodulation
- 120. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which enzyme is deficient in Chronic Granulomatous Disease (CGD)? ‣ Superoxide dismutase ‣ Collagenase ‣ NADPH oxidase ‣ Lipase
- 121. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which enzyme is deficient in Chronic Granulomatous Disease (CGD)? ‣ Superoxide dismutase ‣ Collagenase ‣ NADPH oxidase ‣ Lipase ‣ A deficiency in NADPH oxidase means these patients cannot produce superoxide radicals and so are less able to phagocytose pathogens via the oxygen dependent pathway.
- 122. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which enzyme is responsible for the conversion of superoxide radicals to hydrogen peroxide? ‣ Collagenase ‣ Lysozyme ‣ NADPH oxidase ‣ Superoxide dismutase
- 123. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which enzyme is responsible for the conversion of superoxide radicals to hydrogen peroxide? ‣ Collagenase ‣ Lysozyme ‣ NADPH oxidase ‣ Superoxide dismutase
- 124. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which process involves the generation of reactive oxygen species to kill pathogens? ‣ Oxidative burst ‣ Oxygen independent pathway ‣ Diapedesis ‣ Chemotaxis
- 125. PHAGOCYTOSIS REVIEW QUESTIONS ‣ Which process involves the generation of reactive oxygen species to kill pathogens? ‣ Oxidative burst ‣ Oxygen independent pathway ‣ Diapedesis ‣ Chemotaxis
- 127. THE COMPLEMENT SYSTEM OVERVIEW ‣ The complement system, also known as the complement cascade, forms a part of the innate immune system ‣ Complement components are generally made in the liver and circulate in their inactive form until they are needed ‣ The overall aim of the complement system is to support other parts of the immune response by opsonizing pathogens and triggering inflammation ‣ Learning Goal ‣ To cover the activation of the complement system, its roles in the immune response and relevant clinical conditions
- 128. THE COMPLEMENT SYSTEM ACTIVATION OF THE COMPLEMENT SYSTEM ‣ There are three ways to activate the complement system, involving different molecules initially but converging to produce the same effector molecules ‣ Each involves activation of enzymes that cleave their substrates to form a cascade, so that the complement response is amplified ‣ The Classical Pathway ‣ The Mannose-Binding Lectin Pathway ‣ The Alternative Pathway ‣ All three pathways produce C3 convertase, an enzyme which triggers further effects downstream
- 129. THE COMPLEMENT SYSTEM THE CLASSICAL PATHWAY ‣ The classical pathway is activated when a complement protein called C1q binds either directly to a pathogen, or onto an antigen-antibody complex ‣ This will then trigger cleavage of the subsequent complement proteins in the cascade, resulting in production of C3 convertase and it’s downstream effects ‣ Its involvement in antigen-antibody complexes means it has a role in the adaptive immune response as well as the innate
- 130. THE COMPLEMENT SYSTEM THE MANNOSE-BINDING LECTIN (MBL) PATHWAY ‣ Mannose-Binding Lectin (MBL) is a protein produced in the liver ‣ Its role is to detect carbohydrates containing mannose on the surface of pathogens, activating a protease called MASP ‣ MASP is responsible for cleaving complement components, which activates a similar cascade to the classical pathway, eventually producing C3 convertase
- 131. THE COMPLEMENT SYSTEM THE ALTERNATIVE PATHWAY ‣ The alternative pathway is usually activated by bacterial endotoxin, a lipopolysaccharide present on the outer membrane of gram negative bacteria ‣ This results in spontaneous hydrolysis of C3 into small amounts of factor C3b, which combines with other factors to produce C3 convertase
- 132. THE COMPLEMENT SYSTEM IMMUNE EFFECTS OF THE COMPLEMENT SYSTEM ‣ Whichever way C3 is activated it will then activate C5, which in turn activates C6, C7, C8 and C9 in a cascade ‣ As such even a small signal can lead to the rapid activation of many thousands of complement molecules – this is important in the immune response as pathogens are also able to replicate very quickly within the body ‣ Once activated the complement system has several effects, including: ‣ Opsonization ‣ Lysis of pathogens ‣ Chemotaxis ‣ Inflammation
- 133. THE COMPLEMENT SYSTEM OPSONISATION ‣ C3 convertase is a product of all the pathways triggering the complement cascade and is responsible for converting factor C3 into C3a and C3b ‣ C3b binds to antigens on the pathogen, which stimulates neutrophils and macrophages to phagocytose pathogens ‣ this is called opsonization
- 134. THE COMPLEMENT SYSTEM LYSIS OF PATHOGENS ‣ Lysis of pathogens is facilitated by the formation of the membrane attack complex (MAC) ‣ C3 convertase is vital to the production of the MAC because it generates C3a and C3b ‣ C3b combines with other factors to produce C5 convertase, an enzyme which converts factor C5 to C5a and C5b ‣ C5b combines with several factors to produce the MAC ‣ The MAC ruptures the bacterial cell membrane, allowing fluid to enter the bacteria and causing cell lysis ‣ Note: because they possess a cell wall, gram positive bacteria and fungi do not swell and hence cannot be lysed by the complement system
