Presentation is loading. Please wait.

Presentation is loading. Please wait.

Lecture 19 Host Defense Against Infection Innate immunity Adaptive Immunity.

Similar presentations


Presentation on theme: "Lecture 19 Host Defense Against Infection Innate immunity Adaptive Immunity."— Presentation transcript:

1 Lecture 19 Host Defense Against Infection Innate immunity Adaptive Immunity

2 Response to Initial Infection

3 Stages of Response to Infection

4 Course of Typical Acute Infection

5 Innate Host Defense Mechanisms Anatomic Factors Anatomic Factors Mechanical Factors Mechanical Factors Biochemical Factors Biochemical Factors

6 Skin Stratified and cornified epithelium provides a mechanical barrier Stratified and cornified epithelium provides a mechanical barrier Indigenous microbiota competes with pathogens Indigenous microbiota competes with pathogens Acid pH inhibits growth of disease producing bacteria Acid pH inhibits growth of disease producing bacteria Bactericidal long chain fatty acids in sebaceous gland secretions Bactericidal long chain fatty acids in sebaceous gland secretions

7 Respiratory Tract Upper Respiratory Tract Upper Respiratory Tract Nasal hairs induce turbulence Nasal hairs induce turbulence Mucous secretions trap particles Mucous secretions trap particles Mucous stream to the base of tongue where material is swallowed Mucous stream to the base of tongue where material is swallowed Nasal secretions contain antimicrobial substances Nasal secretions contain antimicrobial substances Upper respiratory tract contains large resident flora Upper respiratory tract contains large resident flora Lower Respiratory Tract Lower Respiratory Tract Particles trapped on mucous membranes of bronchi and bronchioles Particles trapped on mucous membranes of bronchi and bronchioles Beating action of cilia causes mucociliary stream to flow up into the pharynx where it is swallowed Beating action of cilia causes mucociliary stream to flow up into the pharynx where it is swallowed 90% of particles removed this way. Only smallest particles (<10µ in diameter) reach alveoli 90% of particles removed this way. Only smallest particles (<10µ in diameter) reach alveoli Alveoli Alveoli Alveolar macrophage rapidly phagocytize small particles Alveolar macrophage rapidly phagocytize small particles

8 Alimentary Tract General defense mechanisms General defense mechanisms Mucous secretions Mucous secretions Integrity of of mucosal epithelium Integrity of of mucosal epithelium Peristaltic motions of the gut propel contents downward Peristaltic motions of the gut propel contents downward Secretory antibody and phagocytic cells Secretory antibody and phagocytic cells Stomach Stomach Generally sterile due to low pH Generally sterile due to low pH Small Intestine Small Intestine Upper portion contains few bacteria Upper portion contains few bacteria As distal end of ilieum is reached flora increases As distal end of ilieum is reached flora increases Colon Colon Enormous numbers of microorganisms Enormous numbers of microorganisms 50-60% of fecal dry weight is bacteria 50-60% of fecal dry weight is bacteria

9 Genitourinary Tract Male Male No bacteria above urethrovesicular junction No bacteria above urethrovesicular junction Frequent flushing action of urine Frequent flushing action of urine Bactericidal substances from prostatic fluid Bactericidal substances from prostatic fluid pH of urine pH of urine Bladder mucosal cells may be phagocytic Bladder mucosal cells may be phagocytic Urinary sIgA Urinary sIgA Female (Vagina) Female (Vagina) Large microbial population (lactobacilli) Large microbial population (lactobacilli) Microorganisms produce low pH due to breakdown of glycogen produced by mucosal cells Microorganisms produce low pH due to breakdown of glycogen produced by mucosal cells

10 Eye Flushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynx Flushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynx Tears contain a high concentration of lysozyme (effective against gram positive microorganisms Tears contain a high concentration of lysozyme (effective against gram positive microorganisms

11 Innate Immune Recognition All multicellular organisms are able to recognize and eliminate pathogens All multicellular organisms are able to recognize and eliminate pathogens Despite their extreme heterogeneity, pathogens share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs) Despite their extreme heterogeneity, pathogens share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs) Host cells do not share PAMPs with pathogens Host cells do not share PAMPs with pathogens PAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs) PAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)

12 Three Functional Classes of PRRs/PRMs Endocytic receptors Endocytic receptors Macrophage mannose receptor Macrophage mannose receptor Macrophage scavenger receptor (SR) Macrophage scavenger receptor (SR) Integrin CD11b:CD18 Integrin CD11b:CD18 Secreted proteins Secreted proteins Mannose-binding protein/lectin Mannose-binding protein/lectin Pulmonary surfactant proteins A and D Pulmonary surfactant proteins A and D C-reactive protein (CRP) C-reactive protein (CRP) Signaling receptors Signaling receptors Toll receptor family Toll receptor family

