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Public Health MP 3304 The Innate Immune Response Chapters 15 and 19 Nester 4th. Ed. Anjum Odhwani, MD MPH Definition of Immunology The branch of science that is devoted to the study of many mechanisms the body uses to defend itself against invading organisms or microbes. Types of Defense Mechanisms Non-specific (Innate immunity) Specific (adaptive immunity)- Immune Response One branch of immunity Non-specific immunity – found in most of the humans and animals – inborn, innate, natural – already in place before the organism enters the host – directed against any organism that tries to invade a host Mechanisms involved in Nonspecific immunity Tissue barriers – Mechanical – Chemical Non-specific antimicrobial substances Acute inflammation Phagocytosis Fever Changes in iron metabolism First – line defense Physical barriers Normal flora Antimicrobial substances Innate Immunity Mechanical Barriers that prevent entry of microorganisms (Fig 15.1-15.3) – Skin • Most difficult barrier • Physically prevents microbes from accessing the tissues • Skin is tough and durable • Outer layer Keratin constantly slough off • Arid environment • Sweat high in salt and lysozyme • Sebum (fatty acid) Epithelial barriers Innate Immunity Mechanical Barriers that prevent entry of microorganisms (Fig 15.1-15.3) Mucous membranes – Constantly bathed with mucus and other secretions – Propel microbes • Ciliated epithelium • Peristalsis • Urine flushes organisms Anatomical barriers Figure 15.1 Innate Immunity Chemical Barriers (Figure 15.3) – Acid mantle • urine, stomach acid and vaginal pH First-line defense mechanisms in humans Innate Immunity Normal flora (resident flora) – Covers binding sites – Compete – Consume resources – Produce toxins e.g. Propionibacterium, Lactobacillus species in vagina – Stimulate host defense mechanism Normal flora Establishment – fetus has no normal flora – acquire some at birth – acquire some in food – acquire some from other people – colonization Normal flora Importance of Normal Flora Prevent growth of other organisms – by taking up space - commensals – by competing for nutrients – by preventing attachment Importance of Normal Flora Prevent growth of other organisms – by making products that are toxic to other organisms • lipid catabolic by-products e. g. Propionibacterium (sebaceous secretion to fatty acid) • Colicins (E. coli synthesis protein toxic to other organisms) • Lactic acids (lactobacillus in vagina acidic environment) Importance of Normal Flora Prevent the growth of other organisms – by stimulating immunity • an immune response to one organism may help against a similar organism Providing a useful function – degrading cellulose for nutrients – making vitamins (biotin, panthothenic acid (B5), folic acid and Vitamin K) Normal flora – Types of symbiotic relationships • Mutualism – An association in which both partners benefit e.g. intestinal bacteria synthesize vit K and vit B • Commensalism – An association in which one partner benefits but other remains unharm • Parasitism – An association in which one organism, the parasite derives benefit at the expense of the other organism, the host Normal Flora Can Change How? – increased perspiration – acidity of the stomach (Alteration of the acid barrier of the stomach by disease, surgery, drugs or antacids) – ingestion of antibiotics – meat diet vs. vegetarian diet (People living on the high carbohydrate diet have significantly fewer Bacteroides and more Enterococci in their faeces) – changes in peristalsis (e.g. diarrhea) Innate Immunity Non-specific antimicrobial factors Antimicrobial substances found in saliva, tears, mucus and skin – Lysozyme – Peroxidase – Lactoferrin – Interferons Innate Immunity Non-specific antimicrobial factors – Lysozyme • Found in tears, saliva, mucus, in phagocytic cells, blood and fluid that bathes tissues • Enzyme that degrades peptidoglycan • Gram-positive bacteria peptidoglycan is exposed • Gram-negative peptidoglycan not exposed Innate Immunity Non-specific antimicrobial factors – Lactoferrin and transferrin • Found in saliva, mucus, milk, blood and tissue fluids • Iron binding protein • Major element for growth of the organism • Sequester iron from the organisms Innate Immunity Non-specific antimicrobial factors Peroxidase • Found in saliva, milk, body tissues and phagocytes • Peroxidases