Bio217 F2014 Unit 2 • Bio217 Pathophysiology Class Notes • Professor Linda Falkow Innate Immunity: Inflammation & Wound Healing • Unit 2: Mechanisms of Defense – Chapter 5: Innate Immunity: Inflammation & Chapter 5 Wound Healing – Chapter 6: Adaptive Immunity – Chapter 7: Infection & Defects in Mechanisms of Defense – Chapter 8: Stress and Disease 1 2 Human Defense Mechanisms First Line of Defense • Physical and mechanical barriers • First line of defense – Skin – Innate resistance (or natural immunity) – Mucous Membranes – linings of the GI, – Includes natural barriers genitourinary, and respiratory tracts • Second line of defense Mechanical removal: – Inflammation • Sloughing off of cells • Third line of defense • Coughing and sneezing – Adaptive (acquired or specific) immunity • Flushing from urinary system – Involves “memory” • Vomiting • Mucus and cilia 3 4 First Line of Defense Second Line of Defense • Inflammatory response • Biochemical barriers – Caused by a variety of materials – Enzymes synthesized and secreted in saliva, • Infection, mechanical damage, ischemia, tears, ear wax, sweat, and mucus nutrient deprivation, temperature extremes, radiation, etc. – Local manifestations – Antimicrobial peptides ( _______________) • _________, ____________, _________, ________________ – Vascular response – Normal bacterial flora on the skin and in gut • Vasodilation (VD), blood vessels become leaky, WBCs adhere to inner walls of vessels & migrate through the vessels 5 6 1 Bio217 F2014 Unit 2 Inflammation Inflammation • Goals (Benefits of Inflammation) – Limit tissue damage and control the inflammatory process – Prevent and limit infection and further damage – Initiate adaptive immune response – Initiate healing 7 8 Plasma Protein Systems Cellular Mediators of Inflammation • Protein systems • Cellular components – ______________ system - Granulocytes, monocytes, platelets, lymphocytes • Circulating proteins that can destroy pathogens directly – Neutrophils & macrophages (mature monocytes) phagocytic – ____________ system • Forms a clot that stops bleeding – Eosinophils kill parasites – Platelets clotting sequence & release mediators – ___________ system – Lymphocytes (NK cells) attack virus and cancer • Bradykinin - causes VD, pain, SMC contraction, vascular permeability, and leukocyte chemotaxis infected cells 9 10 Mast Cells Mast Cell Degranulation • Important activator of inflammatory response • Contain granules, located in loose CT • Skin, digestive lining, and respiratory tract • Release: – Histamine VC of large blood vessels & VD of venules – Leukotrienes SMC contraction, incr. vascular permeability – Prostaglandins • Similar to leukotrienes; they also induce pain (affect nerves) – Platelet-activating factor (PAF) • Similar effect to leukotrienes and platelet activation 11 12 2 Bio217 F2014 Unit 2 Phagocytes Phagocytosis • Neutrophils (PMNs) – Predominate in early inflammatory responses • arrive 6-12 hr after injury – Ingest bacteria, dead cells, and cellular debris – Cells are short lived and become component of purulent exudate 13 14 Phagocytes Monocytes and Macrophages • Monocytes and macrophages – Monocytes - produced in bone marrow blood inflammatory site, where they develop into macrophages – Macrophages typically arrive at the inflammatory site 24 hours or later after neutrophils Increased cell size and lysosomal granules 15 16 Phagocytes Phagocytes • Eosinophils • Natural killer (NK) cells – Mildly phagocytic – Function against cells infected with viruses – Duties and cancer • Main defense against parasites and regulation • Platelets of vascular mediators from mast cells – Activation results in degranulation (release of serotonin) and to stop bleeding 17 18 3 Bio217 F2014 Unit 2 Cytokines Cytokines Most cytokines are classified as: • Interleukins (IL) – Produced by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation • Interferon (INF) – Protects against viral infections – Produced and released by virally infected host cells in response to viral double-stranded RNA 19 20 Local Manifestations of Exudative Fluids Acute Inflammation • Due to vascular changes & leakage of • Serous exudate – _________ exudate: indicates early circulating components into the tissue inflammation – Heat • Fibrinous exudate – Thick, ________ exudate: indicates more – Redness advanced inflammation – Swelling • Purulent exudate – ____: indicates a bacterial infection – Pain • Hemorrhagic exudate – Exudate contains _________: indicates bleeding 21 22 Systemic Changes due to Chronic Inflammation Acute Inflammation • Fever • Inflammation lasting 2 weeks or longer – Caused by exogenous and endogenous pyrogens act on hypothalamus • Often related to an unsuccessful acute inflammatory response • Leukocytosis – Increased numbers of circulating leukocytes • Increased plasma protein synthesis - Produced in liver 23 24 4 Bio217 F2014 Unit 2 Wound Healing : Healing Resolution and Repair • Resolution: • Primary intention – Restoration of damaged tissue – Wounds that heal under conditions of • Repair: minimal tissue loss – Replacing destroyed tissue with scar tissue • Secondary intention – Wounds that require a great deal more tissue replacement • Open wound 25 26 Healing by Primary Intention Healing by Secondary Intention 27 28 Dysfunctional Wound Healing Dysfunctional Wound Healing - Keloid (scar) formation • Dysfunction during inflammatory response due to: – Hemorrhage – Fibrous adhesion – Infection – Excess scar formation 29 30 5 Bio217 F2014 Unit 2 Dysfunctional Wound Healing Concept Check • 1. Inflammation: – A. Confines and destroys injurious agents • Wound disruption – B. Stimulates and enhances immunity –Dehiscence – C. Promotes healing – • Wound pulls apart at the suture line D. All of the above – Excessive strain and obesity are causes • 2. Which of the following is not a local • Increases risk of wound sepsis manifestation of inflammation? – A. Swelling – B. Pain – C. Heat and redness – D. Leukocytosis 31 32 • 3. The inflammatory response: – A. Prevents blood from entering injured tissue – B. Elevates body temp. to prevent spread of infection – C. Prevents formation of abscesses – D. Minimizes injury and promotes healing • 4. Scar tissue is: – A. Nonfunctional collagen and fibrous tissue – B. Functional tissue that follows wound healing – C. Regenerated tissue formed in area of injury – D. Fibrinogen with entrapped phagocytes and neurons 33 34 Adaptive (specific) Immunity - state of protection against infectious agents mainly - 3rd line of defense Adaptive Immunity • Antigens – found on infectious agents, environmental substances, cancers Chapter 6 • Specificity – of antigens for antibodies • Memory – long lived response • Antibodies – protect individual from infection • Lymphocytes – mediate immune response 35 – B and T cells 36 6 Bio217 F2014 Unit 2 Humoral & Cellular Immunity Active & Passive Immunity • Adaptive immunity has 2 components: • Active acquired immunity (active immunity) – Produced individual as result of natural exposure or – _______________ _________________ immunization • Humoral Immunity – Long lived – interaction of antibodies with antigens to destroy microbe directly or indirectly via inflammatory • Passive acquired immunity (passive immunity) mediators – Antibodies or T cells are transferred from donor to • Cellular (cell-mediated) immunity recipient ( i.e. during pregnancy, immunoglobulin - T cells that kill target directly shots) – 37 Donor antibodies or T cells destroyed 38 Antibodies Antigens • Also called immunoglobulins (Ig) • Antigen – proteins or CHO that bind to • Produced by plasma cells (mature B cells) in antibodies or receptors on B and T cells response to exposure to antigen • Classes of antibody • Immunogen – will solicit an immune response – IgG - most abundant class (80-85%), • major antibody found in fetus & newborn – IgA – found in blood and secretions st – IgM – largest, produced 1 in initial response to antigen – IgE - lowest blood conc., allergic rxn. 39 – IgD – low conc. in blood, receptor on B cells40 Antibodies Antibodies Structure of Different Immunoglobulins 41 42 7 Bio217 F2014 Unit 2 Primary and Secondary Responses Primary and Secondary Responses • Primary response • Secondary response – Initial exposure – More rapid – Latent period or lag phase – Larger amounts of antibody are produced • B cell differentiation is occurring – Rapidity is caused by the presence of memory cells that do not have to – After 5 to 7 days, an IgM antibody for a differentiate specific antigen is detected – IgM is produced in similar quantities to the – An IgG response equal or slightly less primary response, but IgG is produced in follows the IgM response considerably greater numbers 43 44 • 3. The antibody with the highest concentration in Concept Check blood is: • 1. An antigen is – A. IgA A. A foreign protein capable of stimulating immune – B. IgD response in healthy person – C. IgE B. A foreign protein capable of stimulating immune – D. IgG response in susceptible person C. A protein that binds with an antibody D. A protein that is released by the immune system • 4. If a child develops measles and acquires immunity to subsequent infections, the immunity is : • 2. Antibodies are produced by – A. Acquired A. B cells – B. Active B. T cells – C. Natural C. Plasma cells – D. A and B are correct D. Memory cells 45 46 • 5. Which cells are phagocytic? – A. B cells – B. T cells Infection & Defects in – C. T killers Mechanisms of Defense – D. Macrophages • 6.