Physical Characteristics of Blood

1. Physical Characteristics of Blood • Thicker (more viscous) than water and flows more slowly than water • Temperature of 100.4 degrees F • pH 7.4 (7.35-7.45) • 8 % of total body weight • Blood volume • 5 to 6 liters in average male • 4 to 5 liters in average female • hormonal negative feedback systems maintain constant blood volume and osmotic pressure

2. Components of Blood • Hematocrit • 55% plasma • 45% cells • 99% RBCs • < 1% WBCs and platelets

3. Blood components • 55% plasma: 7 to 8% dissolved substances (sugars, amino acids, lipids & vitamins), ions, dissolved gases, hormones • ions are involved in membrane excitability, determination of fluid pH and osmotic pressure • most of the proteins in plasma are plasma proteins: provide a role in balancing osmotic pressure and water flow between the blood and extracellular fluid/tissues • loss of plasma proteins from blood – increases osmotic pressure in blood and results in water flow out of blood into tissues – swelling • do not exit the blood due to their size – creates a protein gradient between blood and interstitial fluid • partially responsible for the plasma’s capacity to buffer pH • most common plasma proteins: albumin, globulins, clotting proteins (fibrinogen) • albumins – most abundant • globulins – three classes • alpha, beta and gamma • fibrinogen – cleaved by thrombin to produce a very stick mass of fibers made of fibrin • participate in clot formation

4. Blood: Cellular elements • 45% of blood is the cellular elements or formed elements • 99% of this is erythrocytes or RBCs • formed by differentiation of hematopoietic stem cells (HSCs) in the red bone marrow of long bones and pelvis – makes about 2 million per second! • immature RBCs = reticulocytes • still possess a nucleus and organelles • lack mitochondria and cannot use the oxygen they transport for ATP synthesis • maturation of the reticulocyte causes loss of nucleus and organelles and the filling of the RBC with close to 250 million Hb molecules • also contain crucial erythrocytic enzymes • 1. glycolytic enzymes • 2. carbonic anhydrase – converts the soluble form of CO2 (HCO3 in carbonic acid) into CO2 gas at the lungs and CO2 gas into HCO3 at the tissues • most numerous cell type in the body – 4 to 6 million per ul blood • flat, biconcave discs • provides a larger surface area for diffusion of oxygen across their membrane • thinness of the membrane allows rapid diffusion • very flexible membrane that allows their deformation for travel through thin capillaries

5. Hematopoiesis

6. Erythrocytes: Red Blood cells & their development • hemoglobin • pigment – naturally colored that is red due to its iron content • combines with • oxygen • binding sites • carbon dioxide • the acidic portion of carbonic acid • oxidation of CA occurs at the tissue level • carbon monoxide • occupies the oxygen binding sites • nitric oxide • binds to Hb in the lungs where it vasodilates pulmonary arterioles to ensure efficient transport of oxygenated blood from the lungs back to the heart • composed of a: • 1. globin portion • four, highly folded protein chains • 2. heme component • four molecules of iron-based heme bound to each globin protein chain • each heme can bind one oxygen – total binding capacity of 4 oxygen molecules per Hb

7. Erythropoiesis • produced first by the yolk sac • then from myeloid stem cells in the red bone marrow • controlled at the level of the kidneys by the secretion of erythropoietin (EPO) • increased differentiation of the myeloid stem cell • release of mature RBCs or, if needed, the release of reticulocytes • synthetic EPO – can now be made in the lab • used to boost RBC production during chemotherapy, diminishes the need for transfusions • role in blood-doping

8. Feedback Control of RBC Production • Tissue hypoxia (cells not getting enough O2) • high altitude since air has less O2 • anemia • RBC production falls below RBC destruction • circulatory problems • Kidney response to hypoxia • release erythropoietin • speeds up development of proerythroblasts into reticulocytes

9. RBC life-span and recycling • RBC lives only about 120 days – destroyed by macrophages in the liver, bone marrow and spleen • most RBCs are destroyed in the spleen – small vessels tend to lyze the fragile RBCs as they travel through this organ • 1. liver/spleen/bone marrow degrades the hemoglobin to its globin component and heme • 2. heme is degraded into free iron and biliverdin – Fe released into the blood • transported in blood attached to transferrin protein (4&5) • stored in liver, muscle or spleen (6) • attached to ferritin or hemosiderin protein • sent to the bone marrow for hemoglobin synthesis (7&8) • 9. biliverdin is converted into bilirubin in the liver (11) which travels to the small intestine in the bile where it is converted into a series of compounds – end up expelled in urine as urobilin (13) or in the feces as stercobilin (14)

