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Transcript
The Immune Response: • Introduction to Immunity • Part I: Innate Immunity: Major Cells • Part II: Innate Immunity: The Inflammatory Response • Part III: Treatment of Inflammation • Part IV: Adaptive Immunity 1 Introduction to Immunity 2 Functions of the Immune Response 3 The Immune Response The Immune Response: A collective and coordinated response of cells of the immune system 1. Protects host from invasion of anything foreign • Ex. foreign pathogens, bacteria, parasites, viruses, the environment in general 2. Distinguishes “self” from non-self • Ex. cancer, autoimmune reactions • The immune system has a surveillance mechanism to identify itself – When it recognizes something that is nonself, the immune system has mechanisms to kill the cell – When the surveillance system breaks down or is over-challenged, disease occurs 3. Mediates healing • Modulate inflammatory process and wound repair • Immunity and inflammation are wrapped up together to make healing more efficient 4 Results of Immune Dysfunction or Deficiency 5 Results of Immune Dysfunction or Deficiency • Immunodeficiency – Do not have the requisite amount of immunological ability • Cannot keep up with what is going on • Allergies/Hypersensitivities – The response to something is exaggerated • Transplantation pathology • Autoimmunity 6 Innate Immunity 7 Innate Immunity • Natural resistance that a person is born with – Do not need anything else special • Comprises physical, chemical, and cellular barriers that keep the self and the nonself apart • First line of defense • Ex. skin, mucosa – When radiator heat comes on, it dries out the mucosal membranes and makes you more susceptible to microorganisms – A person in the healthcare system needs to take care of the skin because dry skin makes a person more susceptible to invasion 8 Adaptive Immunity 9 Adaptive Immunity • Acquired – When you are born and come into contact with antigens in the environment, your body mounts a response • Are able to recognize the pathogen in the future • Specific • Amplified response with memory – Has a recognition system – There is a molecular memory in the body about what happened – Able to respond more quickly to the pathogen when interact with it in the future 10 Components of the Adaptive Immune Response 11 Components of the Adaptive Immune Response • Divided into two major components: 1. Cell-mediated adaptive immunity - T cells 2. Antibody-mediated (humoral immunity) - Circulating antibodies - B cells produce the antibodies for humoral immunity a. Antibody-mediated immunity is triggered by encounters with Antigens (Ags) b. Antibodies are also known as Immunoglobulins (Igs) 12 Part I: Innate Immunity 13 Primary Immune Cells of Innate Immunity 14 Primary Immune Cells of Innate Immunity • • • • • • Monocytes, macrophages, dendritic cells Neutrophils Eosinophils Basophils Mast cells Natural killer cells 15 Monocytes, Macrophages, and Dendritic cells 16 Monocytes, Macrophages, and Dendritic cells • • Phagocytic cells that are located in different areas of the body While macrophages are important cells of the innate immunity, they also play key role in adaptive immunity • Monocytes in blood Macrophages in tissues: • Dendritic cells are phagocytic cells in the nervous system • Include Kupffer, Langerhans, alveolar, peritoneal oligodendrocytes etc • Phagocytize antigen present antigen (APC-antigen presenting cell) • – – • Takes the antigen, sticks it outside of itself, and presents it When activated, secrete cytokines (tumor necrosis factor, interleukin-1, and others), oxygen radicals, proteolytic enzymes, arachidonic acid metabolites, prostaglandins – • Internalize and consume pathogens with lysosomes and peroxisomes Process the antigen out of the substance that is foreign Release molecules that are very important in inflammation Macrophages are phagocytes 17 Neutrophils 18 Neutrophils • AKA Polymorphonuclear leukocytes (PMN) • Antigen binding and non-specific phagocytosis • Inflammatory response: First-line defender against bacterial invasion, colonization, and infection • Important in innate immunity – Responsible for antigen binding and phagocytosis 19 Eosinophils 20 Eosinophils • Inflammatory response • Fight parasites (worms especially) • May release chemicals in respiratory tract during allergic asthma – Release chemical mediators 21 Basophils 22 Basophils • Release potent mediators during allergic responses (e.g. histamine) • Have binding sites for IgE antibodies (Type 1 Hypersensitivity) – The antibody will bind to antigen, and the basophil will release the inflammatory substances • Reside in blood 23 Mast Cells 24 Mast Cells • Also from bone marrow and share characteristics with basophils • Located in tissues; not blood • Releases histamine which is the hallmark of tissue inflammatory response. 25 Natural Killer Cells 26 Natural Killer Cells Natural Killer Cells: an effector cell important in innate immunity. • Small % of lymphocytes – Part of the lymphocyte population but are a small amount • Can bind with antibody coated target cell Antibody dependent cell-mediated cytotoxicity (ADCC) – Can recognize the antibody and destroy the cell • Can attack virus-infected cells or cancer cells without help or activation first – Important in immunosurveillance • Can recognize antigen without MHC restrictions – Major histamine compatibility • NO MEMORY – Lives by the minute by doing what it does • Regulated by cytokines, prostaglandins and thromboxane • Release NK perforins, enzymes, and toxic cytokines to destroy target cells 27 Outline of Immunity 28 29 Cytokines and the Immune Response 30 Cytokines and the Immune Response • Small, low molecular weight proteins (hormone-like) which are produced during all phases of the immune response. – They are released form one area, move, and act on another area – Short half-life – Work in a parocrine system (acts locally) rather than an endocrine system • This is characteristic of many of the immunological cytokines • Primarily made by T cells and macrophages (lymphokines/ monokines) and act primarily on immune cells – Lymphokines – a cytokine released from a lymphocyte (T cell) – Monokines – a cytokine released from a macrophage 31 Processes that Cytokines are Involves in 32 Processes that Cytokines are Involves in • Innate immunity • Adaptive immunity • Hematopoiesis 33 Cytokines and Innate Immunity 34 Cytokines and Innate Immunity • IL-1, IL-6, TNF (tumor necrosis factor) are important in the early inflammatory response. • Derived mainly from macrophages,endothelial, and dendritic cells, and lymphocytes (T cells) • Processes – Stimulate acute phase protein production by the liver – Stimulate the hypothalamus for a fever response – Increase adhesion molecules on the vascular endothelium 35 Acute Phase Protein Production by the Liver 36 Acute Phase Protein Production by the Liver • Overlaps with the ESR • Increases cytokine release in the bodysensed by the liver-liver increases amount of acute-phase proteins (complement, clotting factors) – Increased cytokines due to inflammation causes liver to produce more proteins, which increases ESR 37 Stimulate Hypothalamus for Fever Response 38 Stimulate Hypothalamus for Fever Response • Hypothalamus in the base of the brain thermoregulates the body • One of the main reasons that you get a fever is because a cytokine burden increases enough to pass through the vasculature of the hypothalamus and resets the temperature of the body – Reason why anti-inflammatory decrease fever – decrease the burden of the cytokine production, which decreases the reason that the hypothalamus causes fever 39 Increase in Adhesion Molecules 40 Increase in Adhesion Molecules • Cytokines trigger the endothelium to put out adhesion molecules so that when a macrophage comes by it sticks to it and squeezes between the endothelium cells out into the tissue to fight infection 41 Cytokines and Adaptive Immunity 42 Cytokines and Adaptive Immunity • Activate immune cells to proliferate and differentiate into effector and memory cells. 