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Transcript
Belinda Mandrell Belinda is a Pediatric Nurse Practitioner and works in the Nursing Research department at St. Jude. She has over 16 years of experience in pediatric oncology here at St. Jude. She received a BSN and MSN from the University of Maryland. She holds a BS in Public Health and is a PhD candidate at the University of Tennessee. Her research interests are in gene expression profile and genotype comparison in pediatric Hodgkin Disease survivors. Belinda has numerous journal publications and several book chapters on Pediatric Oncology. She has spoken at numerous conferences in the United States and Internationally. 1 Blood Cell Development and Interpretation Belinda Mandrell, PNP 2 Formation of Blood Cells Begins in the Bone Marrow with pluripotential hemopoietic stem cells Depending upon the body needs, the cell will become committed and will develop into a particular cell As these cells differentiate and grow, they are assisted by growth inducer proteins 3 Formation of Blood Cells Growth inducers and differentiation inducers are extrinsic to the bone marrow For example: If you have an infection the growth inducers will stimulate the bone marrow to increase white cell production 4 Growth Inducers Four major growth inducers (proteins) have been described Interleukin-3: promotes growth and reproduction of virtually all the different types of stem cells The others induce growth of only specific types of committed stem cells 5 Differentiation Inducers This is another set of proteins that differentiates the stem cell one or more steps toward a final mature blood cell 6 7 Function of Red Blood Cells AKA “erythrocytes” Transport hemoglobin, which carries oxygen from lungs to the tissues of the body Catalyze the reversible reaction between CO2 and H2O via carbonic anhydrase Forms HCO3- Acid-base balance 8 Production of RBC’s Early gestation made in yolk sac, then in liver (small amount by spleen and lymph nodes)… Last month gestation produced by bone marrow Marrow of all bones make RBCs until approx. age 5 yrs, beyond childhood greatest production is in the vertebrae, sternum, ribs and ilia 9 10 CFU-E stimulated to differentiate into proerythroblasts Proerythroblasts mature and divide into basophil erythroblasts (little hgb, have all organelles) Basophil erythroblast nuclei condense and endoplasmic reticulum is reabsorbed = reticulocyte Reticulocytes leave bone marrow, further basophilic material is reabsorbed, nucleus extruded, increased hgb is incorporated = mature erythrocyte (within 1-2 days, only 1% retics in circulation) 11 Differentiation of RBC’s •Endoplasmic reticulum is reabsorbed & nucleus condenses •Reticulocytes still contains small amount of golgi apparatus, mitochondria and nucleus •Nucleus is extruded from the cell, increased hgb content 12 Production of RBC’s Tissue oxygenation is the most essential regulator of RBC production Anemia, hypoxemia, circulatory failure, high altitude Erythropoietin Hormone (glycoprotein) 90% released by the kidney, likely made by tubular epithelium when PaO2 is low in peritubular capillaries Response to catecholamine and prostaglandins Some hepatic production 10% 13 14 Erythropoetin Stimulates hematopoetic stem cells to differentiate into proerythroblasts Induces cells to pass through differentiation and maturation stages more quickly During times of increase RBC synthesis there will be a greater percentage or reticulocytes in circulation Marker of bone marrow function 15 Maturation of RBC’s Vitamin B12 (dependent on dietary intake and intrinsic factor made by parietal cells of the stomach) Folic Acid (dependent on dietary intake) Required for formation of DNA Decreased DNA synthesis = decreased nuclear divisions and reduced cell proliferation / slow reproduction Cells formed are large with fragile membranes = “macrocytes” 16 Life-Span of RBC’s 90-120 days Cytoplasmic enzymes metabolize glucose and produce ATP to keep RBC’s viable • Maintains integrity of cell membrane (pliability and transport of ions) • Keeps iron in the ferrous rather than the ferric state (preventing methemoglobin form which can not carry oxygen) • Prevents oxidation of cell proteins With aging membrane becomes fragile and RBC’s lyse (often in red pulp of the spleen) 17 Destruction of RBC’s After RBC lysis, hemoglobin is phagocytized by macrophages throughout the body Liver Kuppfer cells, spleen & marrow Macrophages release the iron from the hemoglobin and pass it back into the blood to be carried by transferrin (for further production of hgb in marrow erythroblasts or to liver and other organs to be stored as ferritin) Porphyrin is converted to bilirubin, which is released into blood and then secreted by liver into bile 18 Blood Types Two antigens (agglutins) occur on the Red Cells and are classified as Type A and Type B These antigens are inherited so a person may have neither of these antigens, have one, or both. 19 Blood Types No A or B antigen= Type O A antigen= Type A B antigen= Type B A and B antigens present= Type AB 20 Rh Antigens Six common Rh antigens but Type D is most prevalent and is more antigenic that the other Rh antigens. Persons with this antigen are Rh Positvie and all others are Rh Negative. 