Patho Exam 2 SG.docx

Exam #2 Study Guide MODULE 4 Hematology Understand basic physiology of hematopoiesis, erythropoiesis, and what erythropoietin is and what it does. Hematopoiesis – how blood cells are made (watch Khan academy video) Process of blood cell production in adult bone marrow or in the liver and/or splee...

Exam #2 Study Guide MODULE 4 Hematology Understand basic physiology of hematopoiesis, erythropoiesis, and what erythropoietin is and what it does. Hematopoiesis – how blood cells are made (watch Khan academy video) Process of blood cell production in adult bone marrow or in the liver and/or spleen of the fetus Hemato – blood, poiesis – to form/to make Bone marrow – adult, spleen (sometimes liver) – fetus 2 stages: Mitosis (proliferation) – divided Maturation (differentiation) Happens using hematopoietic stem cells. Stem cells differentiation (maturation), keeps some as stem cells myeloid/lymphoid progenitor cells blood cells Continues to occur through life. Replaces blood cells that are lost d/t age/death, disease, or bleeding. Ex. Hemorrhage or hemolytic anemia It is normal to see elevated WBC & RBC counts in infants at birth. Bone marrow (myeloid tissue) Red – produces RBCs (erythrocytes) Yellow – does not Active sites: pelvic bones, vertebrae, cranium, mandible, sternum, ribs, humerus, femur Common myeloid progenitor cell erythroid progenitor cell (+ erythropoietin) pro-erythroblast (blast means dedicated to become that cell) erythrocyte Common lymphoid progenitor cell lymphoblast B & T lymphocytes **All committed immature cells -blast, know the myeloid & what it means when it becomes a “blast” ** Hematopoiesis occurs in 2 separate pools (stem cell & bone marrow) Stem cell – maintains # of pluripotent cells & progenitor cells Bone marrow – contains proliferating (dividing) & differentiating (maturing) cells Granulocytes (WBCs) – highest amount stored in vessel walls (50% stored, 50% functional) Storage (stored around blood vessel walls) Neutrophils adhere to vessel wall. Blood flow is slow. Rapid movement into tissues/mucus membranes for inflammatory response. Thrombocytes (platelets) – small amount stored (30% stored) Erythrocytes (RBCs) – NONE stored, all are functional (0% stored), lifespan is 100-120 days Factors to hematopoiesis: Conversion of yellow bone marrow (which does not produce) to hematopoietic red marrow by erythropoietin Erythropoietin – hormone that stimulates RBC production in peritubular cells of kidney Faster differentiation (maturation) of progenitor cells Faster proliferation (mitosis) of stem cells into progenitor cells Erythropoiesis – how RBCs are made Negative feedback loop: Erythropoietin (EPO) is released from kidney when it senses low O2 NOT low RBCs EPO stimulates stem cells proerythroblasts formed erythroid cells formed reticulocyte erythrocyte Each step the Hgb & nucleus (see below) EPO is always present in plasma. It has a short half-life (4-12hr) & is given to chemo/dialysis pts. Reticulocyte is the last immature form of erythroblast. It contains polyribosomes (globin synthesis) & mitochondria (heme synthesis). A high Retic count = new RBCs are being made. Measuring a reticulocyte count is a good indicator of Erythropoiesis (new RBCs being made) Know different anemia’s basic patho and how they classified Anemia – too few cells. Problem w/ quality/quantity of Hgb. Hemoglobin – O2 carrying portion of RBC Normal: 13-16gm/dL in adults O2 is attached to heme on hemoglobin. Each Hgb molecule has 2 pairs of globin chains and 4 complexes of iron & heme. Each heme has 1 molecule of O2. Every molecule of Hgb can carry 4 molecules of O2. Globin – protein that contains heme (it surrounds & protects heme molecule). Most common globin chain is Hgb-A (2 alpha chains & 2 beta chains) RBCs use glycolysis for energy (no mitochondria = no ATP), if it lacks 2 enzymes it can result in anemia G6PD and pyruvate kinase deficiency Pyruvate kinase is necessary for glycolysis absence damage and death of RBCs G6PD involved in protecting the RBC against oxidative stress Erythrocytes are recycled: iron is removed from heme & recycled (transferrin ferritin) ** Refer to Anemia chart for patho, clinical manifestations, & individuals affected** Iron basics – transferrin and ferritin Ferritin – major iron storage protein Transferrin – Protein that transports iron in blood Transferrin Ferritin Stored Iron Transferrin binds w/ ferritin (protein that stores iron) to bring iron to RBC production to bind w/ new cells Transferrin binds to transferrin receptors on erythroblasts *in bone marrow (essential for maturation) Transferrin releases iron, then returns back to bloodstream for reuse Iron is liberated from heme, oxidized, & recycled TIBC – Total Iron Bind Capacity Transferrin inversely related to TIBC How many seats are available for iron to bind? (measures saturation) High TIBC – more seats/spots for iron. Less transferrin b/c there is more seats available (more room to bind) than there is transferrin. Low TIBC – less seats/spots for iron. More transferrin b/c there is not enough seats available (less room to bind) for the