Nonspecific Host Resistance Study Unit 6

Study Unit 6 Nonspecific (Innate) Host Resistance 1 6.1 –Cells, tissue, and organs of the immune system 2 On completion of this study unit, you should be able to: Discuss the role of different physi...

Study Unit 6 Nonspecific (Innate) Host Resistance 1 6.1 –Cells, tissue, and organs of the immune system 2 On completion of this study unit, you should be able to: Discuss the role of different physical, mechanical, and chemical barriers against infection. Describe different cells, tissues, and organs of the immune system and explain their various roles; Describe the role of cytokines as molecular regulators of the immune response. 3 Host Resistance Overview Pathogens—disease-causing microbes. Must overcome surface barriers and antimicrobial activity. Immune system Composed of widely distributed proteins, cells, tissues, and organs. Neutralize or destroy foreign substances. Immunity Ability of host to resist infection or disease. Immunology – Study of immune responses and how they protect the host. 4 Immunity Innate immunity – First line of defense. – Offers resistance to any microbe or foreign material. – Includes general mechanisms such as skin, mucus, and antimicrobial chemicals. Adaptive immune response – Activated by cells and chemicals of innate immunity. – Tailored to a particular foreign agent. – Has “memory”—effectiveness increases on repeated exposure to foreign agent. 5 Antigens Name comes from antibody generators Any substance recognized by the immune system. Immune system can differentiate between self-antigen and non- self (foreign) antigen. – Enables immune system to rid the host of foreign invaders as well as eliminate cancer cells. – When discrimination goes awry, it is the basis for allergic response and autoimmune diseases. 6  Barriers Skin Mucous membranes – Lysozyme – Lactoferrin – Lactoperoxidase – Eye – IgA Respiratory system Gastrointestinal tract – Gastric acid – Enzymes – Peristalsis – Normal microbiota Genitourinary tract – Low pH – Urea – flushing 7 31.3 Innate Resistance Relies on Chemical Mediators a. Discuss host molecules that have antimicrobial actions. b. Describe in general terms the activation of the host complement system and its three outcomes. c. List three categories of cytokines and discuss their major functions. 8 Major Components of Mammalian Immune System – Innate and Nonspecific 9 Major Components of Mammalian Immune System – Adaptive and Specific 10 Chemical Mediators in Innate Resistance Mammalian hosts have a chemical arsenal with which to combat continuous onslaught of microorganisms. Lysozyme—hydrolyzes bond of bacterial cell wall. Lactoferrin—similar to transferrin in blood. – Sequester iron, reducing its availability for microbes, limiting their ability to multiply. 11  Chemical mediators in innate resistance Antimicrobial peptides – cationic peptides – Bacteriocins (normal microbiota) Complement Cytokines – intercellular signal molecules, eg. interleukins, interferons Acute-phase proteins 12 Cationic Peptides Three classes whose biological activity is related to their ability to damage bacterial plasma membranes: – Linear, α-helical peptides (that is, cathelicidins) Antimicrobial activity against bacteria, enveloped viruses and fungi Respiratory and urogenital epithelial cells, alveolar macrophages – Defensins α defensins—smaller and found in granules of neutrophils, intestinal Paneth cells, and intestinal and respiratory epithelial cells. β defensins—found in epithelial cells and stimulate release of chemical mediators. – Histatins Larger peptides found in saliva. Compromise mitochondrial function and generate oxidative and osmotic stress resulting in fungal death. 13  Bacteriocins Toxic peptides produced by normal microbiota. Kill closely related species. Colicins produced by E. coli. Bind reporters on the cell envelope of sensitive target bacteria and cause cell lysis. Lantibiotics Produced by Streptococcus, Bacillus, Lactococcus, and Staphylococcus. 