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Lecture notes, lecture 3 - Inflammation and Overview of Immune System
Integrated Biological Bases of Nursing Practice II (Hth Sci 2C06)
McMaster University
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of Immune System 1. Cell and mediators involved Cells of Inflammation: Acute inflammation involves 2 components: A. Vascular Stage B. Cellular Stage Tissues cells are involved, including endothelial cells, circulating WBC, connective tissue cells and components of extracellular matrix fibrous proteins like collagen and elastin, adhesive glycoproteins and proteoglycans) Cells in Acute Inflammation below Endothelial line blood vessels lymphatics produce antiplatelet antithrombotic agents maintain vessel patency and vasodilators regulating blood flow selective permeability barrier to exogenous (microbial) stimuli regulate immune responses through release of inflammatory mediators, regulate immune proliferation through (colony stimulating factors) repair production of growth factors angiogenesis (new BV) and extracellular matrix synthesis involved in cellular mechanisms of primary hemostasis release of potent inflammatory mediators increasing vascular permeability, altering adhesiveness of endothelial cells platelets are inflammatory mediators examples of inflammatory atherosclerosis, migraines, lupus erythematosus associated with platelet activation Neutrophils, phagocytic leukocytes , in large , within hours site of inflammation Mannose receptors bind glycoproteins of response to diff types of microbes, cell communication receptors specific cytokines response to infection primary phagocyte early site of a contains enzymes and antibacterial substances used in destroying microbes dead tissue destruction of engulfed pathogens (hydrogen peroxide and nitric oxide) vasoactive mediators (prostaglandins, leukotrienes, platelet activating factor, cytokines and growth factor to promote regeneration of tissues) Engulfs larger and bigger foreign material than neutrophils these phagocytes destroy causative agent, signalling process of immunity, resolve inflammatory process initiation of healing process lipid mediators and cytokines that induce inflammation induce inflammation increase in the blood during parasitic infection, allergic reaction Highly toxic to parasitic worms (cannot be phagocytized) controlling release of chemical mediators (as in allergic reactions) derived from bone marrow, contains histamine and other bioactive mediators involved in inflammation both bind an antibody Immunoglobulin E (IgE) secreted plasma cells through receptors on their cell surface, binding triggers release of histamine Mast do not develop until leaves circulation and lodges in tissue cells Release of mast cells results in release of histamine, cytokinesTNF and Interleukin 16, lipid mediator synthesis, and stimulation induce inflammation and potentiate effects of histamine and other mediators (NSAIDS reduce inflammation inactivating the pathway for prostaglandin synthesis) constriction of bronchioles important in bronchial asthma and limiting inflammation bronchoconstriction Activating Factor induces PLT aggregation activates neutrophils, bronchospasm and eosinophil infiltration Plasma Proteins belong to 3 interrelated systems including the clotting, complement and kinin systems clotting vascular phase, fibrinopeptides during final steps of clotting process. Protease thrombin, binds to receptors, providing final link to coagulation inflammation Complement cascade important to both immunity and inflammation, fragments contribute to the inflammatory response causing vasodilation, increasing vascular permeability and enhancing phagocyte activity Kinin bradykinin, which increases vascular permeability and causes smooth muscle contraction, dilation of bv (SIMILAR to histamine). short lived because inactivation occurs kininase and finally, and NO Cytokines including Tumor Necrosis Factor( TNF) and are two of the major ones involved in mediating inflammation produced many other cell types other than macrophages neutrophils, endothelial cells and epithelial cells) TNF and can be stimulated endotoxin, injury, microbial products Chemokines act as chemoattractants to recruit and direct the migration of immune and inflammatory cells 2 classes of Chemokines: inflammatory chemokines and homing chemokines. Inflammatory chemokines produced in response to bacterial toxins inflammatory cytokines (TNF and Homing chemokines during inflammatory reactions immune responses Nitric Oxide and Oxygen