Bio217 F2014 Unit 2

• Bio217 Pathophysiology Class Notes • Professor Linda Falkow Innate : & 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

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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), vessels become leaky, WBCs adhere to inner walls of vessels & migrate through the vessels 5 6

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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

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Plasma Systems Cellular Mediators of Inflammation

• Protein systems • Cellular components – ______system - , , , • Circulating that can destroy pathogens directly – & (mature monocytes) phagocytic – ______system • Forms a clot that stops bleeding –  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

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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) – -activating factor (PAF) • Similar effect to leukotrienes and platelet activation 11 12

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Phagocytes • 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

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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

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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

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Systemic Changes due to Chronic Inflammation Acute Inflammation • • 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

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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

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Healing by Primary Intention Healing by Secondary Intention

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Dysfunctional Wound Healing Dysfunctional Wound Healing - Keloid (scar) formation • Dysfunction during inflammatory response due to: – Hemorrhage – Fibrous adhesion – Infection – Excess scar formation

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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

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Adaptive (specific) Immunity - state of protection against infectious agents mainly - 3rd line of defense Adaptive Immunity • – found on infectious agents, environmental substances, cancers Chapter 6 • Specificity – of antigens for • Memory – long lived response • Antibodies – protect individual from infection • Lymphocytes – mediate immune response

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Humoral & Cellular Immunity Active &

• Adaptive immunity has 2 components: • Active acquired immunity (active immunity) – Produced individual as result of natural exposure or – ______immunization • – 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) • – 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 • – will solicit an immune response – IgG - most abundant class (80-85%), • major antibody found in fetus & newborn – IgA – found in blood and secretions – IgM – largest, produced 1st in initial response to antigen – IgE - lowest blood conc., allergic rxn.

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Antibodies Antibodies

Structure of Different Immunoglobulins 41 42

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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 • 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

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• 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 • 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. When and antigen binds to its appropriate Chapter 7 antibody: – A. Agglutination may occur – B. Phagocytosis may occur – C. Antigen neutralization may occur – D. All of the above

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Microorganisms & Humans Factors for Infection

• Mutual relationship • Pathogenicity – ability to produce disease – Normal flora (supplied with nutrients, temp. & humidity) – Relationship can be breached by injury • Mechanism of action – how organism damages tissue • Pathogens circumvent host defenses • Portal of entry – route of infection Factors for infection include:

• Communicability – ability to spread from one individual to another and cause disease • Toxigenicity – ability to produce toxins • Immunogenicity – ability to induce immune response • Infectivity – ability to invade and multiply in host • Virulence – ability of pathogen to cause severe disease

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Classes of Infectious Countermeasures Microorganisms • Bacteria – produce toxins, septicemia • • Viruses – use host metabolism t proliferate, • Antimicrobials disrupt host activities; transform – Antimicrobial resistance • Fungi – mycoses (yeast or mold) – Can destroy normal flora Dermatophytes – affect integ. system • C. difficle • Parasites • Genetic mutations Protozoa – cause of global infections • Inactivation Helminths – flukes and worms • Multiple antibiotic-resistance bacteria – Methicillin-resistant Staph. aureus ( ______)

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Immune Deficiencies Immune deficiencies

• Failure of immune mechanisms of self-defense • Clinical presentation – Development of unusual or recurrent • Primary (congenital) severe infections – Genetic anomaly • deficiencies • B cell and deficiencies • Secondary (acquired) immunodeficiency • Complement deficiencies – Caused by another illness – More common

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Acquired Immunodeficiency Acquired Immunodeficiency Syndrome (AIDS) Syndrome (AIDS) • Effective antiviral therapies have made AIDS a • Syndrome caused by a viral disease chronic disease – Human immunodeficiency virus (HIV) • Epidemiology – Depletes body’s Th cells – Blood-borne pathogen – Incidence: • Worldwide - 34 million live with AIDS (2011) – Heterosexual activity is most common route worldwide - 1.4 million deaths – Increasing faster in women than men, esp. adolescents • US newly infected 51,000 • Pathogenesis – Retrovirus • Genetic iniformation is in form of RNA • Contains reverse transcriptase to convert RNA to DNA 55 56

Acquired Immunodeficiency Acquired Immunodeficiency Syndrome Syndrome (AIDS) (AIDS) Clinical manifestations • Treatment and prevention Serologically neg. (no Antibodies); serologically positive but – Highly active antiretroviral therapy (HAART) asymtomatic; early stages HIV; or AIDS • Reverse transcriptase inihibitors Window period • Protease inhibitors Th cells <200 cells/mm3 diagnostic for AIDS Diagnosis of AIDS made in assoc. with various clinical conditions – New Drugs and lab tests • Entrance inhibitors . Atypical or opportunistic infections and cancer • Integrase inhibitors . Presence of antibodies against HIV (4 to 7 weeks after blood transmission; 6-14 months after sexual intercourse) – development . Western blot analysis 57 58