transferrin. Roles of fibrin, thrombin Thrombin – changes fibrinogen to fibrin (needs calcium) Fibrin – absorbs excessive Thrombin. See more under “Basics of clotting cascade” TTP, ET, ITP, DIC basic patho TTP – Thrombotic Thrombocytopenic Purpura Damage to microvasculature Genetic predisposition aggregation (combined) of platelets thrombus occlusion of arterioles & capillaries Classic presentation: fever, purpura, AMS, neuro signs, renal dysfunction, thrombocytopenia, hemolytic anemia Children: HUS – hemolytic uremic syndrome. Usually happens after diarrhea (E. Coli, Shigella) TTP following diarrhea *plasmapheresis = treatment ET – Essential primary Thrombocythemia/Thrombocytosis HIGH platelet count. Occurs w/ inflammatory disease. *polycythemiavera Too many megakaryocytes in bone marrow clots in microvasculature ITP – Immune Idiopathic Thrombocytopenic Purpura LOW platelet count w/ absence of other problems. Autoimmune: **IgG antibodies** target platelet Glycoproteins antibody-coated platelets are isolated & removed from circulation Children: acute form of ITP after viral infection, most common childhood bleeding disorder DIC – Disseminated Intravascular Coagulation You clot & then you bleed Happens after infection, massive trauma/surgery, neoplastic disease, chronic inflammatory diseases, complication after child birth *Patho: unregulated release of thrombin w/ fibrin formation, accelerated clot breakdown protease activity in blood clotting factors are depleted excessive bleeding D-Dimer (fibrin degradation products), ischemia, infarction, organ hypoperfusion Sickle cell patho – Refer to Anemia Chart Calcium and platelet (thrombocyte) function Calcium function – important in clotting cascade, converts prothrombin to thrombin to make blood clots. Platelet function Functions: induce **vasoconstriction** (thromboxane A2, regulate blood flow), initiates formation of platelet plug (adhesion, activation, aggregation, plt-plt interactions), activates clotting cascade (stabilize), initiates repair processes (including clot retraction and dissolution/fibrinolysis) Lifespan: 9-12 days. von Willebrand factor (carrier for factor VIII) is necessary for platelet adhesion, from endothelial cells Develop from megakaryocyte progenitor cells (are fragments) Stick to damaged cell walls to help clog damage. Platelet membrane uses glycoproteins to help them know what areas to stick to. Will only stick to damaged epithelium, not healthy d/t presence of nitric oxide **Nitric oxide – protective mechanism by the body to prevent against excessive clotting** Thrombocythemia – platelet count. risk of spontaneous clots. Thrombocytopenia – platelet count. risk of bleeding. Causes: bone marrow suppression, immune disorders, infection. **Vitamin K – important in the synthesis of clotting factors** Vitamin K necessary for II, VII, X, and XI, protein C and S Life cycles of erythrocytes and platelets Erythrocytes (RBCs) – 100-120 days Thrombocytes (Platelets) – 5-12 days Basics of clotting cascade; don’t need to memorize all the steps just understand the basics of what does what Injury to vessel wall formation of prothrombin activator Prothrombin Thrombin (needs calcium!) Fibrinogen Fibrin Clot retraction, assisted by platelets *serum doesn’t have clotting factors Prothrombin activator formation: Intrinsic pathway – tissue injury INSIDE blood vessel. Longer. Activated when there is a problem with blood cells or when they come in contact w/ foreign surface. Ex. cells touching glass in lab tube, skin or collagen Tests: PTT, whole blood clotting time (9-15 mins) (more letters, takes longer, more factors) Extrinsic pathway – tissue injury OUTSIDE blood vessel, Factor VII. Activated when tissue factor (tissue thromboplastin) is released by damaged endothelial cells. Quick, dominant pathway. Tests: PT (less letters, shorter. Re-calcified), INR) Both lead to common pathway Prothrombin thrombin Fibrinogen fibrin Both PT & PTT will be prolonged with ESLD, Coumadin, heparin Chemical mediators associated with clotting/ Von Willebrand factor, protein C, protein S, Factor V Leiden Primary Hemostasis – Platelet Plug: Thromboxane A2 – Makes them sticky. Prothrombotic that’s produced by the activated by platelets. Stimulates activation of new platelets. platelet aggregation. Vasoconstrictor. **An important prothrombotic during the development of the platelet plug** ADP – Makes them spiky. Prothrombotic. Platelet activation. Stimulates shape change (spiky). Von Willebrand factor – Glycoprotein that sticks out from platelet membrane. Bridge that allow platelets to adhere to injured cell wall. Stabilizes Factor VIII. Von Willebrand disease – leads to in ability of platelet to bind to vessel wall. **Results in an increased tendency to bleed**. Bernard-Soulier syndrome, storage pool diseases ( pool of signaling molecules normally released by platelets) Formation of platelet plug: Adhesion – anchoring of platelets Activation – more platelets stick & release their contents Aggregation – more & more platelets accumulate Hemostatic Controls/Hypercoagulable States: Protein C – inactivates excessive