14  The Complement System Composed of >30 heat-labile proteins. “Complements” the antimicrobial activity of the immune system. Major activities: – Stimulate an inflammatory response by helping to recruit white blood cells (leukocytes). – Lysing microbial cell membranes. – Promoting phagocytosis (engulfment and killing) of microbial invaders. Opsonization 15  Opsonization Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Enhanced phagocytosis through binding of antibodies and/or complement on the surface of a pathogen or antigen Phagocytes – neutrophils, – macrophages, – dendritic cells – have Ab and C3 receptors 16 Complement Activation Produced in inactive forms Activated following enzymatic cleavage Must be activated in a cascade fashion Three pathways of activation – alternative – lectin – classical 17 Alternative Complement Pathway Involved in nonspecific defenses against intravascular invasion by bacteria/fungi Dependent on interaction of complement with repetitive structures on pathogens Begins with activation of C3 Results in formation of membrane attack complex 18  Complement: Opsonization Def.: process in which microbes are coated by serum components in preparation for recognition/ingestion by phagocytic cells bind to microbial cells, coating them for phagocyte recognition – forms bridge between bacteria and phagocytes 19 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 20 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Phagocytosis 22 Cytokines Cyto=cell; kinesis=movement soluble proteins or glycoproteins that are released by one cell population that act as intercellular (between cells) mediators or SIGNALLING MOLECULES Soluble protein that initiates a signal transduction pathway that regulates transcription of immune response genes. Categories: – Regulators of innate immunity. – Regulators of adaptive immunity. – Stimulators of hematopoiesis. 23  Cytokine Groups Functional groups: – Chemokines—stimulate cell migration. – Interleukins—produced by one leukocyte, act on another. – Interferons—regulatory cytokines produced in response to infection. – Colony-stimulating factors (CS Fs)—stimulate growth and differentiation of immature leukocytes in bone marrow. – Tumor necrosis factors (TNF)— stimulate an inflammatory response. 24  Acute-Phase Proteins Macrophage responds to sites of injury. Macrophage activation → cytokine release → liver stimulation → acute- phase protein production. – Assist in the prevention of blood loss and ready the host for microbial invasion. Includes C-reactive protein (CRP), M BL, and surfactant proteins A (SP-A) and D (SP-D) which bind bacterial surfaces and act as opsonins. – Collectins—proteins composed of collagen-like motif connected to globular binding sites. 25 Different Types of Human Blood Cells Leukosiete (WBS) Almal oorsprong in hematopoiëtiese voorganger stamselle Elk het gespesialiseerde rol in gasheer verdediging Granulosiete Neutrofiele Basofiele Eosienofiele Mast selle Monosiete, Makrofage, Dendrietselle Aangebore Limfosiete Leukocytes (WBC) All originate from hematopoietic precursor stem cells. Each has specialized role in defending the host. Granulocytes Neutrophils Basophils Eosinophils Mast cells Monocytes, Macrophages, Dendritic cells Innate Lymphocytes 27 29  Mast Cells Bone marrow–derived cells that differentiate in connective tissue. Not phagocytic. Degranulation—release granules into extracellular environment. Local inflammatory reactions Vasoactive mediators—compounds that influence the tone and diameter of blood vessels. – Histamine, prostaglandins, serotonin, heparin, dopamine, platelet-activating factor, and leukotrienes. Play important role in allergic responses. 30  Granulocytes Irregularly shaped nuclei with two to five lobes. Cytoplasm has granules with reactive substances that kill microbes and enhance inflammation. Three types: – Basophils – Eosinophils – Neutrophils 31  Monocytes and Macrophages Monocytes – Produced in bone marrow and enter the blood. – After circulating for about 8 hours, they migrate into tissues, and mature into macrophages. Macrophages – Larger than monocytes that reside in specific tissues. – Highly phagocytic. – Serve as sentinel cells, sounding the chemical alarm when a microbe invades. 32 Monocytes and Macrophages 33  Macrophages Larger than monocytes, reside in specific tissues, highly phagocytic have a variety of surface receptors including (Pattern Recognition Receptors), toll-type receptors – recognize pathogen associated molecular patterns (PAMPs) – lipopolysaccharides, peptidoglycan, foreign DNA, viruses – Receptors for Ab and complement proteins – contact, phagocytose, and process antigens  display foreign antigens on their surfaces (antigen presentation) 34  Dendritic Cells Distinguished by long cellular projections. Present in the skin and mucous membranes of the nose, lungs, and intestines. Programmed to detect and phagocytose pathogens. Display foreign antigens on their surfaces to share vital information with lymphocytes to