13 Endogenous Signals Induced by PAMPs Mediate inflammatory cytokines Mediate inflammatory cytokines Interleukin-1 (IL-1) Interleukin-1 (IL-1) IL-6 IL-6 Tumor necrosis factor (TNF-  Tumor necrosis factor (TNF-  Type 1 interferon (INF-I) Type 1 interferon (INF-I) Major effector cytokines Major effector cytokines Chemokines Chemokines Antigen-presenting cells recognize PAMPs Antigen-presenting cells recognize PAMPs Same APC processes pathogens into specific pathogen-derived antigens and presents them with MHC encoded receptors to T-cells Same APC processes pathogens into specific pathogen-derived antigens and presents them with MHC encoded receptors to T-cells T-cell responds only when presented with both signals T-cell responds only when presented with both signals Different Effector Cytokines in Response to Different Pathogens (Th1 vs. Th2) Different Effector Cytokines in Response to Different Pathogens (Th1 vs. Th2)

14 Antimicrobial Peptides/Defensins Four hundred peptides described to date Four hundred peptides described to date Defensins (3- 5-kD, four families in eukaryotes) Defensins (3- 5-kD, four families in eukaryotes)  -defensins (neutrophils and intestinal Paneth cells)  -defensins (neutrophils and intestinal Paneth cells)  -defensins (epithelial cells)  -defensins (epithelial cells) Insect defensins Insect defensins Plant defensins Plant defensins Defensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane permeability. Defensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane permeability. May also play a role in inflammation and wound repair May also play a role in inflammation and wound repair

15 Complement System Three pathways now known Three pathways now known Classical Classical Alternative Alternative Lectin or MBL pathway (binding to mannose- containing carbohydrates) Lectin or MBL pathway (binding to mannose- containing carbohydrates) Host cells have complement regulatory proteins on their surface that protect them from spontaneous activation of C3 molecules Host cells have complement regulatory proteins on their surface that protect them from spontaneous activation of C3 molecules

16 Inflammatory Mediators in Innate Immunity Cytokines secreted by phagocytes in response to infection include: Cytokines secreted by phagocytes in response to infection include: IL-1 IL-1 activates vascular endothelium and lymphocytes activates vascular endothelium and lymphocytes Increases adhesiveness of leukocytes Increases adhesiveness of leukocytes IL-6 IL-6 Induces B-cell terminal maturation into Ig-producing plasma cells Induces B-cell terminal maturation into Ig-producing plasma cells IL-8 IL-8 Induces expression of b2 integrin adhesion molecules on neutrophils, leading to neutrophil migration to infection site Induces expression of b2 integrin adhesion molecules on neutrophils, leading to neutrophil migration to infection site IL-12 IL-12 Activates NK cells and induces Th1-cell differentiation Activates NK cells and induces Th1-cell differentiation IL-18 IL-18 TNF-  TNF-  Activates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissues Activates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissues

17 Other Mediators and Molecules Phagocytes Phagocytes Toxic oxygen radicals Toxic oxygen radicals Peroxides Peroxides Nitric oxide (NO) Nitric oxide (NO) Lipid mediators of inflammation Lipid mediators of inflammation Prostaglandins Prostaglandins LTB4 LTB4 Platelet activating factor Platelet activating factor Complement component C5a Complement component C5a Stimulates mast cells to release histamine, serotonin and LTB4 Stimulates mast cells to release histamine, serotonin and LTB4 IL-1, IL-6 and TNF-  IL-1, IL-6 and TNF-  Induce acute-phase response in liver Induce acute-phase response in liver Induce fever Induce fever IL-1 and IL-18 signaling pathways activate NF-  B, important in innate immunity IL-1 and IL-18 signaling pathways activate NF-  B, important in innate immunity

18 Immune Cells and Innate Immunity Phagocytes Phagocytes Neutrophils Neutrophils Moncyte/macrophage Moncyte/macrophage Eosinophils (to a lesser extent) Eosinophils (to a lesser extent) NK cells (large granular lymphocytes) NK cells (large granular lymphocytes) Antibody-dependent cell-mediated cytotoxicity (ADCC) Antibody-dependent cell-mediated cytotoxicity (ADCC) Have two major functions Have two major functions Lysis of target cells Lysis of target cells Production of cytokines (IFN-  and TNF-  ) Production of cytokines (IFN-  and TNF-  ) Act against intracellular pathogens Act against intracellular pathogens Herpesviruses Herpesviruses Leishmania Leishmania Listeria monocytogenes Listeria monocytogenes Act against protozoa Act against protozoa Toxoplasma Toxoplasma Trypanasoma Trypanasoma