10. Hematocrit • Percentage of blood occupied by cells – since RBCs are 99% of these cells, hematocrit is a measurement of RBC count • female normal range • 38 - 46% (average of 42%) • male normal range • 40 - 54% (average of 46%) • testosterone

11. Polycythemia • too many RBCs (hematocrit over 65%) • dehydration, tissue hypoxia, blood doping in athletes • primary polycthemia • caused by a tumor-like condition of the bone marrow • overproduction of RBCs through increased differentiation of the myeloid stem cell • too many RBCs can increase the viscosity of the blood and result in dramatic decreases in blood pressure as frictional forces in the vessels increase – increases the workload of the heart • increased viscosity also slows the velocity of blood flow - reduce oxygen delivery to tissues • secondary polycthemia • appropriate EPO-induce adaptive mechanism to improve the blood’s oxygen carrying capacity • occurs at high altitudes or in people with chronic lung diseases

12. Anemia • Symptoms • oxygen-carrying capacity of blood is reduced • fatigue, cold intolerance & paleness • lack of O2 for ATP & heat production • Types of anemia • iron-deficiency = lack of absorption or loss of iron • type of nutritional anemia • failure to take in essential raw ingredients not made by the body • pernicious = lack of intrinsic factor for vitamin B12 absorption from the digestive tract • B12 is essential for normal RBC formation and maturation • binding of B12 to intrinsic factor allows its absorption • intrinsic factor – synthesized by the small intestine • hemorrhagic = loss of RBCs due to bleeding (ulcer) • hemolytic = defects in cell membranes cause rupture • rupture of too many RBCs by external factors such as malaria (normal RBCs) or genetic disorders like sickle cell anemia (defective RBCs) • thalassemia = hereditary deficiency of hemoglobin • aplastic = destruction of bone marrow (radiation/toxins) • failure of the bone marrow to produce enough RBCs • may selectively destroy the ability to produce RBCs only • but may also destroy the myeloid stem cells – affect WBCs and platelets

13. Sickle-cell Anemia (SCA) • Genetic defect in hemoglobin molecule (Hb-S) that changes 2 amino acids in the globin protein • at low very O2 levels, RBC becomes deformed by changes in hemoglobin molecule within the RBC • sickle-shaped cells do not pass through capillaries well and get stuck = causing occlusions and decreased blood flow to organs • also rupture easily = causing anemia & clots • Found among populations in malaria belt • Mediterranean Europe, sub-Saharan Africa & Asia • Person with only one sickle cell gene • increased resistance to malaria because RBC membranes leak K+ & lowered levels of K+ kill the parasite infecting the red blood cells

14. Blood disorders • http://members.aol.com/Sheffbp/products/bludphys.htm (Simulation of anemia diagnosis) • http://www.udel.edu/Biology/Wags/histopage/colorpage/ch/ch.htm (Hematopoiesis) • http://www.bloodline.net (Hematology education and news) • http://www.thrombosis.net/lframes/intro.htm (Introduction to thrombosis) • http://www.vh.org/adult/patient/cancercenter/blooddisorders/index.html (Blood disorders) • http://www.bmtnews.org (Blood and Marrow Transplant Information Network) • http://www.psbc.org/hematology (Introduction to hematology) • http://www.pediatrics.emory.edu/ (Sickle cell anemia) • http://www.bloodjournal.org (Journal of the American Society of Hematology) • http://medir.ohsu.edu/cliniweb/C15/C15.378.html (Blood protein disorders)

15. Blood Groups and Blood Types • RBC surfaces are marked by genetically determined glycoproteins & glycolipids • agglutinogens or isoantigens • distinguishes at least 24 different blood groups • ABO, Rh, Lewis, Kell, Kidd and Duffy systems

16. RH blood groups • Antigen was discovered in blood of Rhesus monkey • People with Rh agglutinogens on RBC surface are Rh+. Normal plasma contains no anti-Rh antibodies • Antibodies develop only in Rh- blood type & only with exposure to the antigen • transfusion of positive blood • during a pregnancy with a positive blood type fetus • Transfusion reaction upon 2nd exposure to the antigen results in hemolysis of the RBCs in the donated blood

17. Hemolytic Disease of Newborn • Rh negative mom and Rh+ fetus will have mixing of blood at birth • Mom's body creates Rh antibodies unless she receives a RhoGam shot soon after first delivery, miscarriage or abortion • RhoGam binds to loose fetal blood and removes it from body before she reacts • In 2nd child, hemolytic disease of the newborn may develop causing hemolysis of the fetal RBCs