stimulate an adaptive immune response. Functions: – Destroy pathogens – Trigger specific immune response 35  Innate Lymphocyte Stimuli and Responses Bridge between innate and adaptive immunity Diverse ILC with different functions, target cells – Kill infected cells, activate T cell, enhance inflammation – Respond to injured cells, tissue repair, regulate inflammation – Regulate antibody production – Kill tumour cells (Left top) Nixxphotography/Getty Images; (Left middle) Olgaru79/Shutterstock; (Left bottom) Jezperklauzen/iStock/Getty Images 36 Natural Killer (NK) Cells Non-phagocytic granular lymphocytes – Cytotoxic enzymes – destroy malignant cells and cells infected with viral pathogens Several surface receptors. If activated to kill the target cell, they releases a pore-forming protein (perforin) and enzymes called granzymes trigger the target cell to undergo apoptosis. Two ways of recognizing target cells – bind to antibodies which coat infected or malignant cells (antibody- dependent cell-mediated cytotoxicity (ADCC)) – recognizes cells that have lost their class I major histocompatibility antigen due to presence of virus or cancer 37  Abnormal cells Natural killer cells Antibody-dependent cell- mediated cytotoxicity 38 31.5 Organs and Tissues of the Immune System Are Sites of Host Defense / Organe en weefsels van die immuunsisteem is plekke van gasheer verdediging a. Differentiate between primary and secondary lymphoid tissues and organs in terms of structure and function. b. Explain the role of the spleen in host defense. c. Rationalize the cellular architecture of skin- and mucosal-associated lymphoid tissues. 39  Organs and Tissues of the Immune System Primary organs and tissues – Where hematopoietic stem cells differentiate into immune cells. – Bone marrow—B cells – Thymus—T cells secondary organs and tissues – Where lymphocytes are activated by antigen interaction. followed by proliferation and differentiation into fully mature effector cells – Spleen, lymph nodes and lymph tissue, mucosa associated tissue 40 Primary Lymphoid Organs and Tissues Thymus – Precursor cells move, enter from bone marrow and proliferate. – Negative selection—removal of T cells not able to distinguish between self and non-self antigens. – Remaining cells become mature T cells and enter the bloodstream where they await activation by innate immune cells. Bone marrow – Site of B cell maturation in mammals. – Maturation involves removal of self-reactive cells. – Enter bloodstream and migrate to lymph nodes and spleen to await introduction to the antigen to which they will make targeted antibody. 41 Secondary Lymphoid Organs and Tissues—Spleen Most highly organized secondary lymphoid organ. Filters blood and traps blood- borne particles for assessment by phagocytes and B cells. Macrophages and dendritic cells phagocytose blood-borne pathogens. – Present antigens to T cells, activating specific immune response. 42  Secondary Lymphoid Organs and Tissues—Lymph Nodes and tissues Lymph nodes Capture phagocytosed antigens and present them to T cells. Outer region is rich in B cells that can bind antigen directly from the blood or lymph. Follicles—inner region where T cells await interaction with DC or B cells. Lymphoid tissues Located throughout the body. Highly organized and loosely associated lymphoid tissues exist. Sample host microbial environment in a region where leukocytes location is optimized. Associated lymphoid tissues – Skin-associated lymphoid tissue (SALT) – Mucosal-associated lymphoid tissue (MALT) 43 Study unit 6.2 Phagocytosis and inflammation 46  On completion of this study section, you must be able to: Describe events during the inflammatory response and the role thereof in non-specific defence of the body; give a review / an outline of the different types of immune cells and chemical mediators that act during the inflammatory response; describe the process of phagocytosis and explain its role in inflammation; and discuss the role of different receptors in MHC proteins in phagocytic destruction of microbes. 47 31.6 Phagocytosis Destroys Invaders a. Explain the methods by which pathogens are recognized by phagocytes. b. Compare and contrast the processes of autophagy and phagocytosis. c. Correlate the biochemical activities within the phagolysosome with pathogen destruction. 