43 Cytokines and Hematopoiesis 44 Cytokines and Hematopoiesis • Cytokines that stimulate bone marrow pluripotent stem cells, progenitor cells and precursor cells to produce large numbers of platelets, erythrocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils and dendritic cells are termed Colony Stimulation Factors (CSFs) 45 PART II Innate Immunity: THE INFLAMMATORY RESPONSE 46 Inflammation 47 Inflammation Reaction of vascularized tissue to local injury (cellular) manifesting as redness, swelling, heat, pain, loss of function • Non-specific, chain of events similar regardless of injury type and extent • Includes vascular and cellular changes • Triggered when FIRST LINE OF Defense's integrity has been breached – Stereotypic no matter the size of the injury (skin, mucus membranes and damaged the endothelium or gotten to a vessel) – May be from the outside into the body or from the inside of the body out (ex. vacularitis) • • Unpleasant and uncomfortable, but essential for survival May lead to inflammatory diseases 48 Acute Inflammation 49 Acute Inflammation • 1. vascular phase • 2. cellular phase 50 Acute Inflammation Vascular Phase 51 Acute Inflammation Vascular Phase After injury or insult, inflammation initiates a rapid vasoconstriction of small vessels in the local area • – The same thing as the rapid vasoconstriction that occurs in hemostasis • This vasoconstriction is then followed by a rapid vasodilatation of arterioles and venules (vasoactive hyperemia) that supply the local area. – Results in the erythema (redness) and warmth in the area due to the increased blood flow to the area • Capillary permeability increases and fluid moves into the tissues (edema) causing swelling and pain. – – Due to cytokines that are released The capillaries become more permeable – cells that make up the cell wall become looser, allowing fluids and proteins to move out of the capillaries and into the tissue 52 Vascular Phase Possible Scenarios 53 Vascular Phase Possible Scenarios 1. Immediate transient response to minor injury • Ex. very small, sterile cut (ex. razor cut, paper cut) • At first you do not notice the blood because of the rapid vasoconstriction but then after rapid vasoconstriction the vasodilation occurs 2. Immediate sustained response (several days; results in damaged vessels) • More of a traumatic event and possibly a less sterile field • Ex. step on a garden hose • The issue cannot resolve quickly and due to the hemostasis and clotting necessary, the several day response results in extra damage to the skin and vessels 3. Delayed hemodynamic response (increase in capillary permeability 4-24 hours after injury ; e.g., radiation burns, sun burns) • Have an insult but do not realize an effect until 4-24 hours after an injury • Ex. sunburn cooks the cells and damages them but they take a while to build up the response and the damage so that the response takes a while to show 54 • Redness is the vasodilation, vascular permeability leads to the edema Acute Inflammation Vascular Phase 55 Acute Inflammation Cellular Phase 56 Acute Inflammation Cellular Phase • • • • Ex. step on a garden rake and bacteria enters the site of injury Characterized by the movement of phagocytic cells into the site of injury • Need to remove them by recycling them Release of chemical mediators by sentinel cells in the tissue (mast cells, basophils, macrophages) • Sentinel cells in the tissues release cytokines, the endothelial cells recognize them, stick out adhesion molecules to allow phagocytic cells to stick to them • Chemotaxis of the phagocytic cells from the vessels to the tissue because the cells of moving to the area of high signaling Increases capillary permeability and allows leukocytes to migrate to the local area. • Water wants to leave the vasculature, making it easier for the cells to get out of the blood and into the tissue where they can 57 fight infection Acute Inflammation Cellular Phase 58 Inflammatory Mediators 59 Inflammatory Mediators • • • • • Histamine Plasma proteases Arachidonic acid metabolites Platelet aggregating factors Cytokines 60 Histamine 61 Histamine • One of the first mediators of inflammation causing dilatation and increased capillary permeability. • Histamine high concentration in platelets, basophils, and mast cell – Allows there to be a cross talk between the clotting cascade and platelet plug • In mast cells histamine is released in response to binding of IgE Antibodies 62 Plasma Proteases 63 Plasma Proteases • Kinins, activated complement, clotting proteins • Bradykinin causes increased capillary permeability and pain. – Byproduct of plasma proteases – Causes pain by binding to nociceptors 64 Arachidonic Acid Metabolites 65 Arachidonic Acid Metabolites • Metabolism of arachidonic acid into prostaglandins via the cyclooxygenase pathway • Metabolism of arachidonic acid into leukotrienes via the lipoxygenase pathway 66 Metabolism of Arachidonic Acid into Prostaglandins via the Cyclooxygenase Pathway 67 Metabolism of Arachidonic Acid into Prostaglandins via the Cyclooxygenase Pathway • Arachidonic metabolics are very, very important inflammatory mediators • PGE1(prostaglandin E1) and PGE2, prostaglandin intermediates, are important in inducing inflammation – – – – – – • – • – Promoting the inflammatory pathways Induces vasodilation and bronchoconstriction Inhibits inflammatory cell function Prostaglandins released during the pulsatile flow are important in making blood not stick Control of acid production in the stomach Some are pro-inflammatory and some are pro-other things that are important and beneficial to the body TXA2 (Thromboxane A2) promotes platelet aggregation and vasoconstriction Promotes branchoconstriction Non-steroidals (aspirin etc) inhibit the first enzyme in the cyclooxygenase pathway. Used pharmacologically to reduce inflammation 68 Metabolism of Arachidonic Acid into Leukotrienes via the Lipoxygenase Pathway 69 Metabolism of Arachidonic Acid into Leukotrienes via the Lipoxygenase Pathway • Leukotrienes are critically important in the generalized response of anaphlaxis • • C4, D4, E4: the slow releasing substances of anaphylaxis (SRA’s). They cause slow sustained contraction of bronchiole smooth muscle. Are important in asthma and anaphylaxis. Target of the newer anti-asthma drugs, e.g., montelukast (Singulair), which act as leukotriene inhibitors 70 Arachidonic Acid Diagram 71 72 Platelet Aggregating Factor 73 Platelet Aggregating Factor • Induced platelet aggregation – Pathways that are important for hemostasis are also important in the immune and inflammatory pathways • Neutrophil activation • Eosinophil chemotaxis 74 Complement System 75 Complement System • Functionally analogous to the clotting cascade in hemostasis • Primary mediator of the innate and adaptive humoral immune response. Produce inflammatory response, lyse foreign cells, increase phagocytosis • About 20 plasma proteins. Circulate in inactive form much like clotting factors (C1, C4, C2, C3, C5C9). Proteins must be activated in the proper sequence in order to have their end effect (as with the clotting factors) • Non-specific and no memory 76 Complement Pathways for Activation 77 Complement Pathways for Activation • Classical pathway depends on: 1. Binding of IgG or IgM to invading organisms - antibodies bind to invading organisms 2. Binding of complement to circulating antigen-antibody complex (complement fixation) - undergoes molecular change that promotes the activation complement - complement sees this and there is a molecular recognition • Alternate pathway is triggered by interactions between complement and polysaccharides on microbes • Lectin pathway is activated by binding proteins interacting with cell surface proteins in bacteria and yeast – Lectin can be recognized by complement and activates it – Lection is located inside cells and is seen when cells lyse 78 Results of Complement 79 Results of Complement • MAC (membrane attack complex) insertion into target cell membrane holes in cell membrane (lysis) – Form a pore that sticks into a cell and causes the cell to die through membrane depolarization • Opsonization - C3b coats Ag-Ab complexes – Helps out neutrophils and macrophages with phagocytosis – Opsonization is when an antibody binds to bacteria • Complement binds to the antigen-antibody complex and opsonizes it so that the phagocytes want to phagocytize the complex even more • Chemotaxis - C3a stimulates mast cells and basophils to release histamine and attract neutrophils and others • C3a and C5a produce anaphylatoxin inducing histamine release in mast cells and basophils: • • Leads to contraction of smooth muscle, vascular permeability, edema Complement, if activated, will bind to these cells and cause them to release histamine 80 Complement Pathways Diagram 81 82 Chronic Inflammation Persistent Irritants 83 Chronic Inflammation Persistent Irritants • Ex. talc, silica, asbestos that are breathed deeply into the respiratory tract, surgical sutures – The chronic inflammation causes persistent problems that results in disease • Some bacteria (tuberculosis, syphilis) – Can be in the body for a long time, escape surveillance, and cause inflammation • Injured tissue surrounding healing fracture – Keep stressing the healing fracture, leading to inflammation • Inflammatory process lasts a prolonged amount of time – Sustained types of response 84 Chronic Inflammation Patterns 85 Chronic Inflammation Patterns • Non-specific diffuse accumulation of macrophages and lymphocytes leading to fibroblast proliferation and scar tissue formation – Relsease cytokines and mediators that lead to the fibroblast proliferation and scar tissue formation – Ex. in the respiratory tract of smokers the epithelium begins dying and as the body goes to replace it, it says that the epithelium is difficult to replace so it replaces it with less ciliated, good cells, and then a scar tissue and fibroblasts • Granulomatous lesion epitheloid cells form granuloma: – Lesions are very discrete • Ex. splinters, foreign bodies • After a couple of days, a granulomatous lesion forms and encapsulates the splinter • Eventually fibroblasts form around it and the nodule stays there for a long time – Ex. Tuberculosis tubercle • Waiting for the immune system to decrease so that the tuberculosis can come back 86 Chronic Inflammation Causes and Characteristics 87 Chronic Inflammation Causes and Characteristics Due to: • Recurrent or progressive acute inflammation (smoking), OR • Low-grade responses that fail to evoke acute responses (talc, silica, asbestos, tb) Characteristics: • Infiltration by mononuclear cells (Macs and Lymphs); not