85% of whites are Rh + 95% American Black are Rh+ 100% Africian Black are Rh+ 21 Erythroblastosis Fetalis Mother is Rh- and infant is Rh+ Mother develops anti-Rh agglutinins that diffuse into the placenta causing agglutination of the fetus’ blood. Red cells hemolyze releasing hemoglobin. Macrophages convert hem into bilirubin Liver and spleen enlarge producing red blood cells 22 Erythroblastosis Fetalis Infants die from anemia or have mental impairment from increased bilirubin Treatment:Exchange transfusion with Rh-blood. 23 Platelets Formed from precursor megakaryocytes No nuclei, use mitochondria to form ADP / ATP, life-span 8-12 days / cleared by spleen macrophages Contain the contractile proteins actin, myosin & thrombosthenin Secrete enzymes, prostaglandins, hormones and calcium ions Synthesize fibrin-stabilizing factor protein Secrete growth factor that encourages vascular endothlium, smooth muscle and fibroblasts to regenerate 24 Characteristic of Platelets Cont ... Specialized cell membranes Glycoproteins prevent adherence to normal endothelium of blood vessels … platelets selectively adhere to damaged blood vessels with exposed collagen Large volume of phospholipids Activating roles in clot formation 25 Conditions That Cause Excessive Bleeding Liver Disease: All clotting factors are formed in liver Vitamin K deficiency: Vit K is needed for liver formation of prothrombin, factor VII, IX, and X. Vit K is synthesized by bacteria in the GI Tract. 26 Bleeding Hemophilia: Genetic deficiency of factor VIII or IX Thrombocytopenia will result in bleeding within small venules or capillaries rather than large vessels 27 Immune System Overview System of eradicating infectious organisms (and toxic substances) from the body White Blood Cells Destroy invading bacteria or virus by phagocytosis Form antibodies and sensitized lymphocytes which destroy or inactivate invaders 28 White Blood Cells AKA “leukocytes” Mobile units of the body’s protective system Formed in bone marrow granulocytes, monocytes and some lymphocytes Formed in lymph tissue Lymphocytes and plasma cells 29 Types of WBC’s Polymorphonuclear neutrophils Polymorphonuclear eosinophils Polymorphonuclear basophils Monocytes Lymphocytes Plasma Cells Granulocytes or “Polys” have multiple nuclei 30 Normal Concentrations of WBC’s Neutrophils 50-60% Eosinophils 2-3% Basophils 0.5-1% Monocytes 5-10% Lymphocytes 20-40% 31 Infant White Blood Cell Counts Newborns may have total count of 30,000 – 40,000 Throughout first year of life gradually decreases to adult levels 32 Production of WBC’s Pluripotential hematopoetic stem cells differentiate into committed stem cells Committed stem cells further differentiate into RBC’s and WBC lineages WBC lineages or Colony Forming Units CFU’s Myelocytic - myeloblasts Granulocytes & monocytes (formed in bone marrow) Lymphocytic - lymphoblasts Lymphocytes & plasma cells (formed in lymph tissue) 33 34 Differentiation of WBCs 35 Life Span of WBCs Formed and stored until needed Approximately 6 day supply Granulocytes: Survive in blood 4-8 hours Survive in tissue 4-5 days Monocytes: Spend 10-20 hours in blood then deposit in tissue = tissue macrophages which survive for months Lymphocytes stored in lymph tissue / pass in and out of blood Survive weeks to months 36 Neutrophils & Macrophages Destroy invading microorganisms via phagocytosis Enter tissue spaces via diapedesis Move through tissues spaces by ameboid like motions Neutrophils are mature WBC’s in circulating blood Macrophages were circulating blood monocytes that matured after moving into a tissues 37 Chemotaxis of Neutrophils & Macrophages Chemical substances attract neutrophils and macrophages to a site of injury / inflammation Bacterial and viral toxins Cytokines Complement proteins Clotting proteins Associated with increased capillary membrane permeability to facilitate movement of the WBCs from the blood into tissue spaces 38 Phagocytosis Cellular ingestion of an offending agent Selection of offending agent: Rough surface (healthy tissues of the body have smooth cell membranes) Lack of protein coats (healthy tissues of the body have protein coats that repel phagocytes - dead and foreign materials do not) Antibodies