Derived Free in inflammatory response. muscle relaxation and antagonism of platelet aggregation. Regulator of leukocyte recruitment. NO production reduces cellular phase of inflammation anti microbial actions host mediator against infection Oxygen Derived Free leukocytes after exposure to microbes, cytokines and immune complexes or during phagocytic process during inflammation. Hydrogen peroxide combine with NO to form nitrogen intermediates inflammatory High these mediators produce endothelial cell damage and increase in vascular permeability (protects against lung damage in smokers) 2. Pathogenesis of inflammation, fever, wound repair, and healing pg. 366 has excellent demonstration on Acute too much to write the response of body tissue to immune reaction, injury, or ischemic damage Classic response to inflammation includes redness, swelling, heat, pain or discomfort, and loss of function Acute Inflammatory response attributed to the immediate vascular changes that can occur such as vasodilation and increased capillary permeability, influx of inflammatory cells such as neutrophils, and sometimes the effects of inflammatory mediators which produce fever and other systemic Inflammatory Response A. Occurs in tissues with a blood supply B. Activated rapidly within seconds after damage occurs C. Depends on the activity of both cellular and chemical components D. taking place in approximately the same way regardless of the type of stimulus Inflammatory in the microcirculation capillaries, venules near site of A. vasodilation, slower blood velocity and increases blood flow to injured site B. Increased vascular permeability blood vessels from contraction of endothelial and leakage of fluid out of vessel, causing swelling site of injury, blood in the microcirculation becomes more viscous, and flows slowly and increased BF at the site causes local C. WBC adherence to inner cell walls of vessels through enlarged junctions between endothelial cells lining vessels into surrounding tissue As the above figure demonstrates, inflammation is initiated cellular injury and may be complicated infection. Mast cell degranulation, activation of 3 plasma systems and release of subcellular components from damaged cells occur as consequence. These systems are so that mast cell degranulation can result in the induction of another two Characteristic microscopic and clinical hallmarks of inflammation as result Fever Pathogenesis Fever is one of the 3 primary systemic changes associated with acute inflammation (aside from increase in the levels of leukocytes) and increased levels of circulating plasma proteins Fever, is induced specific Cytokines released from neutrophils macrophages) these are known as endogenous pyrogens Pyrogens act directly on the hypothalamus, the part of the brain that controls the thermostat formation of WBC into wound site 1st cells to arrive are ingest and remove bacteria debris post 24 neutrophils macrophages ingest debris B. Proliferative Phase building of new tissue to fill wound Key cell is the connective tissue that secretes collagen and glycoproteins for wound healing and growth factors to induce angiogenesis (growth of new blood vessels) and endothelial cell proliferation Final component, epithelial cells wound edges form new layer C. Wound Contraction Remodelling Phase 3 WEEKS after injury and development of fibrous scar tissue, more decrease in vascularity and continued remodelling of scar tissue synthesis of collagen fibroblasts and lysis collagenase enzymes scar shrinks due to increased tensile strength, decreasing visible scar 3. definitions, pathogenesis and clinical presentations Definitions Shock is the most common type of vasodilatory shock and it is associated with severe infection and the systemic response to infection. inflammatory response syndrome (SIRS) is an overwhelming inflammatory response, which is not necessarily due to infection. with two or more alterations in temperature, heart rate, respiratory rate, or white blood cell count. is defined as suspected or proven infection, plus a systemic inflammatory response (e fever, tachycardia, tachypnea, elevated white blood cell count, altered mental state, and hyperglycemia in the absence of diabetes. sepsis is sepsis with organ dysfunction (e hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia or obtundation). shock is severe sepsis with hypoperfusion, despite fluid resuscitation. Pathogenesis a complex process of cellular activation resulting in the release of proinflammatory mediators such as cytokines: activation of