Neutrophils like in acute inflammation. • Proliferation of fibroblasts ( scarring) ; not exudates 88 Manifestations of Inflammation Exudation 89 Manifestations of Inflammation Exudation • Local manifestation of inflammation • Extra vascular influx of fluid with high concentration of proteins, salts, cells (WBC) and cell debris – The fluid from the vessel leaves the vessel and enters into the tissues • Fluid dilutes injurious chemicals • Fluid brings in complement, Abs, and other chemotactic substances to injured areas in the tissues due to osmotic gradient • The extra vascular proteins also act to pull water out of plasma blood viscosity clotting because water is taken out and cells are left behind (increase hemotocrit); containment of pathogens cellular phase begins 90 Manifestations of Inflammation Types of Exudate 91 Manifestations of Inflammation Types of Exudate • Serous watery; low in protein – Early exudate • Fibrinous large amounts of fibrinogen in the exudate • Membranous necrotic debris in fibrinous matrix on mucus membrane surfaces – Forms a muscosy sheen on certain membranous surfaces • Purulent degraded white cells, protein, tissue debris – Ex. white looking acne blemish • Hemorrhagic severe leakage of red cells from capillaries – Blood leaves the vasculature and enters the tissue – Ex. petechiae, purpura 92 Systemic Manifestations of Inflammation 93 Systemic Manifestations of Inflammation • Most all of the inflammatory mediators have very short half lives so autocrine and paracrine signaling predominates. – Mechanisms whereby cells secrete substances and they act very, very locally • Compared to endocrine systems • If the site of inflammation is large enough or robust enough of if the inflammation is in the circulation, systemic manifestations can be evident in addition to the local manifestations • Acute phase response • Lymphadenitis 94 Acute Phase Responses 95 Acute Phase Responses Acute-Phase Response (hours-days after onset) • Increase in plasma proteins (e.g., C-reactive protein) – Increased erythrocyte sedimentation rate (ESR) • Fever (IL-1, IL-6 and TNF effects on hypothalamus) – Drive the hypothalamus to increase body temeprature • Leukocytosis (presence of immature neutrophils; “band cells”) – Are consuming leukocytes to significant amounts and are trying to replace them – Similar to the reticulocytes in red blood cells – Band cells are indicative are immature neutrophils • Skeletal muscle catabolism (mobilize amino acids for protein synthesis) – When there is active inflammation, individuals do not feel well, lose the drive to eat, do not take in enough nutrition, ask the liver to make a bunch of proteins • Break down the skeletal muscle to increase amino acid pool and make more proteins – Negative nitrogen balance – Skeletal muscle is wasting 96 Lymphadenitis 97 Lymphadenitis • Regional swelling of lymph nodes, painful upon palpation • A swollen lymph node is indicative of an inflammatory event in a local area or regional area – The regional swelling is an indication of systemic inflammation 98 Part III: Treatment of Inflammation 99 Types of Treatment of Inflammation 100 Types of Treatment of Inflammation • Focus: Prevent the synthesis and release of pro-inflammatory mediators, such as prostaglandins • NSAIDs • Steroids 101 Treatment of Inflammation Diagram 102 Treatment of Inflammation Diagram 103 Treatment of Inflammation NSAIDs 104 Treatment of Inflammation NSAIDs • NSAIDS: nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins and thromboxane (e.g., aspirin, et al.) through the cyclooxygenase pathway • Inhibit the enzymatic conversion 105 Treatment of Inflammation Steroids 106 Treatment of Inflammation Steroids • Steroids: given systemically or topically • Have a multiplicity of actions, many of which impair immune cell proliferation or cytokine release. • Stop the metabolism of arachidonic acid from cell membrane phospholipids 107 COX-1 and COX-2 108 COX-1 and COX-2 • Both produce prostaglandins and thromboxane (TXA) and convert arachidonic acid into prostaglandins 109 COX-1 110 COX-1 • Found in many different tissues • Inhibition of COX-1 is responsible for the adverse effects of NSAID’s because the drug works on all COX-1 tissue types • COX-1 inhibition impairs the gastrointestinal mucosal barrier and gastric erosion and ulceration may result • COX-1 inhibition impairs renal function so that sodium and water retention can result • • Leads to edema and hypertension COX-1 inhibition decreases the creation of thromboxane, which prevents platelet aggregation, which may produce bleeding. • Such inhibition may also prevent myocardial infarction or ischemic (thrombotic) 111 stroke in patients with overactive coagulation pathways. COX-2 112 COX-2 • COX-2 is predominantly in immune cells. • • Inhibiting COX-2 results in the therapeutically desirable effects of NSAID’s: • If you are targeting inflammation, you should really be targeting COX-2 because it is more specific • Suppression of inflammation • Decreasing systemic side effects • Alleviation of pain • Reduction of fever However, many of the non-steroidals inhibit both COX-1 and COX-2 113 Contraindications 114 Contraindications • NSAIDs • Hypersensitivity syndrome 115 NSAIDs 116 NSAIDs • NSAIDs should be avoided in mid to late pregnancy since: • They may cause premature closure of the ductus arteriosus. • • • A shunt in the heart in the developing fetus that allows proper blood flow Important in maternal-fetal circulation and oxygenation of the fetus They might also cause prolonged bleeding following delivery because of their effects on platelets. 117 Hypersensitivity Syndrome 118 Hypersensitivity Syndrome • Hypersensitivity syndrome caused by COX inhibition: • This is not an allergic response because there are no antibodies to the NSAID; in susceptible individuals, any NSAID can trigger the reaction. • Certain people are more sensitive to NSAIDs just because • Symptoms are similar to those of anaphylaxis. • Susceptible individuals should avoid all NSAIDS 119 Aspirin 120 Aspirin • An irreversible inhibitor of both COX-1 and COX-2 (it is nonselective). • Metabolized (with a half-life of ~20 minutes) to salicylic acid, which inhibits both COXs reversibly and has a longer half-life than aspirin • The anti-inflammatory activity is due to both the irreversible inhibition of both COXs by aspirin and reversible inhibition by salicylic acid. 121 Uses of Aspirin 122 Uses of Aspirin • • • Anti-inflammatory Anti-pyretic (suppression of fever) Analgesic • Dysmenorrhea • • Menstrual cramps are due to the production of prostaglandins • Aspirin decreases smooth muscle cramping Suppression of platelet aggregation 123 Uses of Aspirin Suppression of Platelet Aggregation 124 Uses of Aspirin Suppression of Platelet Aggregation • • This use is usually accomplished by administration of an 81-mg enteric-coated tablet each morning. – Allows the drug to pass through the stomach and be absorbed in the intestine – Do not want aspirin to dissolve in the stomach because it affects gastric pH The aspirin irreversibly inhibits COX-1 in platelets it encounters in the portal circulation, but in its 81 mg form it is completely metabolized on first pass and has no systemic effects. – When aspirin is taken, any platelets in circulation are irreversibly inhibited but on the second time, the aspirin is converted to salicyclic acid and reversibly inhibit platelets • • Taking the small dose allows it to be that only the platelets in the circulation are irreversibly affected (because of the short life of the platelets) Over time, a substantial portion of platelets are affected by the low dose aspirin without undue systemic side effects. 125 Adverse Effects Common to all Aspirin Formulations 126 Adverse Effects Common to all Aspirin Formulations • Salicylism: tinnitus, headache and dizziness caused by high doses such as the doses that are used in rheumatoid arthritis. Respiratory alkalosis may also result. • Reye’s syndrome: a fatal syndrome of liver failure in children suffering from chickenpox or influenza who use aspirin. For this reason, it is recommended that children be only given acetaminophen or ibuprofen for febrile illness. With this recommendation, the incidence of Reye’s syndrome has plummeted. • Poisoning: before childproof caps were mandated by law, aspirin poisoning was a common cause of illness and death in children. This is no longer such a problem • The toxicity of aspirin in children is what prompted the mandation of childproof safety caps 127 Aspirin Formulation 128 Aspirin Formulation • Plain aspirin tablets. • Buffered aspirin: includes sodium bicarbonate to neutralize stomach acid and prevent gastric irritation. • The sodium bicarbonate acts as the buffer • Inhibit the prostaglandins, allowing the gastric mucosa to temporarily go down but you are also buffering the aspirin so you are helping it out • Enteric coated aspirin: remains intact in the stomach and dissolves in the duodenum; prevents gastric irritation. • Timed released: makes no sense for an irreversible drug that is completely metabolized on first pass • Rectal suppositories: Not recommended due to inconsistent absorption and rectal ulceration. 