Lecture 19 Host Defense Against Infection Innate immunity Adaptive Immunity In this lecture you should develop a sense of how innate and adaptive immunity are interrelated. How does the nature of the innate response influence the subsequent adaptive response?

Response to Initial Infection

Stages of Response to Infection

Course of Typical Acute Infection

Innate Host Defense Mechanisms Anatomic Factors Mechanical Factors Biochemical Factors The material on anatomical and mechanical factors will not be covered in class due to time limitations. You are responsible for the concepts.

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

Respiratory Tract Upper Respiratory Tract Lower Respiratory Tract Nasal hairs induce turbulence Mucous secretions trap particles Mucous stream to the base of tongue where material is swallowed Nasal secretions contain antimicrobial substances Upper respiratory tract contains large resident flora Lower Respiratory Tract 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 90% of particles removed this way. Only smallest particles (<10µ in diameter) reach alveoli Alveoli Alveolar macrophage rapidly phagocytize small particles

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

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

Eye 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

Innate Immune Recognition 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) Host cells do not share PAMPs with pathogens PAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)

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

Endogenous Signals Induced by PAMPs Mediate inflammatory cytokines Interleukin-1 (IL-1) IL-6 Tumor necrosis factor (TNF-a) Type 1 interferon (INF-I) Major effector cytokines Chemokines Antigen-presenting cells recognize PAMPs 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 Different Effector Cytokines in Response to Different Pathogens (Th1 vs. Th2)

Antimicrobial Peptides/Defensins Four hundred peptides described to date Defensins (3- 5-kD, four families in eukaryotes) a-defensins (neutrophils and intestinal Paneth cells) b-defensins (epithelial cells) Insect defensins Plant defensins 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

Complement System Three pathways now known Classical Alternative 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

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

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

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

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

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

Adaptive Immunity and Infection

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

Toxin Neutralization

Diseases caused by bacterial toxins

Preventing Bacterial Adherence

Virus-blocking Antibodies

Activation of the Complement Cascade Cell Activation (anaphylatoxins) Activate inflammatory cells Induce smooth muscle contraction and blood vessel permeability Cytolysis ("membrane attack complexes“) Loss of cell membrane integrity Opsonization Complement receptors on phagocytic cells Renders cells vulnerable to phagocytosis Study Guide What are immune adherence and opsonization? Why would a chemotactic factor be important in inflammation? What is the basis for chemotaxis?

Fc Receptors

Opsonization and Immune Adherence C3B (C4B) Facilitates adherence of bacteria, viruses and neutrophils to monocytes and macrophages Facilitates ingestion of certain bacteria by neutrophils and monocytes Facilitates ingestion by activated macrophages Augments mediated phagocytosis and IgG-mediated cell cytotoxicity (ADCC) Antibody antibody may opsonize by itself, or bridge phagocyte and target cell, enhancing complement immune adherence Study Guide What is the immune adherence receptor? On what cell type is it found?

Chemotaxis Site of inflammation, tissue damage and immune reactions capillary blood vessel phagocyte endothelium basement membrane Site of inflammation, tissue damage and immune reactions PAVEMENTING C5a DIAPEDESIS Study Guide Why does the granulocyte migrate out of the vessel? CHEMOTAXIS

Phagocytosis

Bactericidal Agents in Phagocytic Cells

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

Inflammation Increased blood supply to the infected area 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 Increased blood supply to the infected area Increased capillary permeability Migration of leukocytes into tissues (Chemotaxis) What are the characteristic signs of inflammation? What is responsible for them?