are a group of enzymes that catalyze oxidation-reduction reactions • H2O2 + peroxidase + Cl = yields chlorine and hypochlorite (bleach) • H2O2 + catalase yields H2O and O2 • Catalase (+) organisms are more resistant to peroxidase • Catalase –negative organisms are sensitive to perxidase killing Innate Immunity Non-specific antimicrobial factors – Defensins • Short antimicrobial peptides • Found on mucus membranes and within phagocytic cells (macrophages and neutrophils) • Insert themselves into bacterial membranes and form pores • Distrupt the integrity of bacterial membrane Interferon Innate Immunity Non-specific antimicrobial factors – Interferons • Group of glycoproteins (control viral infection) See Figure 15.11 • Inhibits protein synthesis in cells near virally infected cells • Prevent viral replication • Are species specific with regards to host Cells and Tissues Involved in Defense Mechanisms Cells are mainly the leukocytes – Figure 15.4 – Table 15.2 – Non-specific are the granulocytes, monocyte/macrophages and null cells (natural killer cells) – Specific are the lymphocytes Cells and Tissues Involved in Defense Mechanisms Tissues – lymphoid tissues (dense accumulation of lymphocytes e.g. Peyer’s patches) – Lymphoid organ (spleen, lymph nodes, tonsils, bone marrow, adenoids and appendix) Professional phagocytes Professional phagocytes Cells and Tissues Involved in Defense Mechanisms Acute bacterial infection Neutrophils ↑ Inflammation and allergic reaction Basophils ↑ Eosinophils ↑ Allergic reaction and parasitic infestation Eosinophils ↑ Cell Communication Trauma or invasion Communicate to immediate environment and to other cells How do they communicate? – Surface Receptors (eyes and ears) – Cytokines (Voice) – Adhesion molecules (hands) Cell Communication Surface receptors – Are integral membrane proteins – Bind specific compound or compounds – Molecule binds to a particular receptor is called a ligand for that receptor – Internal portion of the receptor becomes modified – Elicit response (chemotaxis) Cell Communication Cytokines – Low molecular weight proteins – Made by certain cells • lymphokine (cytokines made by lymphocytes) • monokine (cytokines made by monocytes) • chemokine (cytokines with chemotactic activities) • interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cell Communication Cytokines – Communicate with other cells (chemical messengers) – Short-lived – Very powerful – Act at extremely low concentration – Act locally, regionally or systemically Cell Communication Cytokines – Cytokines binds to cytokine receptors • Induce a change such as growth (different kind of leukocytes, precursors of blood cell and mast cells) • Differentiation (different leukocytes) • Movement • Cell death Cell Communication Cytokines • See Table 15.3 • Chemokines • Colony stimulating factors • Interferons • Interleukins • Tumor necrosis factor Direct immature leukocytes into the appropriate maturation pathway Cell Communication Cytokines: Groups of cytokines work together – Chemokines • 50 different varieties • Chemotaxis of immune cells – Colony-stimulating factors (CSFs) • multiplication and differentiation of leukocytes Cell Communication Cytokines – Interferons (IFNs) • Glycoproteins • Control viral infections • Gamma-interferon helps regulate the function of the cells involved in inflammatory response (phagocytes) • Modulates certain responses of adaptive immunity Cell Communication Cytokines – Interleukins (ILs) • Produced by leukocytes • At least 18 interleukins been studied • Innate and adaptive immunity – Tumor necrosis factors (TNFs) • TNF- alpha produced by macrophages plays an instrumental role in initiating the inflammatory response • Programmed cell death or appoptosis (destroy self-cells without eliciting inflammation) Cell Communication Cytokines – Groups of cytokines work together • Pro-inflammatory cytokines contributes to inflammation (TNF-alpha, IL-1, IL-6) • Promotion of antibody responses (IL-4, IL5, IL-10 and IL-14) • Promotion of T cell activity (IL-2, and INFgamma) Cell Communication Adhesion molecules – Allow cells to adhere to other cells – Ex. Endothelial cells bind to phagocytic cells grab cells – Slow down phagocytic cell movement – Allow cells to adhere to other cells and deliver cytokines or other compounds Cell Communication Sensor Systems – Present within blood and tissues – Senses