neutrophils, monocytes and endothelial involvement of neuroendocrine and activation of complement coagulation and fibrinolytic systems. of response begins with activation of the innate immune system receptors receptors of TLRs stimulates transcription and release of a number of proinflammatory and (Tissue necrotic and B. They are involved in leukocyte adhesion, local inflammation, neutrophil activation, suppression of erythropoiesis, generation of fever, tachycardia, lactic acidosis, abnormalities and other signs of sepsis. endothelial cells release nitric potent vasodilator that as a key mediator of septic shock. important aspect: alteration of the balance with an increase in procoagulation factors and decrease in anticoagulation factors. (on microorganisms) stimulates endothelial cells lining blood vessels to increase their production of tissue factor, activating coagulation. is then converted to fibrin, leading to the formation of microvascular thrombi to further amplify tissue injury. Manifestations and septic shock typically manifest with hypotension and warm, flushed skin. shock only presents with a decrease in systemic vascular resistance. is a maldistribution of volume due to extensive arterial and venous dilation, and leakage of plasma into the interstitial spaces. changes in cognition of behavior (due to reduced cerebral blood flow) and increased leukocytes serum lactate or metabolic acidosis indicates anaerobic metabolism due to tissue hypoxia or cellular dysfunction and altered cellular metabolism. Treatment use of antibiotics followed antibiotic therapy specific to the infectious agent. therapy therapy vasopressin, norepinephrine and phenylephrine (to counteract the vasodilation caused inflammatory mediators) o Neurologic: Restlessness, anxiety, lethargy progressing to coma o Urine output: Oliguria to anuria 3. Low SVR distributive shock Caused immunologic reactions that trigger abnormal dilation of blood vessels. Can occur in anaphylactic shock, septic shock or in cases where a patient has been given excessive amounts of sedatives or vasodilators Clinical manifestations of anaphylactic shock: o Skin: Generalized itching, flushing, sensation of warmth, urticaria (hives), angioedema (edema of eyelids, lips, and tongue) o Neurologic: Restlessness, anxiety, decreased level of consciousness o Respiratory: Difficult breathing, stridor, wheezes, laryngospasm o Cardiovascular: Hypotension, tachycardia, bronchoconstriction o Gastrointestinal: Nausea, vomiting, diarrhea Clinical Manifestations of Septic Shock: o Cardiovascular: Heart rate greater than 90 beats per minute o Respiratory: Respiratory rate greater than 20 or PaCO2 less than 32 mm Hg o Temperature: Below or above o Other: WBC count less than mm3, greater than mm3, or greater than immature neutrophils Late Septic Shock o Cardiovascular: Profound hypotension despite adequate fluid rapid, thready dysrhythmias o Respiratory: Rapid, shallow with dyspneic o Skin: Cold, cyanotic extremities o Neurologic: Confused to lethargic to comatose o Urine output: Oliguria to anuria 4. Neurogenic shock Caused changes in the sympathetic tone of blood vessels Occurs in cases such as spinal cord injuries or brain injuries Clinical Manifestations: o Cardiovascular: Hypotension, bradycardia o Skin: Warm, dry o Neurologic: Anxiety to restlessness to lethargy o Urine output: Oliguria to anuria o Other: Lowered body temperature Common Pathway: 5. Similarities and differences between inflammation and immune system function Inflammation describes a local response to tissue injury and can present as an acute or chronic condition Classic signs of acute inflammatory response are redness, swelling, local heat, pain and loss of acute is also Acute inflammation is orchestrated endothelial cells that line the blood vessels, phagocytic leukocytes (mainly neutrophils and monocytes) that circulate in the blood and tissue cells (macrophages and mast cells) that direct tissue responses Inflammatory response is coordinated chemical mediators such as cytokines and chemokines, histamine, prostaglandins, PAF, complement fragments and reactive molecules liberated leukocytes Chronic inflammation is prolonged and usually is caused persistent irritants, most of which are insoluble and resistant to phagocytosis and other inflammatory mechanisms Chronic inflammation involves the presence of mononuclear cells (lymphocytes and macrophages) rather than granulocytes Mediated B lymphocytes (b cells) Principle defense against extracellular microbes and toxins Circulating antibodies interact with and destroy