thrombin. Heparin enhances Protein C’s activity. Deficiency – risk of venous thromboembolism (NOT arterial). Purpura fulminans in newborns (fatal). Congenital or acquired, protein C inhibits factors V and VIII Protein S – Vitamin-K dependent. Cofactor w/ Protein C. Inactivates Factors Va & VIIIa. Deficiency – impaired function/activity of Protein S degradation (break down) of these factors risk of venous thrombosis **Protein C, S, & Antithrombin III serve as checks & balances in clotting system – normally anticoagulants. Mutation leads to deficiency tendency to clot** Factor V Leiden – autosomal dominant disorder. Mutation of factor V (unable to be inactivated by Protein C). risk of clotting (DVT’s), almost always restricted to veins Antiphospholipid antibodies predispose to hypercoagulability. Other predisposing factors: pregnancy, malignancy, oral contraceptives, turbulent flow (a-fib), heart failure, stenosis, immobility, DVT PE Myeloproliferative RBC Disorders: Polycythemia – too many RBCs (thick blood) Relative polycythemia – loss of fluid, RBC counts increase (dehydration). Resolves w/ fluid. Patho: Hyperproliferative state of bone marrow/excessive EPO secretion Polycythemia Vera – acquired genetic mutation in JAK2 gene. There is no “off” button for EPO receptors to stop producing EPO. EPO doesn’t accumulate b/c it’s used up to stimulate RBC production – high RBCs, LOW EPO. S/s are burning/itching hands & feet w/ blue discoloration. Can develop gouty arthritis. Secondary Polycythemia – EPO (either needing more RBCs or tumor). HIGH EPO. Needs more RBC – altitude, COPD, CLD, etc. excessive hypoxia excessive RBCs Tumors – inappropriate secretion of EPO (renal cell carcinoma, HCC) Iron Overload: Primary hemochromatosis – autosomal recessive disorder or iron metabolism. iron absorption in intestines (iron is deposited in tissues). Heart, liver, pancreas restrictive CM, cirrhosis, VM “Bronze Diabetes” d/t iron deposits in skin (can see skin bx) Fatigue, abd pain, hepatomegaly, elevated LFTs, low/normal TIBC, ferritin & transferrin MODULE 5 Immune System, Inflammation, Alterations of the Immune System, and Stress Understands the basic of the physiology of the innate and adaptive immune system; as well as cell types: B and T cells Immune system’s main function is protection against foreign organisms. Key strategy is distinguishing “self” from “non-self” to eliminate foreign bodies. Innate Immune System 1st line of defense. Is innate (natural/native) immunity Natural barriers are skin & mucous membranes, mechanical cleansing Biochemical barriers, antimicrobial peptides, normal bacterial flora FAST Cells included: monocytes (precursors to macrophages), tissue phagocytic cells, granulocytes (BEN), & platelets Molecules included: interferons, lysozymes, complement, c-reactive protein, prostaglandins & leukotrienes, kinins, interleukins, tumor necrosis factor (TNF), TGF-beta, cytokines Plasma protein systems: essential for an effective inflammatory response. Provides biochemical barrier against invading pathogens. Complement system - enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. Can destroy pathogens directly Anyphylatoxic activity mast cell degranulation; leukocyte chemotaxis; opsonization; cell lysis Coagulation (clotting) system prevents spread of infection, keeps microorganisms and foreign bodies at the site of greatest inflammation, forms clot that stops bleeding, provides framework for repair and healing Kinin system – causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, & leukocyte chemotaxis Primary kinin = bradykinin *interactions among 3 plasma protein systems are finely regulated to prevent injury to host tissue & guarantee activation when needed* Inflammation 2nd line of defense. Nonspecific. Mast cell degranulation: histamine – vasoactive amine causes temporary/rapid constriction of large blood vessels, dilation of post capillary venules, & retraction of endothelial cells lining the capillaries blood flow into capillaries capillary permeability/leakage edema Receptors: H1 (pro-inflammatory, bronchoconstriction) & H2 (anti-inflammatory, secretion gastric acid) Inflammatory response is initiated when tissue injury occurs or when PAMPs are recognized by PRRs on cells of the innate immune system Exudative fluids Adaptive Immune System 3rd line of defense. Is adaptive (acquired) immunity. More specific. More specific – involves B & T cells, antibodies. No mediators. SLOW (is invader foreign or not?) Products included: immunoglobulins (antibodies), lymphocytes, & antigens B lymphocytes – humoral immunity mediated by circulating antibodies. Produce immunoglobulins (antibodies) T lymphocytes – cell-mediated immunity. Kills target directly. **both produce memory cells** Antigens: Epitope – antigenic determinant. Precise recognition. Paratope – antigenic binding site. Matching portion (lymphocyte receptor/antibody) Haptens – antigens too small to induce immune response, but can function as carriers w/ larger molecules (Ex penicillin, poison ivy) Allergens – antigens allergic rxn Major Histocompatibility Complex (MHC) – glycoproteins on