18. Thrombocytes: Platelets & clotting • Disc-shaped, 2 - 4 micron cell fragment with no nucleus • not whole cells! • do have organelles and cytosolic enzymes for generating energy from glucose • Normal platelet count is 150,000-400,000/drop of blood • Platelets form in bone marrow by following steps: • myeloid stem cells to megakaryocyte-colony forming cells to megakaryoblast to megakaryocytes whose cell fragments form platelets • one megakaryocyte forms 1000 platelets • Short life span (5 to 9 days in bloodstream) • formed in bone marrow • few days in circulating blood • aged ones removed by fixed macrophages in liver and spleen • 30% of platelets are stored in the spleen – in blood-filled spaces since platelets do not leave the blood

19. Platelet Plug Formation • hemostasis = arrest of bleeding from a broken vessel • 3 steps: • 1) vascular spasm – constriction of smooth muscle layer in damaged vessel • intrinsic response triggered by physical damage • 2) platelet plug formation • 3) blood clotting • Platelets store chemicals in granules needed for platelet plug formation • platelets do not stick to the smooth endothelium • damage to the endothelial lining exposes collagen fibers to the platelet – results in their activation and adhesion to the collagen fibers to form a plug • alpha granules • clotting factors –clot formation • platelet-derived growth factor – repair of damaged vessel wall • dense granules • ADP, ATP, Ca+2, serotonin, fibrin-stabilizing factor, & enzymes that produce thromboxane A2 • thromboxane – chemotactic factor for other platelets – platelet aggregation • ADP causes circulating platelets to become sticky – adhere to the first layer of aggregating platelets – results in the secretion of more ADP by the incoming platelets • release of serotonin, epinephrine and thromboxane act as vasoconstrictors to reinforce the initial vascular spasm • aspirin – inhibits COX enzyme which inhibits the production of thromboxane A2

20. Platelet Plug formation • Steps in the process: • (1) platelet adhesion & activation – by collagen interaction • (2) platelet release reaction – from their storage granules • -Release thromboxane A2 & ADP - arrival and activation of other platelets • -Serotonin & thromboxane A2 are also vasoconstrictors decreasing blood flow through the injured vessel • (3) platelet aggregation – self-perpetuating • -inhibited at a specific level by the release of inhibiting factors by the adjacent normal endothelium • -actin-myosin interactions contract within the aggregating platelets – strengthens the plug • -plug becomes reinforced through the formation of sticky fibrin strands

21. Blood Clotting • in a test tube gel separates into liquid (serum) and a clot of insoluble fibers (fibrin) in which the cells are trapped • in the body the clot stabilizes the weaker platelet plug and initiates healing • ultimate step is conversion of fibrinogen (soluble plasma protein) into insoluble fibrin • Substances required for clotting are Ca+2, clotting factors and plasma proteins from the liver and substances released by platelets or damaged tissues • Clotting is a cascade of reactions in which each clotting factor activates the next in a fixed sequence resulting in the formation of fibrin threads • prothrombinase & Ca+2 convert prothrombin into thrombin • thrombin converts fibrinogen into fibrin threads

22. Overview of the Clotting Cascade -may be triggered through two possible paths 1. extrinsic pathway 2. intrinsic pathway -either path leads to activation of the final pathway in which thrombin cleaves fibrinogen to form fibrin

23. Extrinsic Pathway • short-cut to clot formation • requires contact with tissue factors produced externally from the blood • damaged tissues produce and release Tissue Factor or thromboplastin into bloodstream • In the presence of Ca+2, clotting factor X becomes activated and combines with clotting factor V to form prothrombinase • Prothrombinase forms in seconds

24. Intrinsic Pathway • drivesclotting in damaged vessels and also induces clotting in blood samples in test tubes • Activation of this pathways occurs either when: • endothelium is damaged & platelets come in contact with collagen of blood vessel wall – initiates plug formation by activated platelets • OR platelets themselves become damaged & release phospholipids which activate incoming platelets • Requires several minutes for reaction to occur – occurs concurrently with platelet plug formation and the extrinsic pathway • Substances involved: Ca+2 and clotting factors XII, X and V • first factor – Factor XII (Hageman factor) • activated by contact with exposed collagen or glass surfaces • activated Factor XII requires calcium – which then combines with Factor V to produce prothrombinase

25. Final Common Pathway • activated prothrombinase and Ca+2 • catalyze the conversion of prothrombin to thrombin • Thrombin • in the presence of Ca+2 converts soluble fibrinogen to insoluble fibrin threads • activates fibrin stabilizing factor – clotting factor XIII • stabilizes the forming fibrin mesh • positive feedback effects of thrombin • accelerates formation of prothrombinase • activates platelets to release phospholipids which acts to activate more Factor X and therefore produces more thrombin (positive feedback) • also acts to promote platelet aggregation