129 Aspirin Dosage 130 Aspirin Dosage • Is commonly available in: • • • regular strength (327 mg) extra-strength (500 mg) low-dose (81 mg) tablets • • • Used by adults for the inhibition of platelets There is no evidence that taking more than 81 mg leads to further platelet aggregation Adults: 650-1000 mg in one dose can be repeated every 4 hours. • Children: aspirin is not recommended unless specifically requested by the • Inhibition of platelets: 81 mg per day. child’s physician. 131 Other Non-Selective NSAIDs 132 Other Non-Selective NSAIDs • Non-specific COX-1 and COX-2 inhibitors • Specific COX-2 inhibitors 133 Non-specific COX-1 and COX2 Inhibitors 134 Non-specific COX-1 and COX-2 Inhibitors • Nonspecific COX-1 and -2 inhibitors (aspirin, Ibuprofen, naproxen, etc.): • All have interactions with warfarin (Coumadin); they may potentiate bleeding tendencies produced by warfarin • Coagulation studies should be obtained frequently and warfarin dosage adjusted in patients who take both an NSAID and warfarin 135 Specific COX-2 Inhibitors 136 Specific COX-2 Inhibitors • Have recently been associated with increased risk of heart attacks. • • A result of clinical trials but many of the reasons are not known Could inhibit prostacycline, which is a positive mediator • Purported to produce fewer adverse effects in some individuals, such as GI irritation, bleeding, and sodium/water retention. However, data in the general population to support this contention is shaky. • Much more expensive than nonselective NSAIDS • • A nonselective NSAID is equally effective as a COX-2 inhibitor Include: – – – Rofecoxib (withdrawn from the market) Valdecoxib (withdrawn from the market) Celecoxib (Celebrex) is still available 137 Acetaminophen 138 Acetaminophen • Does not inhibit COX in the periphery; MOA is unclear • • Is not a COX inhibitor Has no anti-inflammatory activity. • Does not decrease inflammatory mediators • No side effects of gastric ulceration, sodium and water retention. • No effect on platelets or coagulation. • Uses – Antipyretic – Analgesic 139 Acetaminophen Adverse Effects 140 Acetaminophen Adverse Effects • Adverse effects: Hepatoxicity • Usually occurs because of overdose • Decreases liver function and may increase toxicity • Greatly exacerbated by concurrent alcohol use; so, hepatoxicity may occur at therapeutic doses in heavy drinkers. • Hepatotoxicity from acetaminophen has resulted in deaths from liver failure. 141 Acetaminophen Drug Interactions 142 Acetaminophen Drug Interactions • May affect warfarin metabolism because it is metabolized by the liver to increase levels of warfarin and increase its anticoagulant effects. 143 Acetaminophen Dosages 144 Acetaminophen Dosages • Available in 327 mg and 500 mg tablets. • Adult dose is 650 mg to 1000 mg every 4-6 hours with a daily limit of 3 g (3000 mg). • Dosage is reduced depending on the age of the child 145 Formulations of NSAIDs and Acetaminophen 146 NSAIDS and acetaminophen are found in many formulations Be careful ! 147 Part IV: Adaptive Immunity 148 Active Adaptive Immunity 149 Active Adaptive Immunity • Active passive immunity - Through immunizations • Active natural immunity - Through having the disease • Present for a life-time 150 Passive Adaptive Immunity 151 Passive Adaptive Immunity • Transferred from another source (in utero, breast milk, antibodies) • Short-term – It is only around as long as we are given the substances 152 Characteristics of the Adaptive Immune Response 153 Characteristics of the Adaptive Immune Response • Self tolerance: Discrimination of self and non-self • Self-regulation: the immune system can initiate, maintain, and down-regulate without help of the nervous system (NS) or other systems – This is one of the only body systems that can do this • Specificity: Targets very specific antigens • Diversity: Can invoke specific immune response to an indefinite number of different antigens • Memory: Makes memory cells (only IS and CNS have memory) 154 Major Functional Cells of the Adaptive Immune Response 155 Major Functional Cells of the Adaptive Immune Response B-Cell Lymphocytes including: • Plasma B Cells • Memory B Cells T-Cell Lymphocytes including: • T-Helper Cells • Cytotoxic T Cells 156 Antigens 157 Antigens Antigens: Initiators of Immune response and Adaptive Immunity Antigens (aka immunogens) are: • Substances foreign to the host which stimulate an immune response • Antigens are ligands that are recognized by receptors on immune cells and by antibodies (immunoglobulin's; Igs) • Often proteins or polysaccharides and less often lipids or nucleic acids. – Your DNA can actually act as an antigen in some instances, but it is not as common 158 Locations of Antigens 159 Locations of Antigens Antigens are found on: • Bacteria, fungi, protozoa, parasites or nonmicrobial agents such as pollens, plant resin, insect venom, transplanted organ. 160 Antigens Diagram 161 Antigens Diagram 162 Immunity Antigens 163 Immunity Antigens • Many antigens are large molecules. – The antigen may be recognized by multiple antibodies at a number of locations • Small fragments, often single sites, can be immunologically active. These sites are called epitopes. • Antigens or epitopes are what is recognized by a specific Ig receptor • Often a single antigen can have several antigenic sites. A distinct lymphocyte clonal population will recognize each distinct site • Certain small molecules are unable to stimulate an immune response (Haptens) . – Too small to stimulate a response – These molecules can become immunologically active when bound to a carrier protein (e.g., penicillin hypersensitivity) • The body is now able to recognize the body as foreign and can recognize the antigen as foreign 164 Major Histocompatibility Complex 165 Major Histocompatibility Complex • Cell surface molecules which provide a mechanism to differentiate “self” from “non-self” – The portion of your DNA that encodes for your MHC molecules is what makes you unique • This becomes important when we want to transplant organs because one person’s MHC may not match the other person’s MHC • Region of genetic information that makes each individual of one and the same species different: • aka Human Leukocyte Antigens (HLA) since these were first identified on white blood cells. • Cytotoxic T cells and helper T cells both recognize MHC complexed with antigen • Because these molecules (MHC) play a big role in transplant rejection, they are also termed antigens in this instance. 166 MHC-II Complex 167 MHC-II Molecules • Found primarily on antigen-presenting cells (APC’s) such as macrophages, dendritic cells, and B lymphocytes. • MHC-II molecule contains a groove in them that contains a recognition site which binds a peptide fragment of an antigen from pathogens engulfed/digested during phagocytosis. • The APC comes into contact with a virus, recognizes an antigen on the virus, activates complement, opsonizes the virus, which increases the phagocytic action, the phagocytic cell ingests the virus, takes the foreign antigen and then presents it on itself – Holds the antigens out to a T helper cell and the T cell agrees that it is foreign – The T cell then calls in other players to become immune to it and calls cytokines to destroy the cell • Helper T cells (Th) recognize these complexes on APC’s and they become activated. 168 MHC-II Molecules 169 MHC-I Molecules 170 MHC-I Molecules • • Found on cell surface glycoproteins on most nucleated cells of body. They Interact with antigen receptor and CD8 molecule on cytotoxic T lymphocytes (Tc) – Tc cells are responsible for direct cell killing • The virus enters a cell and the cell presents the virus on the outside – Indicates that the cell has been infected with the virus • Cytotoxic T-cells (Tc) become activated only when they are presented with an antigen associated with a Class I MHC. • MHC has the ability to present antigens on our body cells – Distinguishes self from non-self • Antigen peptides associate with MHC-I in cells that are infected with intracellular pathogen – E.g., as virus multiplies, small degraded peptides associate with MHC-I and are transported to the membrane. – This antigen-MHC complex communicates with the Tc cell and the host cell is destroyed. 