surface of all human cells (not RBCs). aka human leukocyte antigens (HLAs). Antigen presentation MHC I – present foreign antigens to cytotoxic T cells (CD8 markers) **MHC II – present foreign antigens to T helper cells (CD4 markers)** **both are important in graft rejection** Antibodies – also called immunoglobulins Produced by plasma cells (which come from B lymphoctyes) Classes – IgG, IgA, IgM, IgE, and IgD. Characterized by antigenic, structural, and functional differences. Key function of host protection (direct or indirect protection) **Clonal diversity – when B & T cells are produced to recognize a specific antigen** All necessary receptor specificities are made which results in generation of immature but immunocompetent B & T cells. Most in the fetus. B cell development – production, proliferation, & differentiation occur in Bone marrow. T cell development – Thymus is central organ of T cell development. **both B & T cells are immunocompetent before they have “seen” an antigen on the surface of an Antigen Presenting Cell (APC)** Clonal selection – Antigen processing and presentation. An antigen selects lymphocytes w/ compatible receptors complex cellular interactions. B cell activation: Humoral immune response When an immunocompetent B cell encounters an antigen for the first time, B cells with specific BCRs are stimulated to differentiate and proliferate A differentiated B cell becomes a plasma cell factory for antibody production, dedicated to secretion of single class or subclass of antibody T cell activation: Cellular mediated immunity Binding antigen to specific T cell receptors allows: Direct killing of foreign or abnormal cells (Tc cells, CD8) Assistance or activation of other cells (ex. Macrophages) – carried out by Th (CD4) cells (stimulate proliferation of B cells) T regulatory cells (Tregs) – regulate immune resp. avoid attacking self Memory T cells also produced Understand the basics of the physiology of inflammation including the cell types and which ones activate and come later Inflammation occurs in the vascular tissues. Cells/chemicals limit/control the inflammatory process, prevent/limit infection and further damage, initiate adaptive immune response, & prepare the area of injury for healing. The inflammatory response begins when tissue injury occurs OR when PAMP’s are recognized by PRR’s on the cells of the innate immune system During the inflammatory response, blood vessel dilation with blood flow to the area is responsible for causing the “cardinal signs” of inflammation. Mast cells – important activator of inflammation. Are in the tissue close to the vessel of injury. **Central cell in inflammation** Dendritic cells – connect the innate & adaptive immune responses. Cellular products (chemokines/cytokines) regulate the innate & adaptive resistance by affecting other neighboring cells Cytokines – **alarm cells—tells other cells to get in gear** regulate resistance by affecting neighboring cells: Interleukins (IL) – important function—enhancement of acquired immune response Interferons (IFN) – protect against viral infections. Do not directly kill viruses, but prevent them from infecting additional healthy cells. Tumor Necrosis Factor-Alpha – deaths w/ gram neg sepsis Chemokines – attract leukocytes to site of inflammation Granulocytes vs agranulocytes Granulocytes – contain granules (WBCs) Granules contain enzymes that destroy microorganisms. Granules are VERY important to the inflammatory response. Involved in inflammatory & immune functions Diapedesis – capable of moving. Move through vessel walls to sites where they’re needed. Produced by granulopoiesis in bone marrow. 3 types (BEN): Basophils – < 1%. **Contain histamine**. at sites of allergic inflammatory rxns & parasite infection (exoparasites—ticks). They secrete inflammatory mediators (histamine, chemotactic factors for eosinophils & neutrophils. Contribute to local inflammatory response. Eosinophils – 1-4%. Capable of amoeboid movement & phagocytosis (ingest antigen-antibody complexes & viruses). Release cytokines & leukotrienes that augment inflammatory response. in Type I hypersensitivity allergic rxns & asthma. & attack parasitic infections. Neutrophils – 55%. Defend against infection. Polymorphonuclear neutrophils (PMNs). Serve as phagocytes in EARLY inflammation. Ingest & destroy microorganisms & debris, then die in 1-2 days. Mast cells – not a blood cell. Found in vascular connective tissue (skin, digestive lining, & resp. tract). Really similar to basophils—central cells in inflammation. Activation & degranulation affect body cells, permeability of blood vessels & smooth muscle contraction, contain IgE receptors. **Mast cells are the central cell in inflammation** Agranulocytes – do not contain granules (WBCs) Lymphocytes 36% of leukocytes. Major cells of the immune system. Mature B, T, & plasma cells. Natural Killer (NK) cells 5-10%. Mainly in peripheral blood & spleen. They kill tumor cells & virally infected cells. Recognize infected cells & tumors by changes in MHC I (surface molecule). They do not have to be induced by antigens. Produce cytokines