Hypersensitivity • • Altered immunologic response to an – Deleterious effects of hypersensitivity to antigen that results in disease or environmental (exogenous) antigens • damage to the host – Disturbance in the immunologic tolerance of self-antigens • – Immune reaction to tissues of another individual • transient neonatal diseases (HDN) • and transfusion reaction

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Hypersensitivity Hypersensitivity

• Characterized by the immune mechanism • Immediate hypersensitivity reactions – Type I • • IgE mediated – Type II • Delayed hypersensitivity reactions • Tissue-specific reactions – Type III • mediated – Type IV • Cell mediated

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Type I Hypersensitivity • Manifestations • IgE mediated – Itching • Against environmental antigens () – Urticaria • IgE binds to Fc receptors on surface of – Conjunctivitis mast cells (cytotropic antibody) – • Histamine release – – H1 and H2 receptors – – Bronchospasm – Dysrhythmias – 63 GI cramps and malabsorption 64

Type I Hypersensitivity Type I Hypersensitivity

• Genetic predisposition • Tests – Food challenges – Skin tests – Laboratory tests • Desensitization – cautiously

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Type II Hypersensitivity Type II Hypersensitivity

• Tissue specific • Five mechanisms – Specific cell or tissue (tissue-specific – Cell is destroyed by antibodies & complement antigens) is the target of an immune – Cell destruction through phagocytosis response – Soluble antigen may enter the circulation and deposit on tissues – Antibody-dependent cell-mediated cytotoxicity – Causes target cell malfunction

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Type III Hypersensitivity Type III Hypersensitivity

• Immune complex mediated Immune complex disease • • Antigen-antibody complexes are formed in – Caused by formation of immune complexes that lodge the circulation and are later deposited in in tissues (vessels, kidneys, joints) vessel walls or extravascular tissues • Raynauds • Not organ specific - Temperature dependent deposits of immune complexes in peripheral capillaries • Serum sickness • Raynaud phenomena • – Observed after injection, ingestion, or inhalation • Arthus – Skin reactions after repeated exposure

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Type IV Hypersensitivity Allergy

• Does not involve antibody • Most common hypersensitivity and usually • Cytotoxic T-lymphocytes or lymphokine Type I producing Th1 cells • Environmental antigens that cause atypical – Direct killing by Tc or recruitment of immunologic responses in genetically phagocytic cells by Th1 cells predisposed individuals • Examples – Pollens, molds and fungi, foods, animals, etc. – Acute graft rejection, skin test for TB, contact • is contained within a particle too allergic reactions, and some autoimmune large to be phagocytosed or is protected diseases by a nonallergenic coat • Bee stings 71 72

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Autoimmunity Autoimmune Examples

• Breakdown of tolerance • Systemic erythematosus (SLE) – Body recognizes self-antigens as foreign – Chronic multisystem inflammatory disease • Sequestered antigen – against: – Self-antigens not normally seen by the immune system • Nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, • Infectious disease (, ) platelets, etc. – Molecular mimicry • Neoantigen – become immunogenic when they bind to host proteins

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Autoimmune Examples Autoimmune Examples • Systemic lupus erythematosus (SLE) • Clinical manifestations (SLE) – Deposition of circulating immune complexes containing antibody against host DNA – or arthritis (90% of individuals) – More common in females – Vasculitis and (70%-80%)

– Renal disease (40%-50%)

– Hematologic changes (50%)

– Cardiovascular disease (30%-50%)

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Autoimmune Examples Alloimmunity

• Eleven common findings: • Immune system reacts with antigens on  Facial rash (malar rash)  Renal disorder the tissue of other genetically dissimilar  Discoid rash  Neurologic disorder members of the same species  Photosensitivity  Hematologic disorders  Oral or nasopharyngeal  Immunologic disorders – Transient neonatal alloimmunity ulcers  Presence of antinuclear • Rh incompatibilty  Nonerosive arthritis antibodies (ANA)  Serositis – Transplant rejection (MHC and HLC) and transfusion reactions (ABO blood groups)  Serial or simultaneous presence of at least four indicates SLE

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• 3. Which is not an ? Concept Check – A. MS – B. Pernicious anemia • 1. What is not characteristic of hypersensitivity? – C. Transfusion rxn. A. Specificity – D. Ulcerative colitis B. Immunologic mechanisms – E. Goodpasture disease C. inappropriate or injurious response