171 MHC-I Molecules Diagram Virus particles 172 Comparison of MHC-II and MHC-I 173 174 Humoral vs. Cell-Mediated Immunity 175 Humoral vs. Cell-Mediated Immunity • Lymphocyte stem cells are located in the bone marrow 1. Lymphocytes which migrate through lymphoid tissue B cells (make antibodies) 2. Lymphocytes which migrate through the thymus T lymphocytes (cell-mediators) 176 Development of B Lymphocytes and T Lymphocytes 177 Development of B Lymphocytes and T Lymphocytes • If the bone marrow lymph cell matures in the thymus, it is called a T cell – T cells can become memory, cytotoxic, or helper T cells – Cell mediated immune response • If the cell leaves the bone marrow and goes to the bursal equivalent tissue (lymphoid tissue), it becomes a B cell – Can become a memory cell or antibodies (plasma cell) – Produce cells that make antibodies • A part of the humoral immune system 178 Development of B Lymphocytes and T Lymphocytes Diagram 179 180 B Lymphocytes 181 B Lymphocytes Responsible for antibody production (humoral immunity) Function • Identified by the presence of surface immunoglobulin (antibody) bound to them permanently that functions as an antigen receptor, particular CD proteins and complement receptors • Plasma cells are antibody factories • Manufactures specific antibodies that target bacteria, neutralize bacterial toxins, prevent viral infection, and produce immediate allergic response • Formed from bone marrow stem cells --Pre-maturation in the bone marrow to immature precursor cells --Genetic rearrangement results in a unique receptor and type of effector antibody (IgM or IgD) - shown an antigen by a presenting cell - the plasma cell recognizes the cell with the antigen and inside the cell itself, a genetic rearrangement is made so that 182 the antibody will only ever recognize the specific antigen Differentiation of B Lymphocytes 183 Differentiation of B Lymphocytes •Mature B Lymphocytes leave the bone marrow, enter the blood and travel to peripheral tissues • B lymphocytes bind antigens with help of Th and then differentiate into 1. Plasma cells (large # of cells: which are responsible for antibody secretion) 2. Memory cells (small # of cells: pre-programmed to become plasma cells from that clonal line) 184 B Lymphocytes Diagram 185 186 B Lymphocytes Description 187 B Lymphocytes Description • Helper T cell can present cell to B cell and the B cell can recognize the antigen from then on – Later, if the B cell recognizes the antigen it can do something about it • A mature B cell produces a memory B cell and a plasma cell • A memory just remembers what antigen it should recognize and then goes dormant • Plasma cells are not dormant like memory cells – Produce antibodies – Look for the foreign antigen 188 Activation of B Lymphocytes 189 190 Antibodies Primary Immune Response 191 Antibodies Primary Immune Response • Sensitization – Antigen is first introduced into the body – Antigen is processed by Antigen Presenting Cells (APCs) • Activation – MHC complexed Antigen is recognized by Th cells • Differentiation – Activated Th cells release cytokines and trigger B lymphocytes to proliferate into a clonal line of plasma cells and memory cells – Plasma cells release antibody • This time course has a significant lag time. 192 Antibodies Secondary Immune Response 193 Antibodies Secondary Immune Response • Once re-challenged with antigen at a later time, the memory cells recognize antigen and respond quickly to the antigen. • Immunization boosters (e.g., tetanus) take advantage of this response. 194 Primary and Secondary B Lymphocyte Immune Response Diagram 195 Primary and Secondary B Lymphocyte Immune Response Diagram 196 Primary and Secondary B Lymphocyte Immune Response Description 197 Primary and Secondary B Lymphocyte Immune Response Description • A B cell that has never been exposed to an antigen but is mature is naïve – A naïve B cell does not know what it wants to be yet • The first time that a B cell sees the antigen, the antigen has to be injected, complement binds to it, presented to helper T cells, B cell is sensitizes and becomes a memory B cell or a plasma cell – Takes about two weeks – Creates a bunch of memory B cells that remember the antigen and can mount a quicker response • The second exposure is very quick because the memory B cell is present – Secondary immune response 198 Antibody Types (Immunoglobulins) 199 Antibody Types (Immunoglobulins) • • • • • IgA IgM IgD IgE IgG 200 IgA Antibodies 201 IgA Antibodies •Secretory (saliva, colostrum, bronchial, pancreatic, GI,prostatic, vaginal). •Prevents viral and bacterial binding to epithelial tissues. •IgA is first line of defense in mucosal tissues –Secretions can bind the pathogen so that it does not enter the vasculature 202 IgM Antibodies 203 IgM Antibodies •Large macromolecular Ig complex. •First Ig made in response to an antigen. •First antibody type made by a newborn –During fetal development, the fetus is receiving Igs passively 204 IgD Antibodies 205 IgD Antibodies • Found primarily on cell membranes of B Lymphocytes. • Acts as antigen receptor. 206 IgE Antibodies 207 IgE Antibodies • Involved in inflammation, allergic responses and combating parasitic infections. • Antigen binding to IgE on mast cells or basophils causes histamine release • Important in inflammation and allergies. 208 IgG Antibodies 209 IgG Antibodies • Most abundant circulating antibody in blood • Only Ab that can cross the placenta. • Ig in fetus/newborn is passed from mother until new Ig’s are formed by newborn. • Targets bacteria, virus and toxins. • Can activate complement. 210 Maternal vs. Fetal/newborn IgG Contributions 211 Maternal vs. Fetal/newborn IgG Contributions 212 T Lymphocytes 213 T Lymphocytes Responsible for cell mediated immunity • Formed from bone marrow stem cells which migrate to the thymus (T) for maturation. Mature T-cells then migrate to peripheral lymphoid organs • Genetic modification to form a unique T-cell antigen receptor (clonal selection) • • Produce a specific receptor (T cell receptor) which recognizes the antigen TCR: two polypeptide grooves that recognize processed antigen-peptide MHC complexes. -TCR is associated with CD3 cell surface molecules, which is a protein • • • The TCR is bound to the CD3 protein Subpopulations of CD proteins offer further cell specificity: • • 1. CD4+: T-helper cells (have CD3 and CD4) 2. CD8+: T-cytotoxic (have CD3 and CD8) 214 Types of T Lymphocytes 215 Types of T Lymphocytes • CD4 cells: T helper cells • CD8 cells: Cytotoxic T cells 216 Helper T Cell 217 Helper T Cell • Helper T cell (Th or CD4+ cell): Regulatory cells Master switch of immune system • Do not do direct cell killing • Recognizes Ag-MHC-II complex • Once activated by APC, they release cytokines that affect most other cells of immune system – Orchestrate the immune response by telling the B cells what to become and by secreting cytokines • Activated Th cell can differentiate into distinct sub-populations based on cytokines secreted by the APC. 218 Cytotoxic T Cell 219 Cytotoxic T Cell Cytotoxic T cell (Tc or CD8+ cell): Effector • Get activated by Th cells • Recognize Ag-MHC-I complex on infected cells • Destroy infected cells by releasing cytolytic enzymes, toxic cytokines, Perforins • Important in controlling intracellular pathogens (bacteria and viruses) • Do a lot of self vs. nonself checking • Natural killer cells do not check the MHC, like the cytotoxic cells do – Tc cells are much more selective 220 Types of T Lymphocytes Diagram 221 222 Cell-mediated Immunity 223 Cell-mediated Immunity • Provide protection from viruses, bacteria, cancer cells • T lymphocytes and macrophages predominate • APC cells present MHCII-Ag to Th cells – Th cells become activated by antigen recognition and by interleukin-2. – Th cells then produce IL-2 and IL-4 to drive clonal expansion of Th cells and Interferon-gamma which activate Tc cells (cytotoxic T cells). • Tc cells and macrophages form the basis of the cellmediated cell destruction in the immune response, while 224 Th cells modulate the process. Cell-mediated and Humoral Immunity Diagram 225 226 Cell-mediated and Humoral Immunity Description 227 Cell-mediated and Humoral Immunity Description • T helper cell recognizes the antigen that becomes activated, releases cytokines, sensitizes B cell, helper T cell recruits Tc cell, Tc cell can kill cells that recognize the MHC-1 antigen • When B cells are sensitized, they either make memory cells or plasma cells • T helper cells orchestrate virtually the entire process • Both the memory cells and the other cells all have specific genetic memory for the certain antigen 228 Natural Killer Cells 229 Natural Killer Cells Natural Killer Cells: an effector cell important in innate immunity. • Small % of lymphocytes • Can bind with antibody coated target cell Antibody dependent cell-mediated cytotoxicity (ADCC) • Can attack virus-infected cells or cancer cells without help or activation first • Can recognize antigen without MHC restrictions – Difference between NK and T cells • NO MEMORY • Activity is regulated by cytokines, prostaglandins and thromboxane locally • Release NK perforins, enzymes, and toxic cytokines to destroy target cells – They do not phagocytize 230 Cytotoxic C vs. Natural Killer Cells 231 Cytotoxic C vs. Natural Killer Cells Cytotoxic T Cells • T lymphocyte • Do phagocytize • Do have memory • Do require MHC-1 restrictions Natural Killer Cells • Small percentage of lymphocytes • Do not phagocytize – Release NK perforins, enzymes, and toxic cytokines to destroy target cells • Do not have memory • Do not require MHC restrictions • Activity is regulated by cytokines, prostaglandins and thromboxane locally 232 Secondary Lymphoid Organs 233 Secondary Lymphoid Organs • Connected by blood and lymphatic vessels • The secondary lymphoid organs provide an environment for lymphocytes to circulate, meet and fight antigens, spread antigens, encounter information • Lymphocytes circulate constantly between blood tissuelymphatic ducts lymph nodes thoracic duct –bloodstream – This is a good place for immunosurveillance 234 Lymph Nodes 235 Lymph Nodes • Localize and prevent the spread of infection • Contain both B and T cells • Discrete locations of concentration of the lymphatic system • Good place to aggregate and look for antigens 236 Spleen 237 Spleen • Filters and processes antigens from blood • Contains both B and T cells • Functions as a reservoir for blood (red pulp) • RBC “graveyard” Hb released • Macrophages and other phagocytic cells in white pulp • Some parts innervated by sympathetic NS 238 MALT 239 MALT MALT (Mucosa –Associated Lymphoid Tissue): • Major