involved in immune response. Monocytes – precursor to macrophage & dendritic cells Macrophages – initiate immune response Found in tissue & lymphoid organs. Cleanse the blood by removing old/injured/dead blood cells. Predominant phagocyte LATE in inflammatory response. **Monocytes & Macrophages provide main line of defense against bacteria in blood stream. ** Dendritic cells – extend projections (dendrites) into tissue & take on a “neuronlike” appearance. “Antigen-processing” & “antigen-presenting” cells that initiate immune responses. Primary vs. Secondary responses Primary response Initial exposure. B-cell differentiation. IgM produced IgG Time necessary for clonal selection Primer of the individual’s immune system – sets stage for additional exposure Secondary response More rapid. Larger amounts of antibody produced. Rapid b/c presence of memory cells that don’t have to differentiate. IgM is produced, but IgG is produced a lot more. Know basics of patho of infection; bacterial and viral What the bug does: Colonization – infectious microorganisms exist in reservoirs, animals, or other humans Are transmitted by direct contact, indirect contact (vectors), droplet vs. airborne, vertical vs. horizontal (mom to baby vs. grocery cart) Microorganisms adhere to tissue through specific surface receptors Invasion – invade surrounding tissues by evading the host’s defense mechanisms Multiplication – warm and nutrient-filled environment of human tissue cause most microorganisms to multiply rapidly Spread – may stay localized or enter other body areas. If immune system is compromised, spreading is quick Clinical infectious disease Incubation – period from time of exposure to symptoms. Could be hours to years Prodromal – occurrence of initial symptoms are often very mild with feelings of discomfort and tiredness Invasion – invasion is farther and affects other body tissues Convalescence – recovery occurs and symptoms decline, or the disease is fatal, or has a period of latency *Fever is the hallmark of infection Bacterial Gram-negative or gram-positive. (don’t retain violet dye vs. those that do) Invade host through different routes. Patho: attach through pili (fimbriae) colonization direct confrontation w/ defense system (evasion of these defenses may lead to bacteremia and sepsis) Exotoxins (enzymes released during growth. Endotoxins (contained in cell walls of gram negative bacteria and released during lysis of bacteria. Produce toxins & extracellular enzymes to destroy phagocytic cells. They coat a portion of the antibody which prevents complement activation or phagocytosis. They degrade immune cells, bind/neutralize antibodies, evade complement, and cause immune suppression. Resistant – alter surface molecules that express antigens (Ex MRSA) Tissue damage (superantigens) Septic shock (endotoxic shock) – vascular permeability loss of large volumes of plasma hypotension and CV shock, can lead to DIC Viral (most common) RNA or DNA or reverse transcriptase for replication Intracellular parasites Life cycle is completely intracellular Patho: attaches/binds to host cell via protein receptors penetrates host cell releases genetic info translation of mRNA to produce viral proteins new virons released through budding viral DNA integrated into host cell, transmitted by mitosis Bypasses immune system by: dividing rapidly, intracellular survival, coating w/ self-proteins, antigenic variation, neutralization, complement evasion, & immune suppression Inhibits DNA, RNA, or protein synthesis, disrupts lysosomal membranes, promotion of cell apoptosis, fuses adjacent cells, transforms into CA cells, alters antigenic properties Basic patho of HIV and cell types involved HIV virus depletes T helper cells which makes person more susceptible to infections & CA Patho: HIV-1 infection high viral load, decreased CD4 immune system fights to reduce HIV levels w/ killer T cells (CD8) CD4 may rebound low level replication of HIV but immune system continues to deteriorate final phase occurs when CD4 production cannot keep up w/ CD4 destruction Bloodborne pathogen present in body fluids (blood, vaginal fluid, semen, breast milk). Routes of transmission include blood, IVDU, maternal-child transmission 2 types (both are retroviruses = RNA virus/slow virus): HIV-1 (primary) HIV-2 – less virulent variant & is found mostly in western Africa RNA virus stores genetic material on 2 copies of RNA instead of usual dsDNA. Integrase inserts new DNA into the infected cell’s genetic material. May be dormant (no problems) or active (many problems). New DNA becomes part of cell’s genetic material (new virus) & accelerates apoptosis & shedding of infectious HIV Gp120 protein binds to CD4 molecule on T helper cells Th cells Reverses CD4: CD8 ratio thymic production of new T cells Damaged secondary lymphoid organs (especially lymph nodes) Window period – infectious but asymptomatic AIDS Secondary immune deficiency b/c it is an acquired deficiency (results from a virus—HIV). Secondary immune deficiencies may be the result of stress (Ex caring for an older parent w/ Alzheimer’s) Diagnosis: serologically + for antibodies against HIV, have atypical or opportunistic infection (Kaposi sarcoma, histoplasmosis), wasting syndrome, recurrent fevers, or CD4 & T cell counts < 200 CNS vulnerable in children of passive maternal antibodies Understand difference in hypersensitivity reactions; and patho behind disease processes discussed Type I – IgE mediated, anaphylaxis IgE & products of tissue mast cells are released Against environmental antigens (allergens). IgE binds to crystalline fragment (Fc) receptors on the surface of mast cells. Cross linking causes release of histamine from mast cell degranulation. chemotactic activity. Histamine binds with H1 & H2 receptors. H1 – bronchial constriction, edema, vasodilation H2 – gastric secretions, release of histamine from mast cells & basophils (stops further degranulation) Allergic rhinitis – inhaled, airborne allergens trigger immune response in upper airway causing rhinitis & conjunctivitis Anaphylaxis – sudden/rapid progressive urticaria & resp. distress. Systemic or localized. After initial exposure to antigen immune system produces IgE antibodies in lymph nodes antibodies bind to membrane receptors on mast cells in connective tissues & on basophils on re-exposure to antigen, antigen binds to IgE antibodies Anaphylactic Rxn – response to antigen (IgM & IgG bind to antigen) release of chemical mediators (IgE is activated on basophils, histamine, serotonin, leukotrienes) intensified response (mast cells release more histamine) vasodilation resp. distress (lungs histamine causes endothelial destruction & fluid leaks into alveoli) deterioration (meditators vascular permeability causing fluid to leak from vessels) failure of compensatory mechanisms (endothelial cells damage causes basophils & mast cells to release heparin & mediator-neutralizing substances—irreversible!) Type II – tissue-specific rxns, cytotoxic mediated Antibody binds to tissue-specific antigen Binds to antigen directly IN TISSUE Mediated by IgG & IgM, 5 mechanisms: Cell is destroyed by antibodies & complement Cell destruction occurs through phagocytosis Neutrophils release granules Anti-body dependent cell-mediated cytotoxicity is present (ADCC) Causes target cell malfunction Graves’ disease – autoimmune disorder of hyperthyroidism. Excessive thyroid activity. Antibodies bind to TSH receptor & constantly stimulate it high TSH despite feedback to pituitary Autoimmune hemolytic anemia Rheumatic fever – inflammatory disease develops after throat infection. Patho unclear, group A β strep, antibody cross-reactivity. Mature antigen presenting B cells present to CD4T cells which then differentiate into helper T2 cells and then activate to become plasma cells and this induces production of the antibodies against the bacterial antigen Jones criteria Rheumatic heart disease – chronic. Repeated inflammation fibrinous tissue to heart. Patho unclear, group Aβ strep. Leaflet thickening, commissural fusion, shortening and thickening of tendinous cords Valvular stenosis or regurgitation, risk a-fib and endocarditis Type III – immune complex mediated (not organ or tissue specific) Immune complexes form in circulation deposited into vessel walls, kidneys, or joints Immune complex = antigen & antibody bound together Antigen binds to antibody in circulation & is LATER deposited into tissue Complexes are formed in circulation, then deposited into vessel wall/tissue NOT organ specific. s/s have little to do w/ organ complex affected. Damage results from complement activation & neutrophil lysosomal enzymes. Neutrophils move to tissue where immune complexes are deposited. Neutrophils bind w/ antibody & try to ingest that complex. Phagocytosis is not always successful. Neutrophils release enzymes into inflammatory site tissue damage. Examples: vasculitis, nephritis, arthritis. Serum sickness – Ex Raynaud phenomenon. Temp dependent immune complexes are deposited into capillary beds (fingers, toes, nose) & block circulation pallor, numbness cyanosis gangrene Arthus Rxn – repeated local exposure to antigen binds w/ antibody in wall of local blood vessels Type IV – T cell-mediated, delayed T lymphocytes, NOT ANTIBODIES, mediate the process NO ANTIBODY involved Damage is caused by direct killing by toxins from cytotoxic T (Tc) cells (CD8s). Ex MS, skin tests for TB, contact allergic reactions, DM1 (beta cell destruction), Hashimoto disease (T cells are acting against thyroid cells surface antigen destruction of thyroid), Crohn’s disease Ex graft rejections = b/c it’s delayed Poison ivy = comes from contact Allergy response Hypersensitivity response to allergen. Involves a sensitizing process. Atopic pts = genetic predisposition. S/s: conjunctivitis, rhinitis, asthma, N/V/D, Abd pain, urticaria (hives), anaphylaxis (all a histamine response) Type I – block w/ antihistamines. Control is through autonomic NS: Mediators (epi, acetylcholine) bind to receptors on mast cells & target cells of inflammation which controls release of inflammatory meditators from mast cells & degree which target cells respond to inflammatory meditators. Type IV – Haptens react w/ normal self-proteins