produced by lymphocytes coat the pathogens and make then susceptible to phagocytosis (Antibody + C3 protein = opsonization) 39 Phagocytosis Continued... WBC contacts the pathogen and extends pseudopodia to attach and encircle organism Fuse to enclose organism in a phagocytic vesicle or phagosome within it’s cytoplasm Lysosomes and other cytoplasmic granules fuse with phagosome and release digestive and bactericidal enzymes into the phagosome = digestive vesicle 40 Phagocytic Chemicals Proteolytic enzymes - proteases Break down proteins Lipases Break down lipids and phospholipids Bactericidal agents Kill bacteria when enzymes fail to digest them Oxidizing agents from peroxisomes Superoxide (O2-) Hydrogen peroxide (H2O2) hydroxyl ions (OH-) Myeloperoxidase catalyzes H2O2 + Chloride = hypochlorite 41 Monocyte-Macrophage Monocytes, fixed tissue macrophages, mobile macrophages and specialized endothelial cells in the bone marrow, spleen and lymph nodes make up the reticuloendothelial system Fixed tissue macrophages break away and move with strong chemotaxis signal = delay in immediate response to infection (will see increased number of circulating neutrophils in blood stream before increases in monocyte line) 42 Skin & Subcutaneous Tissue Macrophages Histiocytes Second line of defense if skin / subcutaneous tissue is exposed to external environment Histiocytes will divide in-situ in response to local inflammation 43 Brain Macrophages Microglial cells Interlaced with neurons in the central nervous system 44 Macrophages of the Lymph Nodes Microorganisms in tissue do not move through capillary membrane into the blood stream, but can still be filtered by the lymph system Lymph nodes Macrophages line the lymph nodes’ sinuses Organism is destroyed before efferent leads to venous blood 45 Macrophages in the Liver Sinusoids Kupffer Cells Interlaced with epithelial cells of the sinusoids Bacteria in the portal circulation are eradicated before entering the systemic circulation 46 Macrophages of the Spleen and Bone Marrow Act on microorganisms that enter the blood stream Macrophages are entrapped by a reticular meshwork Blood flows through the spleen’s red pulp which contains the macrophages 47 Macrophages of the Lungs Large number of tissue macrophages are embedded in alveolar walls Phagocytize pathogens that are inhaled into the lungs After digestion of a pathogen, alveolar macrophages dump product into lymph system When a pathogen is difficult to digest, many macrophages group together to form a “giant cell” that digests the pathogen over time (common in TB, noxious dust) 48 Neutrophils & Macrophages and the Inflammatory Response Inflammation At site of insult (injury / infection) • Vasodilation (erythema) Histamine, bradykinin, prostaglandin, nitric oxide • Increased capillary membrane permeability Edema • Initiation of clotting cascade • Infiltration of WBCs (monocytes and granulocytes) 49 The “Walling-Off ” Effect of Inflammation The tissue spaces and lymphatics are blocked by fibrin clots Prevents / delays spread of microorganisms, toxins and inflammatory mediators 50 Neutrophil & Macrophage Responses During Inflammation First line = tissue macrophages at site of insult Begin phagocytosis Second line = neutrophils move via chemotaxis and infiltrate the site Margination – neutrophils alter endothelium to cause sticking of WBC’s to capillary wall Vessel membranes become more porous to allow additional WBCs to infiltrate the site Trigger release chemotaxis signals 51 Neutrophil & Macrophage Responses During Inflammation Cont… Within hours, excessive numbers of neutrophils enter blood from the marrow (neutrophilia … “left shift”) When bone marrow is hyper-active, immature forms of WBCs or “bands” may enter blood Next, monocytes enter blood from marrow Many begin deposition into tissue and maturation into macrophages, others remain in blood as monocyte reserves In the later stages of infection, monocytes may predominate the WBC count 52 Feed-back Control of Neutrophil & Monocyte Responses Chemical control Cytokines Tumor Necrosis Factor (TNF) Interleukin-1(IL-1) Granulocyte-Monocyte Colony Stimulating Factor (GM-CSF) Granulocyte Stimulating Factor (G-CSF) Monocyte Colony Stimulating Factor (MCSF) 53 Formation of Pus Neutrophils and macrophages die after they phagocytize pathogens and necrotic tissue After several days, a cavity containing the dead tissue cells, neutrophils and macrophages and interstitial fluid may form within tissue = pus Usually reabsorbed over time, but persistent cavitation - abscess 54 Eosinophils Eradicate parasitic infection Attach to parasites via surface molecules and secrete toxic substances into the parasite Hydrolytic enzymes released by granules or