portion of secondary lymphoid tissues • Non-encapsulates areas of lymphoid tissue • Around mucosal membranes of respiratory, digestive, and urogenital tract. – Located at the interface of the environment and your body • Contains T and B lymphocytes. • E.g. tonsils, Peyer’s Patches (intestine), appendix 240 Secondary Lymphoid Organs Diagram 241 242 Immunodeficiency 243 Immunodeficiency • Abnormality in one or more branches of the Immune System (IS) 1. Antibody-mediated (aka Humoral) 2. Cell mediated 3. Complement 4. Phagocytosis – Increased vulnerability to opportunistic disease (infections and malignancies) – Diseases may cross or more of these branches 244 Normal Immunity in Infancy 245 Normal Immunity in Infancy • After 6 months, maternal Igs • Between 1-2 years adult levels of all Igs are reached • First Ig to be produced by maturing plasma cells is IgM • IgM can transform into other Igs after antigenic stimulus 246 Primary Immunodeficiency 247 Primary Immunodeficiency • Transient hypogammaglobulinemia • Defective congenital or inherited genes are rare and include – X linked agammaglobulinemia – Bruton’s= – DiGeorge Syndrome – lack of thymus development – Severe combined immunodeficiency syndrome (SCID) 248 Transient Hypogammaglobulinemia 249 Transient Hypogammaglobulinemia Transient Hypogammaglobulinemia of Infancy (B cell) involves: • • • • The transient lack of antibodies in infancy Delay in maturation process of B cells Prolonged deficiency in IgG levels Fewer B cells = fewer Antibodies • More prone to opportunistic infections – Increased amount of upper respiratory and middle ear infections • Resolves at ± 2-4 yrs old • Many children are not specifically tested for this because it resolves 250 X-Linked Agammaglobulinemia Bruton’s 251 X-Linked Agammaglobulinemia Bruton’s • Impaired ability of B lymphocytes to produce antibodies • More common in males • Have much less or no humoral immunity 252 DiGeorge Syndrome 253 DiGeorge Syndrome • Affects T cells – Problems with the development of the thymus • Impaired ability of T-helper lymphocytes (Th cells) to orchestrate an immune response or Cytotoxic T- lymphocytes (Tc cells) to mount a cytotoxic response 254 Severe Combined Immunodeficiency Syndrome (SCID) 255 Severe Combined Immunodeficiency Syndrome (SCID) • No T or B cells !!! • Tends to be in the stem cell lineage of these cells • Need a bone marrow transplant 256 Secondary Immunodeficiency 257 Secondary Immunodeficiency Acquired later in life due to: • Selective loss of Igs through GI and/or GU tracts - e.g. Nephrotic Syndrome - the kidney is not able to obtain protein, so it passes into the urine - loss of the protein leads to a loss of antibodies • Chronic or recurrent infections with: – – – AIDS Viruses, Fungi, Intracellular bacteria (TB) Burden the immune system • Neoplasia (e.g. Lymphoma) • – Lead to an inability to produce cells in the bone marrow Iatrogenic causes (e.g. immunosuppressive therapy with cyclosporine) – You are treating one issue by suppressing the immune system but are creating another problem • Stress and aging • Drug abuse and maternal alcoholism – Due to alterations in the nervous system and the liver’s ability to produce proteins 258 Hypersensitivity Disorders 259 Hypersensitivity Disorders •Exaggerated immune responses to allergens (Ags) –Ex. pollen •Leads to inflammation and tissue injury caused by inhalation (depends on the amount of antigen and how we come into contact with the antigen), ingestion, skin contact, or injection •Sensitization depends on: –Allergen –Exposure –Person’s genetic make-up 260 Types of Hypersensitivity Disorders 261 Hypersensitivity Disorders • Four Types Type I: IgE-mediated hypersensitivity Type II: Antibody-mediated hypersensitivity Type III: Immune Complex Allergic Disease Type IV: T-cell mediated Hypersensitivity 262 Type I Hypersensitivity IgE Mediated 263 Type I Hypersensitivity IgE Mediated • Appears within few minutes; fades within few hours • Minor symptoms : localized, pruritic (itchy), skin wheal • Severe symptoms: vasodilation and bronchoconstriction (=anaphylactic shock) • Triggered by the binding of an antigen (allergen) to mast cell or basophil with attached IgE, leading to degranulation: – The antigen-antibody complex binds to a mast cell or basophil and that cell degranulates • Release a lot of histamine • Ex. pollen allergy in the spring 264 Type I Hypersensitivity Primary Response 265 Type I Hypersensitivity Primary Response Primary Phase: Fast-acting or primary mediators: • Histamine • Complement • Acetylcholine causes bronchoconstriction and vasodilation of small vessels • Eosinophil chemotactic factor (ECF) causes chemotaxis • Kinins: Prepared from inactive form • Can result in a significant, localized event 266 Type I Hypersensitivity Secondary Response 267 Type I Hypersensitivity Secondary Response Secondary Phase: Slow-reacting or secondary substances of anaphylaxis: • Leukotrienes: lipid based; cause vasodilation, chemotaxis, bronchioconstriction • Cytokines: ( Interleukins and Tumor Necrosis Factor) • Platelet activating factor (PAF) • Prostaglandins (PGs) : lipid based 268 Type I Hypersensitivity Diagram 269 270 Types of IgE-mediated Hypersensitivity Disorders 271 Types of IgE-mediated Hypersensitivity Disorders • Atopic • Non-atopic 272 Types of IgE-mediated Hypersensitivity Disorders Atopic Disorders 273 Types of IgE-mediated Hypersensitivity Disorders Atopic Disorders • Atopic = Local Anaphylaxis: • Local reaction to common allergens – Ex. allergic rhinnitus – Organ specific – High IgE serum levels and high basophil and mast cell numbers – Allergic rhinitis, allergic asthma, atopic dermatitis (eczema), certain food allergies, certain aspects of latex allergy – Diagnosis needs careful history, identification of nasal eosinophilia and skin testing. 274 Types of IgE-mediated Hypersensitivity Disorders Non-atopic Disorders 275 Types of IgE-mediated Hypersensitivity Disorders Non-atopic Disorders • Non-atopic = Systemic Anaphylaxis: – Not organ specific – Can be lethal (anaphylactic shock) – Common allergens are : Nuts, shellfish, penicillin, insect stings, etc. – Urticaria (hives) , pruritis (itching) , bronchospasm (asthma), angioedema, contraction of GI and uterine muscles, laryngeal edema asphyxiation and erythema 276 Antihistamines (H1 blockers) 277 Antihistamines (H1 blockers) • Two types of histamine receptors – H1 and H2 – H1 receptor blockers block the effects of histamine that are responsible for allergy symptoms (Type 1 hypersensitivity) – H2 blockers block the secretion of stomach acid (to be covered in a later lecture) 278 H1 Blockers 279 H1 Blockers • See Table 66-1 in Lehne • Most first generation H1 blockers also block muscarinic receptors and have sedating properties • Second generation H1 blockers (nonsedating antihistamines) do not cross the BBB very well. – Also do not block muscarinic receptors very well. • More tolerated with fewer side effects 280 H1 Blockers Block Histamine Receptors 281 H1 Blockers Block Histamine Receptors • Block symptoms of allergies that are due to histamine – Remember, histamine is only one of the mediators of Type 1 hypersensitivity • Symptoms of a cold are caused by viral infection, not Type 1 hypersensitivity – H1 blockers are probably not useful for cold symptoms. – However, in many combination cold pills, you will find an antihistamine. 282 Type II Hypersensitivity Antibody-Mediated 283 Type II Hypersensitivity Antibody-Mediated • Have preformed reactions to an antigen and then when you come into contact with the antigen, you have a reaction Types of Type II Antibody-mediated Disorders: • ABO antigens in blood transfusion reactions • Rh Antigens of fetus (erythroblastosis fetalis) • Drug Reactions (e.g., penicillin) – Binds to a carrier in the body and then is recognized • Autoimmune hemolytic anemia: Antibodies against own RBCs • Graft rejections, parasites (lysis without phagocytosis) – Mount a hypersensitivity reaction to the antigens in the graft 284 Type II Hypersensitivity Antibody Cytotoxicity 285 Type II Hypersensitivity Antibody Cytotoxicity • IgG and IgM antibodies interact with antigens on cell surfaces. This activates complement and/or Antibody-dependent cell-mediated cytotoxicity: e.g., the activation of Natural Killer Cells (NK) – Involves antigens on RBCs, neutrophils, platelets, basement membranes – Involves stimulation or inhibition of cellular function 286 Type II Hypersensitivity Injuries 287 Type II Hypersensitivity Injuries • Complement fixation inflammation, opsonization with phagocytosis, or cell lysis – Antibody-dependent cell-mediated cytotoxicity: Null or NK cells recognize antibodies and release toxins causing cell lysis 288 Type III Hypersensitivity Complex Allergic Disease Triggers and Injuries 289 Type III Hypersensitivity Complex Allergic Disease Triggers and Injuries Triggered by: • Formation of insoluble Antigen-antibody complexes in blood circulation or extravascular sites, leading to: - Precipitate formation - Complement activation • Injuries due to: – Change in blood flow – Vascular permeability – Inflammatory response 290 Type III Hypersensitivity Antigen-Antibody Complexes 291 Type III Hypersensitivity Antigen-Antibody Complexes • Antigen-Antibody complexes are formed and – Get deposited in the blood vessels, which activates complement, which in turn causes vasculitis (inflammation of the vessels), and leads to vessel wall damage. • Antigens bound to antibodies bind with one another and become insoluble complexes, settle down toward the endothelium, activate complement, the MAC complex goes into the endothelium and kills the endothelium – Leads to a vasculitis secondary to lack of blood flow 292 Type III Hypersensitivity Diagram 293 294 Immune Complex Disorders Localized 295 Immune Complex Disorders Localized • • At site of injection, localized tissue necrosis due to blockage by Ag-Ab complexes that precipitate Onset within 4-10 hrs 296 Results of Immune Complex Disorders 297 Results of Immune Complex Disorders Vasculitis: - If Blood vessel bursts hemorrhage into surrounding tissue - If Blood vessel becomes occluded ischemia necrosis Immune complex pneumonitis (Allergic Pneumonitis): Probably involves Type IV hypersensitivity as well E.g., Miner’s, farmer’s, pigeon breeder’s, mushroom lung Individuals inhale the antigen that results in vasculitis in the respiratory tract - Cough, malaise, fever, dyspnea, radiographic densities 298 Immune Complex Disorders Systemic 299 Immune Complex Disorders Systemic • Systemic response • Urticaria (hives), edema, rash, fever • Antigen-antibody complexes precipitate in blood vessels, joints, heart, kidneys. This leads to pain and edema in these areas (rheumatoid arthritis) • Usually temporary; symptoms go away when the antigen is taken away • Penicillin, foods, drugs, insect venoms can initiate the response. • Need preformed antibodies to drive this response 300 Type IV Hypersensitivity T-cell Mediated 301 Type IV Hypersensitivity T-cell Mediated • Delayed: 24-72 hours after exposure • Triggered by specifically sensitized T lymphocytes (CD4 memory cells) and Not antibodies • The T cell system is presensitized to the antigen – When the antigen is present, there is an exaggerated response • T cell and Antigen combine and release lymphokines which attracts macrophages. Macrophages then release monokines which leads to inflammation. • Direct attack by Tc cells can also occur • Not tissue specific – Depends on where the antigen is and the route of the administration 302 Type IV Hypersensitivity T-cell Mediated Diagram 303 304 Types of T-cell Mediated Immunity 305 Types of T-cell Mediated Immunity Contact dermatitis: – e.g. poison ivy erythema, papules, vesicles, warm, swollen, exudation, crusting • Not immediate, have been sensitized where it came into contact with skin • Takes a while to react because the T cells must be activated – Latex allergy Response to the Tuberculin test: - Erythema and induration within 8-12 hours at site of injection Granulomatous inflammation with large, insoluble Antigens: - e.g. splinter, silica, tuberculosis bacteria 306 Which type of hypersensitivity disorder is related to ABO antigen blood transfusion reactions? 307 Which type of hypersensitivity disorder is related to ABO antigen blood transfusion reactions? te d ce l T- C e lm ed ia lle ... A om pl ex Em ed Ig Im m un A nt ib od y m ed ia te d 1. Antibody mediated 2. IgE-mediated 3. Immune Complex Allergic Disease 4. T-cell mediated ia te d 25% 25% 25% 25% Host vs. Graft Disease 309 Host vs. Graft Disease • Recipient attacks donor cells: e.g. you receive • Cell-mediated responses: Th Tc (Type IV Hypersensitivity) liver and your body rejects it – Tc and Th severely respond to the graft 310 Results of Host vs. Graft Disease 311 Results of Host vs. Graft Disease • Th cells activate the production of antibodies through B cells which circulate and target graft vasculature. This causes: 1. Complement-mediated toxicity (Type II reaction) 2. Antigen-antibody complexes (Type III reaction) 3. Antibody-mediated cytolysis (Type II reaction) 312 Autoimmunity 313 Autoimmunity • Breakdown of immune system cannot differentiate between self and non-self – Breakdown in the immunosurveillance • Can lead to localized or systemic injury depending on what you have an autoimmune reaction to • Response may be T cell-mediated or involve Ag-Ab complexes that precipitate Type III or even anaphylactic response depending on the severity and type of reaction • More common in females and elderly • May be tissue specific: e.g. Graves’ disease (thyroid), myasthenia gravis (neuromuscular junction) • May be system specific: e.g. systemic lupus erythematosis (SLE), rheumatoid arthritis • Causes unclear: – Possibly due to an inheritance in the alterations of MHC Genes. – However, individuals may still need a trigger event 314 Rheumatoid Arthritis (RA) 315 Rheumatoid Arthritis (RA) • Systemic, inflammatory disease • Affects ± 0.3 – 1.5% of population • Affects all races • Women 2-3 times more than men • Prevalence with age: – Peak for women: 40-60 YOA – Peak for men: 30-50 YOA • Etiology of RA – Not sure, but: • Many patients (not all) have specific genes (although some people have these genes and do not develop RA) • Environment: virus, bacteria 316 Rheumatoid Arthritis (RA) Diagram 317 318 Pathogenesis of Rheumatoid Arthritis (RA) 319 Pathogenesis of Rheumatoid Arthritis (RA) • 70-80% of patients have Rheumatoid Factor (RF): RF is an Antigen against IgG that is found in blood, synovial fluid and synovial membrane – Antigen against protein in own body that is highly enriched in the synovial fluid and membrane, it makes sense that you would get joint problems • • Problems could also happen in similar membranes around the heart and lung RF + IgG form immune complexes which leads to synovitis and the development of PANNUS (granulation tissue) swollen and puffy joint – Complex activates complement, settles in joints, recruits immune cells, inflammation, MAC • Cartilage and subchondral bone get destroyed • Surrounding muscles, ligaments and tendons weaken, and cannot function well. • Reduced joint motion and possibly ankylosis (fusion of joint) due to calcification and inflammation • Pannus differentiates RA from other arthritis (granulation tissue) – This is what separates RA from OA 320 Signs and Symptoms of Rheumatoid Arthritis (RA) 321 Signs and Symptoms of Rheumatoid Arthritis (RA) • Mild: May last only few months or 1-2 yrs • Moderate: Flares and remissions • Severe: Active most of time for many yrs; causes serious joint damage and disability 322 Extra-articular Manifestations in RA Systemic 323 Extra-articular Manifestations in RA Systemic • • • • • • • • • Fatigue Anorexia Weight loss Aching of muscles and joints Stiffness ESR due to significant burden Anemia Rheumatoid nodules: Bumps under skin close to joints. There are Granulomatous lesions that develop around small BVs ± ¼ of patients Vasculitis, pleuritis, pericarditis 324 Emotional and Mental Symptoms of RA 325 Emotional and Mental Symptoms of RA • Depression • Anxiety • Feelings of helplessness • Can’t perform ADL or work (arthritis self-management programs help patients cope) 326 Diagnosis of RA 327 Diagnosis of RA 1. Morning stiffness for > 1 hour 2. Swelling of >3 joints for >6 weeks 3. Symmetric joint swelling - because this is systemically based, it is present bilaterally 4. Rheumatoid nodules present (around small blood vessels) 5. Presence of serum rheumatoid factor (RF) antibody 328 Evaluation of RA 329 Evaluation of RA • History • Physical exam • Radiographs are NOT diagnostic • Lab tests (RF is NOT diagnostic) • Check for Cloudy synovial fluid 330 Goals of RA Treatment 331 Goals of RA Treatment • Relieve pain • Reduce inflammation (anti-inflammatories) • Slow down or stop joint damage • Improve a patient’s sense of well-being and ability to function (Educate patient!) 332 Treatment of RA Lifestyle 333 Treatment of RA Lifestyle • • • • Rest and exercise Joint care Stress reduction Balanced diet 334 Treatment of RA Medications 335 Treatment of RA Medications • • NSAIDs DMARDs (Disease Modifying Anti-Rheumatic Drugs) reduce joint destruction and retard disease progression • Reduced number of immune cells (methotrexate) • Block cytokines (anti-TNF (anti-cytokine); Etanercept) decreases inflammation • • • Immunosuppressants Corticosteroids New approach: Combination therapy 336 Treatment of RA Surgery 337 Treatment of RA Surgery • Joint replacement • Tendon reconstruction and synovectomy • Arthrodesis (joint fusion) 338 Osteoarthritis 339 Osteoarthritis • Degenerative Joint Disease; Osteoarthrosis • Most common form of arthritis • Second to CV disease for chronic disability in US • 1/3 of all adults in US show OA on X-rays • Only affects articular cartilage and subchondral bone of diarthrotic joints – Shows reduction of bone and calcification, not pannus 340 Influences on Osteoarthritis 341 Influences on Osteoarthritis • In age: Men affected at younger age than women, but rate for affected women exceeds that of men by middle age • Occupation • Obesity • Heredity (e.g. hand OA) 342 Causes of Osteoarthritis 343 Causes of Osteoarthritis • Primary OA: Idiopathic; no identified risk factors • Secondary OA: Associated with risk factors: • Joint stress (obesity, sports injuries) • Congenital abnormalities • Joint instability leads to chronic stress of a joint over time • Trauma 344 Pathogenesis of OA 345 Pathogenesis of OA •Joint cannot absorb mechanical stress. – This leads chondrocytes to release cytokines which causes release of enzymes and more joint damage. –Articular cartilage breaks down and wears away. –Bone wears on bone Pain, swelling, loss of motion. •Other