19 Immune Cells and Innate Immunity (cont’d)  /  T cells  /  T cells Two types of T cell receptors Two types of T cell receptors One composed of  and  chains (basic T cell antigen receptor) One composed of  and  chains (basic T cell antigen receptor) One composed of  and  chains (minor population of T cells) One composed of  and  chains (minor population of T cells) Two groups of  /  T cells Two groups of  /  T cells One group found in lymphoid tissues One group found in lymphoid tissues One group located in paracellular space between epithelial cells One group located in paracellular space between epithelial cells Recognizes unprocessed target antigen in absence of APC help Recognizes unprocessed target antigen in absence of APC help B-1 cells (minor fraction of B cells, do not require T-cell help) B-1 cells (minor fraction of B cells, do not require T-cell help) Mast cells Mast cells Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glands Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glands Capable of phagocytosis Capable of phagocytosis Process and present antigen using MHC class I or II receptors Process and present antigen using MHC class I or II receptors LPS can directly induce release of mast cell mediators LPS can directly induce release of mast cell mediators Complement (C3a and C5a) induce mast cells to release mediators Complement (C3a and C5a) induce mast cells to release mediators Chemotaxis, complement activation, inflammation Chemotaxis, complement activation, inflammation TNF-  secreted by mast cells results in neutrophil influx into infected site TNF-  secreted by mast cells results in neutrophil influx into infected site

20 Summary of Innate Immunity External and mechanical barriers External and mechanical barriers Receptors for pathogen motifs Receptors for pathogen motifs Soluble antimicrobial proteins Soluble antimicrobial proteins Pattern of cytokines produced influences adaptive response Pattern of cytokines produced influences adaptive response

21 Adaptive Immunity and Infection

22 Protective Role of Antibodies Against Pathogens Toxin neutralization Toxin neutralization Opsonization/enhancement of phagocytosis Opsonization/enhancement of phagocytosis Sensitization for killing by NK cells Sensitization for killing by NK cells Sensitization of mast cells Sensitization of mast cells Activation of complement system Activation of complement system

23 Toxin Neutralization

24 Diseases caused by bacterial toxins

25 Preventing Bacterial Adherence

26 Virus-blocking Antibodies

27 Activation of the Complement Cascade Cell Activation (anaphylatoxins) Cell Activation (anaphylatoxins) Activate inflammatory cells Activate inflammatory cells Induce smooth muscle contraction and blood vessel permeability Induce smooth muscle contraction and blood vessel permeability Cytolysis ("membrane attack complexes“) Cytolysis ("membrane attack complexes“) Loss of cell membrane integrity Loss of cell membrane integrity Opsonization Opsonization Complement receptors on phagocytic cells Complement receptors on phagocytic cells Renders cells vulnerable to phagocytosis Renders cells vulnerable to phagocytosis

28 Fc Receptors

29 Opsonization and Immune Adherence C3B (C4B) C3B (C4B) Facilitates adherence of bacteria, viruses and neutrophils to monocytes and macrophages Facilitates adherence of bacteria, viruses and neutrophils to monocytes and macrophages Facilitates ingestion of certain bacteria by neutrophils and monocytes Facilitates ingestion of certain bacteria by neutrophils and monocytes Facilitates ingestion by activated macrophages Facilitates ingestion by activated macrophages Augments mediated phagocytosis and IgG-mediated cell cytotoxicity (ADCC) Augments mediated phagocytosis and IgG-mediated cell cytotoxicity (ADCC) Antibody Antibody antibody may opsonize by itself, or bridge phagocyte and target cell, enhancing complement immune adherence antibody may opsonize by itself, or bridge phagocyte and target cell, enhancing complement immune adherence

30 Chemotaxis capillary blood vessel phagocyte endothelium basement membrane PAVEMENTING DIAPEDESIS CHEMOTAXIS C5a Site of inflammation, tissue damage and immune reactions

31 Phagocytosis

32 Bactericidal Agents in Phagocytic Cells

33 Natural Killer Cells and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

34 Inflammation  Increased blood supply to the infected area  Increased capillary permeability  Migration of leukocytes into tissues (Chemotaxis) The four cardinal signs of inflammation (Cornelius Celsus, 30 BC to AD 38): rubor et tumor cum calore et dolore redness and swelling with heat and pain


Download ppt "Lecture 19 Host Defense Against Infection Innate immunity Adaptive Immunity."

Similar presentations


Ads by Google