16 Innate Immunity: Nonspecific Defenses of the Host

Student Learning Outcomes Differentiate between innate and adaptive immunity. Define toll-like receptors. Differentiate physical from chemical factors, and list examples of each. Describe the role of normal microbiota in innate resistance. Classify phagocytic cells, and describe the roles of granulocytes and monocytes. Define and explain phagocyte and phagocytosis. Explain the different stages of inflammation. Describe the cause and effects of fever. Describe two of the three pathways of activating complement and describe the 3 outcomes. Compare and contrast the actions of -IFN and -IFN with -IFN. Describe the role of transferrins and antimicrobial peptides in innate immunity.

The Concept of Immunity Immunity: Ability to ______________________. Susceptibility: Lack of ________________to a disease. Innate immunity: ________________Specific or not? Adaptive immunity: __________________________ Fig 16.1

The Body’s Defensive Cells Can you name them? Host Toll-like receptors (TLRs) attach to Pathogen-associated molecular patterns (PAMPs) Binding to TLRs induces release of cytokines that regulate the intensity and duration of immune responses

TLRs = ? PAMPs recognition Toll-like receptors (TLRs) play a crucial role in the recognition of invading pathogens and the activation of subsequent immune responses against them. Individual TLRs recognize distinct pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs which activates immune cell responses. They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard.[1]

Horseshoe structure of TLR3, showing attached sugars (spheres) and internal structures Fig. 16.7

First Line of Defense: Skin & Mucous Membranes Physical Factors Epidermis Mucus of mucous membranes (Muco)-ciliary escalator Nose hairs Lacrimal apparatus Saliva Fig 16.3

Fungistatic fatty acids in sebum Skin pH and osmolarity Chemical Factors Fungistatic fatty acids in sebum Skin pH and osmolarity Lysozyme in _______________________ pH of gastric juice Transferrins in blood Also important: Antagonism and competitive exclusion of normal microbiota Lysozyme in perspiration, tears, saliva, and tissue fluids.

1st Line Defense in Human Mastering: Host Defenses – The Big Picture

Formed Elements in Blood Compare to Table 16.1 Red Blood Cells Transport O2 and CO2 White Blood Cells: Phagocytosis Histamine Kill parasites. Involved in allergies

Formed Elements in Blood White Blood Cells cont: Phagocytosis Natural killer cells Destroy target cells Cell-mediated immunity Produce antibodies Blood clotting

Second Line of Defense: Formed Elements in Blood 60-70% 2-4% 0.5-1%% 3-8% 20-25%

Process of Phagocytosis Phagocytes engulf and kill microorganisms Steps of phagocytosis: Chemotaxis Adherence: Recognition and attachment Ingestion: Engulfment and creation of phagosome Digestion: Fusion of phagosome with lysosome Destruction and digestion Residual body  Exocytosis Fig 16.7

Phases of Phagocytosis Foundation Fig 16.7

Microbial Evasion of Phagocytosis Inhibit adherence: capsules, M protein S. pyogenes, S. pneumoniae Kill phagocytes: Leukocidins S. aureus Lyse phagocytes: Membrane attack complex L. monocytogenes Escape phagosome Shigella Prevent phagosome-lysosome fusion HIV Survive in phagolysosome Coxiella burnetti

Phagocytosis and Evasion of Phagocytosis Phagocytosis: Overview Phagocytosis: Mechanism Review the Following MasteringAnimations Virulence Factors: Hiding From Host Defenses Virulence Factors: Inactivating Host Defenses Phagocytosis: Microbes That Evade It

Inflammation Tissue damage leads to inflammatory response Purpose: Destroy pathogen limit spread of infection pave way for tissue repair Acute-phase proteins activated (such as TNF-, kinins, and other cytokines)  quickly leads to 1st stage of inflammation (?) 4 (5) cardinal signs:?

The 3 Stages of Inflammation Vasodilation and increased vessel permeability due to histamine, kinins, prostaglandins, and other cytokines Phagocyte migration and phagocytosis Margination and diapedesis (emigration) Chemotaxis(due to various cytokines and components of complement system) Pus formation Tissue repair and regeneration depends on type of tissue

Inflammatory Process Margination Diapedesis Fig 16.8

Inflammation review Treatment of abscess?

Fever: Abnormally High Body Temperature Hypothalamus acts as body’s thermostat. Normally set at? Endotoxin causes phagocytes to release interleukin–1 (IL–1). IL-1= endogenous pyrogen Hypothalamus releases prostaglandins that reset the thermostat Body reacts to raise the temperature. How? When no more IL–1, body temperature falls (crisis).

Beneficial effects of moderate fever: Inhibited pathogen growth Increased cellular metabolism  e.g.: Increased transferrin production Increased IL–1 activity  T cell production  Faster repair mechanisms Problematic effects of high fever: > 40.7C (105F) can be dangerous (Tachycardia, acidosis, dehydration) Death at temp. > 44 - 46C

Antimicrobial Substances Complement system Interferons Transferrins: _________________ Antimicrobial peptides: cause bacterial cell lysis. Produced by mucous membrane cells and phagocytes.

Complement System Summary Series of  30 plasma (serum) proteins, activated in a cascade 3 effects of complement system: Enhances inflammatory response, e.g.: attracts phagocytes Increases phagocytosis through opsonization or immune adherence Creates Membrane Attack Complexes (MACs)  Cytolysis

The Complement System Foundation Fig 16.9 MAC Complement System Overview MAC

Opsonins (complement proteins or antibodies) coat bacteria and promote attachment of micro-organism to phagocyte  Process is called ______________

Classical Pathway Fig 16.12

Alternative Pathway Does not require a specific antibody to get started Fig 16.13

Some Bacteria Evade Complement Capsules prevent Complement activation Surface lipid-carbohydrates of some Gram-negatives prevent MAC formation Enzymatic digestion of C5a by Gram-positives Mastering Animations: Complement System Overview Activation Results

Interferons (IFNs) Family of small glycoproteins Not virus-specific -IFN and -IFN: Produced by virus infected cells. Mode of action is to induce uninfected cells to produce antiviral proteins (AVPs) that inhibit viral replication. -IFN: Produced by lymphocytes. Causes neutrophils and macrophages to phagocytize bacteria. Also involved in tumor immunology. Recombinant interferons have been produced. However short-acting and many side-effects. No effect on already infected cells.

Interferons (IFNs) Fig 16.15

the end Review Questions: 1 – 4 and 9 Multiple Choice Questions: 1 – 3, 5, 6, and 8 – 9 Critical Thinking Questions: 1 and 2 Clinical Application Questions: 2 and 3 the end