modified lysosomes Oxygen free radicals Major basic protein: larvicidal polypeptide Allergic reactions Along with mast cells and basophils that release eosinophil chemotactic factor 55 Basophils Contribute to allergic responses to antigens Release histamine and heparin (similar to mast cells that lie outside of capillaries) Also release bradykinin, serotonin, slow releasing substance of anaphylaxis Local vascular reactions (vasodilation and capillary leak with erythema and edema) IgE type antibodies become attached to basophils (and mast cells) as part of the trigger for an allergic response 56 Innate Immunity Phagocytosis of microorganisms by neutrophils and macrophages Destruction of swallowed organisms by HCL in the stomach and digestive enzymes Resistance of skin to invasion by microorganisms Chemical substances in the blood that attach to and destroy microorganisms Lysozymes Basic polypeptides Complement complex Natural killer lymphocytes 57 Acquired immunity Humoral Immunity or B-cell immunity Antibodies Cell-mediated Immunity or T-cell immunity Activated T-Lymphocytes Activated by antigens Polysaccharide / protein patterns (sterochemical characteristics) on outer surface of a foreign substance Epitope Haptens Small molecules that combine with other proteins in the body to create an antigen 58 The Basis of Acquired Immunity: Lymphocytes Pluripotential hematopoietic stem cells form undifferentiated lymphocytes Lymphocytes destined to be T-lymphocytes travel to the thymus, where they are processed B-lymphocytes (responsible for antibodies) are pre-processed in the liver and marrow Lymphocytes then migrate to lymph nodes, spleen, sub-mucosa of the GI tract, or remain in bone marrow Sites of immediate exposure to antigens 59 The Basis of Acquired Immunity: Lymphocytes Pluripotential hematopoietic stem cells form undifferentiated lymphocytes Lymphocytes destined to be T-lymphocytes travel to the thymus, where they are processed B-lymphocytes (responsible for antibodies) are pre-processed in the liver and marrow Lymphocytes then migrate to lymph nodes, spleen, sub-mucosa of the GI tract, or remain in bone marrow Sites of immediate exposure to antigens 60 Pre-processing of the T-lymphocytes in the Thymus Gland In the thymus gland, maturing T-lymphocytes interact with various antigens Each cell develops reactivity toward a specific antigen The cells divide rapidly Any lymphocytes that develop reactivity toward a “self antigen” are destroyed in the thymus This process occurs most intensely during the first year of life 61 Pre-processing of the B-lymphocytes by the Liver and Bone Marrow Pre-processing occurs during mid and late fetal life, as well as after birth After exposure to antigens, the B-lymphocytes make antibodies specific to the antigen On subsequent exposure to the antigen, the Blymphocytes secrete an antibody Antibodies are proteins capable of destroying the antigenic organism via chemical reactions 62 63 Lymphocyte Clones Stimulated lymphocytes reproduce extensively The progeny of the original lymphocyte are called “clones” The stimulated lymphocyte created new gene segments that were not part of its original DNA prior to processing These new genes, code for the antibody protein of B-lymphocytes or the surface receptor proteins of T-lymphocytes The clones formed automatically have these genes 64 Role of T-cells in Activating B-lymphocytes Most antigens activate both B and T lymphocytes T-helper cells (a line of t-cell clones) are activated and secrete lymphokines Lymphokines activate the antigen specific Blymphocytes Without the T-helper cells, only a small number of antigen specific B-lymphocytes would be activated by the presence of the antigen Increases antibody production 65 Formation of Antibodies by Plasma Cells Activated B-lymphocytes (clones) hypertrophy and take on characteristics of lymphoblasts (can further differentiate, as though they were immature forms) Some lymphoblasts differentiate into plasmablasts, or the precursors of plasma cells The mature plasma cell produces antibodies which is secreted into the lymph tissue and carried to the circulating blood “Primary Response” 66 Formation of “Memory” Cells Some lymphoblasts differentiate into new Blymphocytes called memory cells (instead of plasma cells) Memory B-cells leave lymph tissue and circulate throughout the body and lay dormant in various tissues On subsequent exposure to the antigen, they very quickly respond and produce antibodies to the antigen The wide-spread location allows for activation at multiple sites of infection “Secondary Response” 67 Antibody Production 68 Role of Macrophages in the Activation of Lymphocytes Macrophages are also present in the lymphoid tissue that houses lymphocytes