tissue damage and microbial invasion – Either directly destroy the microbes – Or recruit other components of the host defenses E.g. Toll-like receptors Complement system Sensor systems Toll-like Receptors (TLRs) Figure 15-6 At least 10 TLRs identified Each recognizes a distinct compound or groups of compounds E.g. TLR-2 recognizes peptidoglycan TLR-4 is triggered by lipopolysacchride Sensor systems Toll-like Receptors (TLRs) Other bacterial structures or compounds that activate these receptor Flagellin Bacterial nucleotides What do they do? Sensor systems Toll-like Receptors (TLRs) – What do they do? – Transmit signals to the nucleus of the host cells to alter the expression of certain genes – E.g. – Lipopolysaccharide → triggers a TLRs of monocytes and macrophages → chemokines attracts additional phagocytes Sensor Systems • The Complement System (Figure 15.7 and 15.8) – Series of about 20 proteins • Circulate in the blood and tissue fluids • C1 through C9 are the major components of this system • Routinely circulate in an inactive form • once activated a cascade of events occurs • one event triggers the next event • Activated forms have specialized functions to quickly remove and destroy the offending material Compliment system C3b binds to foreign material called opsonized, C3b called opsonins C3a and C5a→induce changes in endothelial cells and mast cells →↑ vascular permeability Regulatory proteins halt the process inactivate C3b Regulatory proteins are not associated with microbial surfaces C5a attracts phagocytes Membrane attack complex Sensor Systems Complement (continued) – Two pathways of activation • Classical pathway part of specific immunity • Alternate pathway part of innate immunity – Final common pathway • Ultimate function is lysis of a bacteria by the membrane attack complex • C3a and C5a are the anaphylatoxins Sensor Systems Complement System – Classical pathway inflammation • Antigen-antibody complexes red flag portion of the antibody interact with complement component in turn C3a and C5a induce changes in endothelial cells increase permeability associated with inflammation • C5a is a potent chemoattractant Sensor Systems Complement System – Alternative pathway • C3b binds to foreign material is said opsonized (prepared for eating) • Phagocytes more easily destroy C3b coated cells as they have C3b receptors • C3a and C3b cause phagocytes to produce more receptors for C3b Sensor Systems Complement System – Lactin pathway cells Lysis of foreign • Mannan-binding lectins (MBLs), a polymer of mannose found on microbial cells MBL binds to a surface and interact with compliment component initiating classical pathway C5b, C6, C7, C8 and C9 forms doughnut shaped structure called membrane attack complex (MAC) creates pores in membrane, disrupting the integrity of the cell Complement System C3a and C5a→induce changes in endothelial cells and mast cells →↑ vascular permeability C5a attracts phagocytes C3b binds to foreign material called opsonized C3b called opsonins Regulatory proteins halt the process inactivate C3b Regulatory proteins are not associated with microbial surfaces Phagocytosis Innate Immunity Phagocytosis (Figure 15.9) – Chemotaxis- phagocytic cells are recruited – Recognition and adhesion Direct: mannose sugar found on the surface of certain bacteria and yeast • Indirect: binding opsonized (C3b) • – Engulfment • phagocyte engulf the invader forming a membrane-bound vacuole called phagosome Innate Immunity • Phagocytosis • Fusion of the phagosome with lysosome • Phagosome transported towards lysosome forming phagolysosome • Lysosome a membrane bound body filled with various digestive enzymes Innate Immunity • Phagocytosis • Destruction and digestion • Oxygen dependent mechanisms oxidized sugars via TCA cycle • Highly toxic oxygen by-products such as superoxide, hydrogen peroxide and hydroxyl radicals are produced • Once oxygen is depleted fermentation anaerobic metabolism starts • Metabolic pathway switches to lactic acid production lowering pH • Enzymes degrade bacterial cell wall and other components of cells Innate Immunity Phagocytosis Exocytosis – Digested material is expelled to external environment Innate Immunity Neutrophils – First to arrive during an immune response – Involved in inflammation – Inherently have more killing power than macrophages Innate Immunity Macrophages – Located throughout