48  Phagocytosis process by which phagocytic cells (macrophages, dendritic cells, and neutrophils) recognize, ingest, and kill extracellular microbes 49  Phagocytosis… Two mechanisms for recognition of microbe by phagocyte – opsonin-independent (nonopsonic) recognition – opsonin-dependent (opsonic) recognition phagocytosis can be greatly increased by opsonization https://www.youtube.com/watch?v=iZYLeIJwe4w 50 Phagocytosis: Overview https://www.youtube.com/watch?v =7VQU28itVVw  Pathogen-Associated Molecular Patterns (PAMPs) Based on detection, by phagocytes, of conserved microbial molecular structures that occur in patterns PAMPs are unique to microbes, not present in host – e.g., lipopolysaccharide (LPS) of gram-negative bacteria – e.g., peptidoglycan of gram-positive bacteria PAMPs recognized by pattern recognition receptors (PRRs) on phagocytic cells PRRs can work alone or together to trigger phagocytes, e.g. toll- type receptors (TLR) 53  Opsonin-Independent Pathogen Recognition Common pathogen components are non-specifically recognized to activate phagocytes Microbe-associated molecular patterns (MAMPs): – Specific regions within common microbial macromolecules, such as lipopolysaccharide, peptidoglycan, fungal cell wall components, viral nucleic acids, and other microbial structures. – Alert host about the presence of microbe. Pattern recognition receptors (PRR): – C-type lectin receptors – Toll-like receptors – NOD-like receptors – RIG-I-like receptors 54 Recognition of MAMPs by PRRs Source: “Introduction to the Immune System.” What-When-How. 57  Intracellular Digestion Once bound, microbes can be internalized and phagosome delivered to a lysosome to become a phagolysosome Lysosome produces hydrolytic enzymes – lysozyme, Rnases, DNases, proteases acid pH respiratory burst reactions occur once phagosome forms toxic oxygen products are produced which can kill invading microbes 61 Intracellular Digestion—Respiratory Burst 62 Autophagy 63  Exocytosis Process used by neutrophils to expel microbial fragments after they have been digested. Phagolysosome unites with cell membrane. – Results in extracellular release of microbial fragments. Antigen-presenting cells— macrophages and DC. – Move fragments from phagolysosome or autolysosome to the endoplasmic reticulum. – Peptide fragment components unite with glycoproteins, becoming part of cell membrane. – Microbe-specific peptide placed in MHC. – Facing exterior of the cell – Antigen is shown (presented) to T cells – Activates the adaptive immune response 64 Antigen Processing and Presentation: MHC Inflammation Nonspecific response to tissue injury – can be caused by pathogen or physical trauma – acute inflammation is the immediate response of body to injury or cell death cardinal signs – redness (rubor) – warmth (calor) – pain (dolor) – swelling (tumor) – altered function (functio laesa) 69 Inflammation 70 Acute Inflammatory Response… Involves chemical mediators (chemokines) – selectins cell adhesion molecules on activated capillary endothelial cells (attract neutrophils) – integrins adhesion receptors on neutrophils integrins bind to selectins – chemotaxins chemotactic factors released by injured cells 71 Acute Inflammatory Response Various processes occur – margination – diapedesis – extravasasion 72 Acute Inflammatory Response Various processes occur – Margination – neutrophils bind to the epithelium of a blood vessel – diapedesis – neutrophils change shape and squeeze through endothelial wall – extravasation – neutrophils migrate to site of injury 73 More about Acute Inflammation… Tissue injury causes release of kalikrein and various other mediators that increase capillary dilation and increased blood flow bring more antimicrobial factors and leukocytes that kill pathogens fibrin clot may restrict pathogen movement phagocytes accumulate in inflamed area and destroy pathogens bone marrow is stimulated by numerous released chemicals to release neutrophils and increase rate of granulocyte production 74 Prostaglandins – Swelling, pain 75 Pathogen is neutralized: Increase in blood flow, antimicrobial factors, leukocytes Blood leakage into tissue spaces – Increases temperature – Stimulates inflammatory response – Inhibit microbial growth Fibrin clot limit spread Phagocytes ingest pathogens, increased granulocyte production. 76  Chronic Inflammation Slow process Involves formation of new connective tissue Usually causes permanent tissue damage Dense infiltration of lymphocytes and macrophages at site of inflammation Granuloma—mass of cells that forms when phagocytic cells can’t destroy pathogen and instead attempt to wall off the site. Dr. Cornelio Arevalo, Venezuela/CDC 77