Organisms invading the lymph tissue are first phagocytized by the macrophages After partial digestion, the antigenic polysaccharides / proteins of the organism is liberated into the macrophage cytosol The macrophages then pass the antigenic substance to adjacent lymphocytes Creates a new antigen specific lymphocyte or stimulates a B memory cell 69 The Nature of Antibodies Antibodies are gamma globulins called immunoglobulins Variable portion is antigen specific Constant portion facilitates interaction with other immune enhancers 70 Classes of Antibodies The Immunoglobulins IgM Immunoglobulin during primary responses, has 10 binding sites = increased efficacy IgG Constitutes 75% of antibodies and is bivalent IgA Secretory antibodies IgE Involved in allergy IgD 71 Mechanism of Action of Antibodies Agglutination Clumping of multiple particles with the antigen together to increase efficacy of eradication Precipitation Making a dissolved antigenic molecule a solid, so that it can be trapped, agglutinated etc… Neutralization Antibodies cover the toxic sites of the antigenic molecule (i.e.: endotoxins of bacteria) Lysis Direct attack of cell membranes of the antigenic molecule causing rupture and death 72 The Complement System System of 20 proteins / enzyme precursors normally present in the blood in inactive forms The Classic Pathway Activated by antigen-antibody complex, which uncovers an active site on the constant portion of the antibody The antibody binds with C1 (complement protein number 1) C1 enzymes are activated and a successive cascade of reactions takes place An amplified immune response results 73 Effects of Complement Activation Opsonization and Phagocytosis (C3b) Lysis (C5b6789) activates phagocytosis by neutrophils Lytic complex– direct membrane rupture Agglutination Neutralization of Viruses Chemotaxis (C5a) Activation of Mast Cells and Basophils (C3a, C4a and C5a) Inflammatory response is amplified 74 Activated T-cells and Cell-Mediated Immunity Activated antigen-specific T-cells leave the lymph tissue and enter the circulation Activated T-lymphocyte memory cells are produce similarly to B memory cells (via lymphoblast differentiation during first exposure to antigen) Memory T cells contribute to a rapid secondary response and are widely distributed throughout the body 75 Lymphocyte Surface Receptor Proteins Antigen specific receptors present on tlymphocyte clones that have differentiated into T-memory cells May be 100,000 receptor sites on a single T-cell Attach to invading antigen as part of the secondary response Multiple types with multiple responses to activation 76 Helper T-Cells Most numerous type of T-cell Lymphokines (IL2-6, GM-CSF, interferon) Stimulate of Cytotoxic T-cells and Suppressor Tcells (via activity of IL-2) Stimulate B-cell to form plasma cells and antibodies (IL 4,5,6 and B-cell stimulating factor / B-cell growth factor) Activate macrophages and prevent migration of macrophages away from site of insult Feedback stimulation to continue production and function of other helper T-cells (IL-2) 77 Helper T-Cells 78 Cytotoxic T-cells Killer T-cells Directly attack antigenic molecules Secrete digestive enzymes Secrete cytotoxic substances …such as Hole forming proteins or perforins Causes fluid influx and lysis of pathogen cells 79 Killer T-Cells 80 Suppressor T-cells Regulatory T-cells Suppress the function of both cytotoxic and helper T-cells Modifies immune response Prevents erratic systemic inflammation and auto-immunity “immune tolerance” 81 Allergy Immune response to non-toxic or infectious agents Delayed reaction allergy is mediated by T-cells Repeated exposure = increasingly amplified “secondary response” Excess IgE antibodies is mediated by B-cells Called reagins or sensitizing antibodies Strong propensity to attach to mast cells and basophils Inflammatory mediators released from granules 82 Origins of Agglutinins Gamma globulins (just like any other antibody), mostly IgM and IgG forms Small amounts of A and B antigens enter the body in food and bacteria and stimulate the formation of the antibodies in individuals who do not possess the antigen proteins on their RBC’s Immediately after birth, neonates have almost no agglutinins… as the child is exposed during the first 8 months of life, these antibodies are formed (max titer at 8-10 yrs, then decline) 83 Tissue Typing Antigens on organ cell membranes and WBC’s = HLA Type Six basic types, with 150 different variations = over a trillion combinations (only identical twins have the EXACT same antigen patterns throughout the body) When one of these antigens is not present, an individual may develop antibodies to it on exposure = graft rejections after organ or bone marrow transplants 84