- 135. THE COMPLEMENT SYSTEM CHEMOTAXIS ‣ The production of C5a by C5 convertase attracts neutrophils and macrophages to the site of infection and causes extravasation of leucocytes from capillaries to tissues ‣ C3a is another complement component that acts as a chemotaxin
- 136. THE COMPLEMENT SYSTEM INFLAMMATION ‣ C3a, C4a and C5a are the complement components responsible for causing inflammation ‣ They bind to mast cells and basophils to cause degranulation ‣ The histamine and serotonin released increase vascular permeability ‣ C3a, C4a and C5a also promote synthesis of pro- inflammatory cytokines
- 139. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which of these is NOT a way in which the complement system can be activated? ‣ The Antigen Pathway ‣ The Classical Pathway ‣ The Mannose-Binding Lectin Pathway ‣ The Alternative Pathway
- 140. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which of these is NOT a way in which the complement system can be activated? ‣ The Antigen Pathway ‣ The Classical Pathway ‣ The Mannose-Binding Lectin Pathway ‣ The Alternative Pathway
- 141. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ What is the enzyme produced by all three activation pathways? ‣ C1q ‣ Mannose ‣ C3 convertase ‣ C5 convertase
- 142. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ What is the enzyme produced by all three activation pathways? ‣ C1q ‣ Mannose ‣ C3 convertase ‣ C5 convertase
- 143. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which of the following is NOT an immune effect of the complement system? ‣ Opsonization ‣ Phagocytosis ‣ Chemotaxis ‣ Lysis of pathogens
- 144. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which of the following is NOT an immune effect of the complement system? ‣ Opsonization ‣ Phagocytosis ‣ Chemotaxis ‣ Lysis of pathogens ‣ The complement system opsonizes pathogens which then aids phagocytosis, however phagocytosis is not a direct role of the complement system.
- 145. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which enzyme is deficient in hereditary angioedema? ‣ C1 esterase inhibitor ‣ C5 convertase ‣ C3 convertase ‣ C3 esterase
- 146. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which enzyme is deficient in hereditary angioedema? ‣ C1 esterase inhibitor ‣ C5 convertase ‣ C3 convertase ‣ C3 esterase
- 147. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ What is the definition of chemotaxis? ‣ Directional movement of a phagocyte towards a chemical attractant ‣ Activation of resting phagocytes by inflammatory mediators ‣ Leucocytes assume marginal positions in blood vessels ‣ Production of collagenase by leucocytes to allow them to exit blood vessels
- 148. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ What is the definition of chemotaxis? ‣ Directional movement of a phagocyte towards a chemical attractant ‣ Activation of resting phagocytes by inflammatory mediators ‣ Leucocytes assume marginal positions in blood vessels ‣ Production of collagenase by leucocytes to allow them to exit blood vessels ‣ The first option is the correct definition. "Activation of resting phagocytes by inflammatory mediators" describes the process of activation of phagocytes. "Leucocytes assume marginal positions in blood vessels" describes the process of margination and "Production of collagenase by leucocytes to allow them to exit blood vessels" describes the process of diapedesis.
- 149. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which of the following is responsible for directly facilitating lysis of pathogens? ‣ C5 convertase ‣ C3b ‣ C5a ‣ The Membrane Attack Complex
- 150. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ Which of the following is responsible for directly facilitating lysis of pathogens? ‣ C5 convertase ‣ C3b ‣ C5a ‣ The Membrane Attack Complex
- 151. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ What is the role of opsonization? ‣ Direct killing of pathogens ‣ Making pathogens easier targets for phagocytosis ‣ Antigen presentation ‣ Production of interferon
- 152. THE COMPLEMENT SYSTEM REVIEW QUESTIONS ‣ What is the role of opsonization? ‣ Direct killing of pathogens ‣ Making pathogens easier targets for phagocytosis ‣ Antigen presentation ‣ Production of interferon ‣ Opsonization makes pathogens easier targets for phagocytosis, particularly in the case of encapsulated bacteria.
- 153. References These slide reflect a summary of the contents of TeachMePhysiology.com and are to be used for educational purposes only in compliance with the terms of use policy. Specific portions referenced in this summary are as follows: ‣ https://teachmephysiology.com/immune-system/innate-immune-system/barriers-to-infection/ ‣ https://teachmephysiology.com/immune-system/innate-immune-system/cytokines/ ‣ https://teachmephysiology.com/immune-system/innate-immune-system/infection-recognition- molecules/ ‣ https://teachmephysiology.com/immune-system/innate-immune-system/phagocytosis/ ‣ https://teachmephysiology.com/immune-system/innate-immune-system/complement-system/ Additional sources are referenced on the slide containing that specific content.