in skin allergic contact dermatitis (Ex poison ivy) Type II & III – Haptens bind to surface of cells & elicit IgG & IgM response Type II – drug allergy Type III – arthus rxn Endotoxins and exotoxins and their roles Endotoxins – In cell walls of gram-negative bacteria. Released during lysis of bacteria. Pyrogenic bacteria = activate inflammation & produce fever. Exotoxins – enzymes released during growth (damages cell membranes, activates 2nd messengers, inhibits protein synthesis) Understand role of the immunoglobulins and their role Immunoglobulins = antibodies. Produced by plasma cells. Key function of host protection (Direct vs. Indirect). IgA – IgA1 = blood, IgA2 = bodily secretions. Defends against pathogens on body surfaces (resp. & GI). Dominant immunoglobulin in secretory (mucosal) immune system. IgD – low conc. In blood, present in plasma. One type of B cell antigen receptor, easily broken down. IgE – least concentrated. Mediator of many common allergic responses. Defender against parasites. IgG – most abundant (80-85%). Accounts for most of the protective activity against infections. G = Gone (disease is Gone) IgM – 1st antibody produced during primary response to an antigen. Largest in size. M = Miserable (you have disease, active infection, +IgM) Plasma cell disorders Multiple myeloma – many copies of IgG or IgA. Bone marrow is replaced by malignant plasma cells. S/s bone pain, anemia, renal failure, recurrent infections (cause of death), & cord compression Hodgkin’s lymphoma – CA of lymphatic system. Lymphadenopathy noted. Ann Arbor staging system. Can have no s/s, or can have fever, weight loss, night sweats. Non-Hodgkin’s lymphoma – B cell lymphoma, lymphadenopathy noted. Leukemias – accumulation of abnormal WBCs interferes w/ bone marrow production of normal WBCs, RBCs, & Plts Granulocytes or monocytes = myelogenous Lymphocytes = lymphocytic Acute = AML or ALL AML – neoplasm of myelogenous progenitor cells (adults) ALL – curable (children) s/s: anemia, neutropenia, anterior mediastinal mass (T cell ALL), skin nodules (AML) Chronic = CLL or CML CLL – most common leukemia. Least aggressive. Lymphocytosis on CBC is usually how it’s found. CML – blast crisis is when they die. Association w/ translocation t(9.22) Philadelphia chromosome – present in almost all pts w/ CML Autoimmunity vs. alloimmunity and patho of diseases discussed Autoimmunity – misdirected response against the host’s own cells Breakdown of tolerance where body’s immune system begins to recognize self-antigens as foreign. Probably a genetic association/familial association. Characteristic process of exacerbation & remission. SLE – systemic lupus erythematosus (Type III hypersensitivity) Large production of autoantibodies against “self” Autoantibodies against nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, & others why it is such a systemic/destructive disease Most common autoantibody is against nucleic acid (nucleic acid makes up DNA & RNA). Depositing of circulating immune complexes (which contain an autoantibody against DNA) damage at tissue level DNA & DNA containing complexes have a high affinity for the glomerular basement membrane in the kidneys Transient lupus-like syndrome: looks like lupus, but is not autoimmune. Results from prolonged use of hydralazine, procainamide, & UV radiation. Alloimmunity – directed against beneficial foreign tissues of same species Type II hypersensitivity rxn Transfusion rxn ABO system: O = universal donor, AB = universal recipient (IgM antibody) Rh system: expressed on erythrocytes. RhD protein determines if person is +/- (D antigen = +) Transient neonatal alloimmunity – Rh factor Hemolytic disease: Rh – mom gives birth to Rh + baby. Baby gets anemia, jaundiced. Treatment = Rhogam. Transplant (graft) rejection Matching of human leukocyte antigen (HLA)-DR loci is critical for graft to accept. Hyperacute – immediate & rare. Pre-existing antibody in host. Rejection of previous graft/previous transfusion of blood/plts antibodies were already made Acute – Type IV hypersensitivity. Cell-mediated response against unmatched HLA antigens AFTER tissue is transplanted. Chronic – mos. or yrs. d/t weak cell-mediated rxn against minor HLA antigens organ failure (slow and progressive) Physiology of the stress response; including the substances involved and their effect on the body General Adaptation Syndrome (GAS) – 3 stages: Alarm – HPA axis is triggered fight or flight Stage of Resistance or Adaptation – adrenal hormones (cortisol, epi, norepi) Stage of Exhaustion – only happens if stress continues & adaptation is not successful Patho: Stress response initiated by CNS & endocrine system CRH is released from hypothalamus & at inflammatory sites CRH = corticotropin-releasing hormone, released by hypothalamus ACTH = adrenocorticotropic hormone stimulates adrenal gland cortex to release cortisol Catecholamines stimulate fight or flight (epi & norepi) – CO & blood flow to heart, brain, & skeletal muscles by dilating vessels (Ex airway vessels) ALSO constricts blood vessels of viscera & skin (so it can shift blood to vital