results: –Osteophytes –Fragments –Microfractures –Loss of capability to secrete synovial fluid –Joint immobility lubrication more cartilage atrophy 346 Signs of Symptoms of OA 347 Signs of Symptoms of OA •Sudden or insidious •Mild synovitis •Mostly hips, knees, lumbar and cervical regions, proximal and distal joints of hand, first CMC joint and first MTP joint •Joint enlargement •Joint feels hard 348 Process of OA Diagram 349 350 Warning Signs of OA 351 Warning Signs of OA • • • • • Steady or intermittent pain in a joint Stiffness > bed Joint swelling or tenderness in 1 or > joints Crepitus (a grinding sound in the joint) Hot, red, or tender?? No….. probably not OA, maybe RA • Not always pain 352 Diagnosis of OA 353 Diagnosis of OA • No single test • History • X-rays • Lab tests (usually normal) 354 Treatment Goals of OA 355 Treatment Goals of OA • Control pain • Improve joint care • Maintain acceptable body weight • Achieve healthy life style 356 Joint with OA Diagram 357 358 Differences between RA and OA 359 Differences between RA and OA OA is different because... • • • • • • • No or very little synovitis No systemic signs and symptoms Normal synovial fluid (no pannus) Affects cartilage and subchondral bone only Not always symmetric Not always polyarticular Hardness around joint 360 Differences between RA and OA Diagram 361 : 362 Congenital Immunodeficiency 363 Congenital Immunodeficiency • Congenital (primary) – Lymphocyte development disrupted in fetus or embryo (rare) • • T cell B cells 364 Acquired (Secondary) Immunodeficiency 365 Acquired (Secondary) Immunodeficiency 1. Immune /inflammatory deficiency after birth. 2. Not related to genetic defects: • Nutritional • • • • • • Need folate in order to help properly dividing cells develop healthily Iatrogenic Deficiencies Medical treatment - chemotherapy - immunosuppression Trauma: - Burn victims Stress - sympathetic lymphoid innervation - cortisol Acquired Immunodeficiency Syndrome (AIDS) 366 Human Immunodeficiency Virus (HIV) 367 Human Immunodeficiency Virus (HIV) A retrovirus unknown until early 1980s: • • • Contains only RNA; no DNA Most infections caused by HIV-1 variant of the virus Cannot replicate outside of living host cells Infection leads to relentless destruction of immune system AIDS: One of leading causes of death in US and in other countries Patients infected with HIV are at risk for illness and death from: • • Opportunistic infections Neoplastic complications Mainly present in blood, genital secretions, breast milk Presence in saliva, tears, urine, sweat is not important or a high risk for transmission 368 Transmission of HIV 369 Transmission of HIV • Sex: Semen, vaginal secretions, cervical secretions, and rectal secretions • Blood: Open wound, injection with contaminated needle, blood transfusion (<1985) • 1. 2. 3. Perinatally: In utero Inoculation during birth and delivery due to the mixing of blood Breast-feeding • NOT TRANSMITTED BY: 1. Casual contact 2. Mosquitoes or other insects • Occupational transmission is very rare 370 HIV Structure 371 HIV Structure • Viral genome: Two short strands of RNA with three major genes that encode enzymes: – Reverse transcriptase (Makes mistakes mutations HIV variants) – Protease: breaks down proteins – Integrase: incorporates viral DNA into host genome to make more virus • Outer lipid envelope with surface projections containing gp120 antigen which binds to CD4 proteins of Th – CD4 are part of the T cell receptor in T helper cells – When the HIV virus gets into the body, it seeks out cells with the CD4 receptor, and the virus incorporates into contents into the host’s cell, lying dormant and waiting for more virus to be made 372 Mechanism of HIV Infection Description 373 Mechanism of HIV Infection Description • • • • • • Gp 120 antigen binds to CD4 cell Fusion of HIV virus with cell membrane RNA is incorporated Reverse transcriptase makes DNA Protease breaks down proteins Integrase integrates proteins into host’s viral genome • Cell lies dormant • Cell at some time decides to make all of the proteins for HIV, virus buds out of the host cell, killing the host cell (CD4) in the process, the virus incorporates some of the host’s cell markers with it, helping it to further evade detection • Kills T helper cells, which orchestrate the immune system, release cytokines 374 Mechanism of HIV Infection Diagram 375 376 Mechanism of Infection Detailed Description 377 Mechanism of Infection Detailed Description • gp120 of virus binds to CD4 molecule - virus and host membranes fuse - virus enters host and sheds protein coat • Viral RNA is converted to viral DNA with reverse transcriptase • After integration of proviral DNA, virus may remain latent for some time • Eventually, productive virus synthesis occurs virions released (protease) T cell dies • Virions invade other CD4 cells fast amplification first few years, destruction of millions of T cells release of millions of virions, but all T cells still get replaced • After several years, however, T cell numbers begin to crash to very low levels. 378 Clinical Course of HIV Infection 379 Clinical Course of HIV Infection • Latest classification based on CD4 cell count rather than signs and symptoms • Primary or Initial Infection: -Window Phase: Between time of exposure to time Abs are detectable • Latent period 8-10 years -Acute Phase -Latent Phase -Clinically Apparent Disease with Constitutional Symptoms • Full-blown AIDS 380 Primary Infection with HIV 381 Primary Infection with HIV • Immune response HIV Abs (2 weeks to 6 months after infection) Patient will test positive for HIV Ab (seropositive) • Acute phase that may go unnoticed or produce mild disease: – – – – Acute mononucleosis-like syndrome (acute retroviral syndrome) Fever, myalgia, sore throat, nausea, lethargy, lymphadenopathy, rash, headache Symptoms after 1-2 months Burst of viral replication (viremia) CD4 count (as low as 200), but then immune system tries to control viral replication viremia CD4 cells rebound, but not to pre-infection levels • The individual is then asymptomatic because the CD4 cells increase • Both humoral and cell mediated responses play role in the primary infection phase • Sometimes mistaken for flu or cold 382 Viral Load in the Blood (Viremia) 383 Viral Load in the Blood (Viremia) 384 Clinical Latency of HIV 385 Clinical Latency of HIV • May last 10 years • Disease concentrates in lymph nodes – Lymph nodes are areas where T cell congregate • Asymptomatic and little detectable virus in blood – There will not be an active viremia • Gradual fall in CD4 count as more virus occurs • Patient still tests seropositive for antibodies against HIV 386 Clinically Apparent HIV Disease 387 Clinically Apparent HIV Disease • Persistent generalized lymphadenopathy (PGL) (>3mos.) : Lymph nodes swell; not life threatening • Fatigue, weight loss, night sweats, diarrhea, fungal infections of mouth and nails – These occur because immunosurveillance is decreased • CD4 count < 500 cells/l (normal 800-1000) 388 Full-Blown or Clinical AIDS 389 Full-Blown or Clinical AIDS • CD4 count < 200 cells/l • Confirmed by a variety of lab tests • Opportunistic infections (risk correlated with CD4 count) 390 Full-Blown or Clinical AIDS Lungs 391 Full-Blown or Clinical AIDS Lungs • PCP: Pneumocystis carinii pneumoni: Fever, chest pain, sputum, tachypnea • TB: Mycobacterium tuberculosis 392 Full-Blown or Clinical AIDS GI Tract 393 Full-Blown or Clinical AIDS GI Tract • Esophageal candidiasis, thrush: painful swallowing; retrosternal pain • Diarrhea or gastroenteritis 394 Full-Blown or Clinical AIDS Nervous System 395 Full-Blown or Clinical AIDS Nervous System • Toxoplasmosis: Toxoplasma gondii (parasite): affects CNS; fever, altered mental status, seizures, motor deficits • AIDS Dementia: Ataxia, tremor, spasticity, paraplegia • Cerebral atrophy 396 Full-Blown or Clinical AIDS Neoplastic Malignancies 397 Full-Blown or Clinical AIDS Neoplastic Malignancies • Kaposi’s sarcoma - Neoplasm of endothelium - Opportunistic cancer - Small discolored elevated tumors of skin that invade viscera • Lymphoma 398 Full-Blown or Clinical AIDS Wasting Syndrome 399 Full-Blown or Clinical AIDS Wasting Syndrome Wasting syndrome (Cachexia): – Emaciation, severe diarrhea, chronic weakness, fever, fatigue, lethargy, severe negative nitrogen balance 400 Patients with HIV disease are most likely to die from: 401 Patients with HIV disease are most likely to die from: 1. Neoplastic complications 2. Opportunistic infections 3. Neurological disease 4. Wasting at ... co m pl ic in fe c N eo pl a st ic st ic pp or tu ni O N eo p la s tic co m pl ic at .. . All of the above tio .. 33% 33% 33% Diagnosis of HIV Infection 403 Diagnosis of HIV Infection • HIV antibody test (ELISA: enzyme-linked immunosorbent assay): – Detects Abs produced in response to HIV infection • Western Blot (done if ELISA is positive): – Identifies Abs specific to viral Ags • CD4 count • Based on symptoms 404 Treatment of AIDS 405 Treatment of AIDS • No cure; no vaccine • Treat opportunistic infections with drugs • Therapeutic management: – – – – – Inhibit reverse transcriptase Inhibit protease Inhibit integrase Prevent transcription from host DNA into viral RNA Vaccine?? 406 Treatment of HIV Diagram 407 1.Fusion inhibitor 2.RT inhibitor 3.Protease inhibitor 4.Under development 5. Integrase inhibitor 408