microbes present in blood or mucosal surface Acquired Immunity: Mediated T lymphocytes (T cells) Functions in the elimination of intracellular pathogens T cells have receptors that recognize viral peptides and signal destruction Primary immune response: The primary immune response of the body to antigen occurs on the first occasion it is encountered. This response can take up to 14 days to resolve and leads to the generation of memory cells with a high specificity for the inducing antigen. Secondary immune response: Subsequent encounter with the same antigen and is more rapid leading to the activation of previously generated memory cells. This process is quicker and more effective than the primary response. 7. T and B cell formation and differentiation with structure, class and functions of T and B cells Formation all the way to differentiation T Cells mediators of cellular immunity (respond mostly to surface protein antigens) Tm cell activated upon second presentation of an antigen Tc cell destroy virus infected cells and tumour cells play a role in rejection of transplants Treg cell Antibodies 5 Types IgG, IgA, IgM, IgD, IgE IgG is cruddy at first response but excellent at second presentation no the second time you IgM is good at first presentation but real slow on the second round feel miserable as you have all the the second time 8. primary vs. secondary Primary: Genetically determined, may occur alone or as part of a syndrome The molecular basis for about is known. Primary immunodeficiencies typically manifest during infancy and childhood as abnormally frequent (recurrent) or unusual infections. About of patients are 20 yr at because transmission is often are male. Overall incidence of symptomatic disease is about people. Primary immunodeficiencies are classified the main component of the immune system that is deficient, absent, or defective ex: IgA deficiency: celiac Secondary: Causes include: Systemic disorders (eg, diabetes, undernutrition, HIV infection) Immunosuppressive treatments (eg, cytotoxic chemotherapy, bone marrow ablation before transplantation, radiation therapy) Prolonged serious illness Secondary immunodeficiency also occurs among critically ill, older, or hospitalized patients. Prolonged serious illness may impair immune impairment is often reversible if the underlying illness resolves. 9. Autoimmune disease (ITP, Scleroderma, and types with examples Autoimmune diseases are a group of disorders that are caused a breakdown in the ability of the immune system to differentiate between self and antigens. They can be tissue specific or affect multiple organs and systems. Autoimmune diseases specified to cover: Systemic Lupus Erythematosus: Can affect virtually any organ system with cause unknown. It is characterized the formation of antibodies and immune complexes, with hyperreactivity and increased antibodies against self and nonself antigens. The development of autoantibodies can result from a combination of factors including genetic, hormonal, immunological, and environmental factors. JOINTS Scleroderma: Also known as Systemic sclerosis, is an autoimmune disease of connective tissue characterized excessive collagen deposition in the skin and internal organs such as the lungs, GI tract, heart, and kidneys. The skin becomes thickened through fibrosis. The cause is poorly understood. There is evidence of both humoral and cellular immune system SKIN Sjogren syndrome: A systemic disorder in which lymphocytes and plasma cells infiltrate the lacrimal and parotid glands. The disorder is associated with diminished salivary and lacrimal secretions, resulting in dry eye and mouth syndrome. This occurs mainly in women near menopause, often associated with connective tissue disorders such as RA. EYES Immune Thrombocytopenic Purpura (ITP): An autoimmune disorder resulting in platelet antibody formation and excess destruction of platelets. May occur in absence of any known risk factors making it primary or idiopathic ITP, or as a secondary disorder associated with AIDS, lupus, Hep C, lymphoma, and drugs such as heparin. The thrombocytopenia that occurs in ITP is thought to result from antiplatelet antibodies against glycoproteins in the platelet membrane. Manifestations include a history of bruising, bleeding from gums, epistaxis, melena, and abnormal menstrual bleeding
Lecture notes, lecture 3 - Inflammation and Overview of Immune System
Course: Integrated Biological Bases of Nursing Practice II (Hth Sci 2C06)
University: McMaster University
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