the body (Kupffer cells, alveolar macrophages, etc.) – Produce cytokines – Interact with T helper cells – activated macrophages – Help form granulomas (Macrophages, Giant cells and T-helper cells) Innate Immunity Inflammation-A coordinated response to invasion or damage – Types of inflammation – Cardinal signs of acute inflammation – Factors that initiate the inflammatory response – Process of acute inflammation – Outcomes of inflammation Innate Immunity Inflammation – Definition • When a tissue have been damaged, such as when an object penetrates the skin or when microbes produce toxic compound, a coordinated response called the inflammatory response, or inflammation occurs – Types of inflammation • Acute – Immediate and short lived response (neutrophils) • Chronic – Delayed and long lived response (macrophages, giant cells, T cells forms granulomas) Innate Immunity Signs of inflammation – – – – – Swelling Redness Heat Pain Loss of function (sometimes present) Intension of the inflammatory process – limit damage and restore function Innate immunity Inflammation – Factors that initiate the inflammatory response • Microbial products – Lipopolysaccharide, flagellin, bacterial DNA trigger toll-like receptors Innate immunity Factors that initiate the inflammatory • Microbial cell surface – Trigger complement cascasde » leading to production of C3a and C5a » Stimulate changes associated with inflammation – Complement component also induces mast cells to release various proinflammatory cytokines Innate immunity Factors that initiate the inflammatory • Tissue damage – Activate two enzymatic cascades »Coagulation cascade results in blood clotting and catch microbe in a clot too »Bradykinin increases vascular permeability, dilates blood vessels, contracts non-vascular smooth muscle, and causes pain The inflammatory process The inflammatory process Innate Immunity The acute inflammatory response (Figure 15.10) – Two components • Vascular component –Vasodilation- produces redness and heat –Increased vascular permeability produces swelling Innate Immunity The acute inflammatory response (Figure 15.10) – Two components • Cellular component –Cell recruitment –Phagocytosis Innate immunity Inflammation – Outcomes of acute inflammation • • • • Resolution Abscess formation Scarring Chronic inflammation Innate immunity Inflammation – Systemic response is life threatening – Enzymes and toxic products within phagocytic cells can damage healthy tissues – Inflammation in brain and spinal cord can be life threatening Innate immunity Septic shock: Gram-negative bacteria → endotoxins→ proinflammatory cytokines →activate complement cascade and clotting cascade →results in rapid decrease in blood pressure → shock Clot plugs the capillaries of vital organs e.g. liver, lung, brain etc cutting blood supply Innate immunity Apoptosis – Mechanism of eliminating dead self-cells without evoking an inflammatory response – Cell suicide – Dying cells undergo changes • • • • Shape changes Enzyme cut the DNA Portions of the cells bud off Cell shrink Innate Immunity Fever – one of the strongest indications of infectious disease – the hypothalamus regulates our normal body temperature in a narrow range • 98.6ºF or 37 ºC – central temperature receptors and peripheral temperature receptors Innate Immunity Fever – Cytokines and other fever-inducing substances are called pyrogens – Fever-inducing cytokines body makes it e.g. IL-1 and TNF (endogenous pyrogens) – Bacterial endotoxins, cell wall Lipoplysaccharide are (exogenous pyrogens) Innate Immunity Fever – microorganisms can cause the body to respond by changing the “set point” • components of microorganism attach to phagocytic cells • phagocytic cells release interleukin-1 • interleukin-1 travels via the blood to the hypothalamus • the hypothalamus responds by raising body temperature Innate Immunity Fever – inhibits pathogens by: • increasing body temperature above the optimal temperature for growth of microorganisms –enzymes are inactivated • activating and speeding a number of body defenses –there are many examples Innate Immunity Fever – Examples of beneficial effects of fever • enhance inflammation • increase killing by phagocytes • release of chemo-attractants of neutrophils • activation and replication of lymphocytes • increase production of antibody and interferon • decrease host’s ability to absorb iron