26. 12 Clotting: A summary Platelet aggregation

27. Clot Retraction & Blood Vessel Repair • Fibroblasts & endothelial cells repair the blood vessel • Formation of PDGF • release of the fibrinolytic enzyme plasmin dissolves the clot • plasmin – plasma protein present in the blood as inactive plasminogen • activated by Factor XII • plasminogen becomes trapped in the forming clot, becomes activated to plasmin and slowly dissolves the clot as the tissue repairs itself

28. Role of Vitamin K in Clotting • Normal clotting requires adequate vitamin K • fat soluble vitamin absorbed if lipids are present • absorption slowed if bile release is insufficient • Required for synthesis of 4 clotting factors by the hepatocytes • factors II (prothrombin), VII, IX and X • Produced by bacteria in large intestine • anti-coagulants called the coumarin drugs (heparin and warfarin) act by competing with vitamin K in the liver • inhibits the formation of the vitamin K-dependent clotting factors

29. Clotting Disorders: Hemophilia • Inherited deficiency of clotting factors • bleeding spontaneously or after minor trauma • subcutaneous & intramuscular hemorrhaging • nosebleeds, blood in urine, articular bleeding & pain • Hemophilia A lacks factor VIII (males only) • most common • over 150 point mutations in the DNA identified • factor VIII acts as a cofactor for the activation of factor X • Hemophilia B lacks factor IX (males only) • less common • over 300 mutations in the DNA identified • Hemophilia C (males & females) • less severe because alternate clotting activators exist • Treatment is transfusions of fresh plasma or concentrates of the missing clotting factor

30. Clotting Disorders • If clotting occurs in an unbroken vessel is called a thrombosis • clots can form in undamaged vessels if the body’s clotting and anti-clotting mechanisms are not kept balanced and in check • inappropriate clot attached to a vessel wall = thrombus • freely floating clot = embolus • thrombosis can result from several factors • 1. roughening of the endothelial lining during arterosclerotic plaque formation • 2. slow moving blood • 3. unbalanced fibrin-plasmin production • 4. widespread release of thromboplastin by tissues • Disseminated Intravascular Clotting : • Life threatening paradoxical presence of blood clotting and bleeding at the same time throughout the whole body • so many clotting factors are removed by widespread clotting that too few remain to permit normal clotting • Associated with infections, hypoxia, low blood flow rates, trauma, hypotension & hemolysis • Clots cause ischemia and necrosis leading to multisystem organ failure

31. Immunity • Immunity: ability of the body to defend itself from infectious agents, foreign cells, cancer cells • immune system has two functional divisions • innate immune system • non-specific immunity • cell-mediated and humoral (secreted) mediated • chemical and physical barriers • chemical: complement and inflammation • no memory • all forms of life • adaptive immune system • pathogen and antigen specific response • cell-mediated and humoral mediated • chemical barriers • memory results • only jawed vertebrates

32. 1) Non-specific defenses: Innate immunity A)Mechanical barriers: first line of defense - Skin and mucus membranes lining the respiratory tract, digestive & reproductive systems e.g. ciliated epithelium of respiratory system - coated with mucus, coughed out B) Chemical barriers (humoral mediated defense): first line of defense -acidic pH of the stomach interior -E.coli within the small intestine -gastric enzymes in gastric juice -high salt in perspiration kills some bacteria C) Fever: second line of defense -secretion of pyrogen by lymphocytes - raises body temp -rise in body temp enhances the phagocytic activity of immune cells D) Inflammation & complement: second line of defense E) Phagocytosis by phagocytic cells (cell-mediated defense) -dendritic cells, macrophages, neutrophils -cells of the innate system: WBCs with the exclusion of the T and B lymphocytes

33. Complement • group of about 20 proteins who control inflammation • several of these proteins are called acute phase proteins (serum proteins that dramatically increase upon infection) • complement proteins interact with many components of both the innate and adaptive immune systems • similar to a blood clotting system – one complement protein activates another which activated another etc….. • functions • 1. attraction of phagocytes upon activation of the pathway – chemotaxis • 2. coating of foreign cells with complement – recognition of the foreign particle by the incoming phagocytes • 3. intrinsic ability to coat bacteria (opsonization) and lead to their lysis