organs) Glucocorticoid = cortisol. Activated by ACTH. Stimulates gluconeogenesis. Anti-inflammatory & immunosuppressive (poor wound healing & susceptibility to infection) Endorphins Reactive response – psychologic stressor Anticipatory response – anticipates disruption in homeostasis Conditional – phobias or PTSD Stress can lead to cardiac disease or worsen existing disease (IBS, asthma). Can also levels of pro-inflammatory cytokines (affects cell functions). Psychoneuroimmunologic mediator – interaction w/ brain, subconscious, & CNS Infections; clinical manifestations and microorganisms responsible for diseases Viral Infections Name of Infection Microorganism Responsible Clinical Manifestations Picture Example Erythema infectiosum “5th disease” Parvovirus B19 specific IgM “slapped cheek syndrome”, low grade fever, HA, cold-like symptoms, joint symptoms Herpangina Mouth blisters Enterovirus: Coxsackie A & B Fever (up to 106), sore throat, ulcerative mouth lesions, cough, coryza, pharyngitis, rule-out strep Infectious Mononucleosis Epstein-Barr virus (EBV) Fever, fatigue, pharyngitis, adenopathy, splenic rupture (rare) Monospot test Influenza Orthomyxovirus in antigenic types A & B Mild cold like symptoms, fever, chills, malaise, HA, nausea, muscle aches, nasal stuffiness **virus attaches to resp. epithelial cells & enter by endocytosis—new strain each season** Measles (Rubeola) Measles virus (RNA virus) Fever (>104), cough, runny nose, red eyes, Koplik spots, red rash on face then to rest of body Mumps (Parotitis) Mumps virus (Paramyxovirus) Fever, HA, fatigue, tender/swollen parotid glands, + IgG titers or + mumps IgM antibody, testicular swelling infertility Roseola (6th disease) HHV-6 & HHV-7 (herpes) Sudden high fever (febrile convulsions), red rash on trunk legs & neck Rubella (German Measles) 3 day measles Rubella virus Rash (face rest of body), swollen lymph nodes, fever, sore throat, fatigue, joint pain, bleeding probs., testicular swelling, inflammation of nerves Varicella Varicella zoster virus Fever, vesicular rash West Nile Virus Mosquito – Arbovirus (Flaviviridae); CSF w/ IgM antibody for WNV Fever, rash, arthritis, myalgia, weakness, lymphadenopathy, & meningoencephalitis Cytomegalovirus (CMV) DNA virus, Herpesvirus (remains latent in body for a long time) Mono-like symptoms, fever, fatigue, pharyngitis, ulcerative lesions in mouth, loss of vision, worried about w/ transplant pts., immunocompromised at risk for re-infection since it lays dormant your whole life, retinitis Smallpox (bioweapon) DNA virus in orthopoxvirus family High fever, malaise, severe aching pains, prostration, papular rash on face upper & lower extremities Bacterial Infections Name of Infection Microorganism Responsible Clinical Manifestations Picture Example Lyme Disease Tick bite – Borrelia burgdorferi. ELISA + Western blot assay (detects both IgM & IgG) Flu-like symptoms, erythema migrans (bulls-eye rash), joint pain, neuropathy, fatigue, 3 stages: early localized disease = erythema migrans, **early disseminated disease = persistent fatigue**, joint pain, multiple erythema migrans, late disease = recurrent arthritis, CNS & PNS s/s Pertussis (whooping cough) Bordetella pertussis Fever, weeks of coughing fit high pitched “whoop” sound or gasp as person breathes in, coughs so hard you can vomit/break a rib Rocky Mountain Spotted Fever (RMSF) Tick- Rickettsia rickettsii Fever, rash & history of tick bite, cough, myalgia, macular/papular rash Palms and soles of feet Scarlet fever Group A hemolytic streptococcal pharyngitis (vascular response to bacterial endotoxin scarlet fever) Strawberry tongue, rash (skin folds), hallucinations, pain, fever, red cheeks—pale mouth Anthrax (bioweapon) Gram + spore-forming aerobic rod Bacillus anthracis Cutaneous or pulmonary infection, flu-like symptoms get better death Botulism (bioweapon) Neurotoxin produced by Clostridium botulinum Neuro symptoms – symmetric cranial neuropathies, blurred vision/diplopia, symmetric descending weakness in a proximal-distal pattern, resp. dysfunction Plague (bioweapon) Yersinia pestis (Nonmotile), flea bite (bubonic) Pneumonic Enlarged, painful lymph nodes (bubones), gangrenes, fever, pneumonia, bloody sputum Fever, weakness, rapidly developing pneumonia with SOB, chest pain, cough, bloody/watery sputum Fungal infections Candida albicans – yeast, most common. Lives in skin, GI, mouth, & vagina. Body produces antifungal agents. Localized if immune system is intact, systemic if it’s compromised. Tinea (ringworm) – rash is circular w/ ring like appearance; athlete’s foot, nails, groin, body, scalp (cradle cap) Parasitic & Protozoan infections – parasite benefits from host; hookworm (can stunt fetal growth), roundworm, flukes, tapeworms Usually transmitted through vector (Ex Malaria – mosquitos, contaminated water/food) Malaria – parasite (mosquito) enters blood stream & lives in liver infects RBCs. S/s fever, fatigue, vomiting, HA, death Toxoplasmosis – cat is primary host. Parasite microorganism = Toxoplasma gondii. Acquired through contact w/ cat feces & undercooked meat. Can be fatal if immunocompromised.