D. Prior contact not needed to elicit a response • 4. An alloimmune disorder is: 2. Which hypersensitivity is caused by poison ivy? – A. Erythroblastosis fetalis A. Type I – B. IDDM B. Type II – C. Myxedema C. Type III – D. All of the above D. Type IV

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• 5. A positive HIV antibody test signifies that the: – A. Individual is infected with HIV and likely so for life – B. Asymptomatic individual will progress to AIDS – C. Individual is not viremic Stress and Disease – D. Sexually active individual was infected last weekend Chapter 8

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Stress Dr. Hans Selye (1946)

• A person experiences stress when a • Worked to discover a new sex demand exceeds a person’s coping • Injected ovarian extracts into rats abilities, resulting in reactions such as • Witnessed 3 structural changes: disturbances of cognition, emotion, – Enlargement of the adrenal cortex and behavior that can adversely affect – Atrophy of thymus and other lymphoid well-being structures – Development of bleeding ulcers in the stomach and duodenum

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Dr. Hans Selye General Adaptation Syndrome (GAS)

• Dr. Selye witnessed these changes with • Three stages many agents (cold, surgery, restraint). – Alarm stage He called these stimuli “stressors.” • Arousal of body defenses (fight or flight) – Stage of resistance or adaptation • Many diverse agents caused same general • Mobilization contributes to fight or flight response: – Stage of exhaustion – general adaptation syndrome (GAS) • Progressive breakdown of compensatory mechanisms • Onset of disease 85 86

GAS Activation Stress Response

• Alarm stage • Nervous system – Stressor triggers the hypothalamic-pituitary- • Endocrine system adrenal (HPA) axis • Activates sympathetic nervous system (SNS) • Immune system • Resistance stage – Begins with the actions of adrenal • Exhaustion stage – Occurs if stress continues and adaptation is not successful

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Neuroendocrine Regulation Neuroendocrine Regulation

• Catecholamines – Released from chromaffin cells of the adrenal medulla • Epinephrine released – α-adrenergic receptors

• α1 and α2 – β-adrenergic receptors

• β1 and β2 – Mimic direct sympathetic stimulation

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Neuroendocrine Regulation Cortisol and Immune System

• Cortisol (hydrocortisone) • Glucocorticoids and catecholamines – Activated by adrenocorticotropic hormone (ACTH) – Decrease cellular immunity while increasing – Stimulates gluconeogenesis humoral immunity – Elevates the blood glucose level – Increase acute inflammation – Powerful anti-inflammatory and immunosuppressive – Th2 shift agent

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Stress Response Stress-Induced Hormone Alterations

• β-Endorphins – Proteins found in the brain that have pain-relieving capabilities – Released in response to stressor – Inflamed tissue activates endorphin receptors – Hemorrhage increases levels, which inhibits blood pressure increases and delay c compensatory changes

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Stress-Induced Hormone Alterations Stress-Induced Hormone Alterations

• Growth hormone (somatotropin) • Prolactin – Produced by the anterior pituitary and by – Released from the anterior pituitary lymphocytes and mononuclear phagocytic – Necessary for lactation and breast development cells – Prolactin levels in the plasma increase as a result – Affects protein, lipid, and carbohydrate of stressful stimuli metabolism and counters the effects of insulin – Enhances immune function – Chronic stress decreases growth hormone

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Stress-Induced Hormone Alterations Stress-Induced Hormone Alterations

• Oxytocin • Testosterone – Produced by the hypothalamus during – Secreted by Leydig cells in testes childbirth and lactation – Regulates male secondary sex characteristics and – Produced during orgasm in both sexes libido – May promote reduced anxiety – Testosterone levels decrease because of stressful stimuli – Exhibits immunosuppressive activity

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Concept Check • 3. CRF is released by the: • 1. Which is not characteristic of Selye’s stress – A. Adrenal medulla syndrome? – B. Adrenal cortex – A. Adrenal atrophy – C. Anterior pituitary – B. Shrinkage of thymus – D. Hypothalamus – C. Bleeding GI ulcers – D. Shrinkage of lymphatic organs • 4. Stress is defined as any factor that stimulates:

– • 2. Which characterizes the alarm stage? A. Posterior pituitary – B. Anterior pituitary – A. Increased lymphocytes – B. Incr. SNS act. – C. Hypothalamus to release CRF – C. Incr. PSN act. – D. Hypothalamus to release ADH

– D. Incr. eosinophils 99 100

• 5. Which would not occur in response to stress? – A. Increased systolic BP – B. Increased Epi – C. Constriction of pupils – D. Increased adrenocorticoids

• 6. Which would not be useful to assess stress? – A. Total cholesterol – B. Esosinophil count – C. count – D. Adrenocorticoid levels

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