34. Inflammation: 1) injury to tissue 2) release of histamine and kinins (pain) by damaged cells – along with prostaglandins 3) histamine - dilation of capillaries & increased blood flow -histamine causes the gaps between endothelial cells to widen to allow the passage of larger molecules – immune cells and complement proteins 4) delivery of proteins (e.g .clotting, immune cells), increase of fluid in damaged area, reddening of skin – swelling/edema 5) migration of neutrophils and monocytes/macrophages (WBCs) via capillaries - phagocytosis of foreign particles 6) clotting response by blood - cascade/positive feedback - to minimize blood loss 7) macrophages release Colony stimulating factors - differentiation of more WBCs by the bone marrow and increased distribution systemically 8) production and release of lymphocytes from lymph nodes - travel to infection site -anti-inflammatories (ibuprofen, aspirin, cortisones) can be administered to combact chronic or persistent inflammation -act against chemicals produced by WBCs and prostaglandins made by damaged cells -anti-histamines - block the binding of histamine to receptors

35. WBCs • cells of the lymphoid lineage • T and B lymphocytes • cells of the myeloid lineage • phagocytes and other cells

36. -Leukocytes are 1% of the total cellular elements • - found in the Buffy coat together with the platelets: • -granular and agranular classification • -neutrophils: phagocytic properties • -release lysozymes which destroy/digest bacteria • -release defensin proteins that act like antibiotics & poke holes in bacterial cell walls destroying them • -release strong oxidants (bleach-like, strong chemicals ) that destroy bacteria • - releases cytokines that attract other neutrophils • -eosinophils: parasitic defense cells • -also involved in the allergic response • -release histaminase • slows down inflammation caused by • basophils • -basophils: heparin, histamine & serotonin • -heighten the inflammatory response and account for hypersensitivity (allergic) reaction • -monocytes: enter various tissues and • differentiate into phagocytic macrophages • -lymphocytes: T and B cells Leukocytes: White Blood cells & the Immune system

37. WBC Physiology • Less numerous than RBCs • 5000 to 10,000 cells per drop of blood • 1 WBC for every 700 RBC • Leukocytosis is a high white blood cell count • microbes, strenuous exercise, anesthesia or surgery • Leukopenia is low white blood cell count • radiation, shock or chemotherapy • Only 2% of total WBC population is in circulating blood at any given time • rest is in lymphatic fluid, skin, lungs, lymph nodes & spleen

38. Lymphatic & Immune System Lymphatic system: system of lymphatic vessels and organs -multiple functions 1. defense against disease – lymph flows through lymph nodes -the lymph is filtered by the nodes and microorganisms are destroyed 2. transport of absorbed fat 3. return of filtered proteins – return of plasma proteins that have leaked from capillaries -larger lymphatic vessels are similar to blood vessels - presence of valves -lymphatic vessels - for the transport of lymph -lymph: filtrate produced in tissues and NOT reabsorbed by the CV system -lymphatic capillaries join to form lymphatic vessels -lymphatic vessels join to form: 1) thoracic duct 2) lymphatic duct - Right side head, arm & chest empty into lymphatic duct and rest of body empties into thoracic duct -then dumped directly into left & right subclavian veins -lymphatic system is ONE WAY (from tissues to heart)

39. Lymphatic organs: • lymph nodes: found at certain points along the lymphatic system • -for the cleaning of lymph • -capsule surrounding an outer cortex and inner medulla • -cortex contains immune cells = lymphocytes (fight pathogens) • -medulla contains immune cells = macrophages (clean lymph) • 2) tonsils: lymphatic tissue located in the pharynx (adenoids) or oral cavity (palatine tonsils) • -defense against pathogens ingested through food and drink • 3) spleen: upper left region of the abdomen • -cleanses the blood • -capsule, white and red pulp • -white pulp contains lymphocytes • -red pulp contains red blood cells & macrophages • 4) bone marrow (red): adult - within the spongy bone of the epiphyses, pelvis, skull, clavicle, sternum • -site of origin for all blood cells (RBCs, WBCs) • -derived from hematopoietic stem cells (hematopoiesis) • -also the site of origin for all mesodermal cells (bone, muscle, cartilage, fat…..) • -derived from mesenchymal stem cells • 5) thymus gland: located below the trachea, on top of the heart • -divided into lobules • -larger in children • -production of T lymphocytes • -production of hormones - thymosin - stimulates the lymphocytes located in other tissues

40. Cells of Innate and Adaptive Immunity: Phagocytes • one of the first cells to arrive upon inflammation • Two major kinds: monocytes/macrophages and polymorphonuclear granulocytes (neutrophils) • attracted through the process of chemotaxis (soluble chemicals that attract cells) • need a method of recognizing the foreign antigen – use antibodies/immunoglobulins (macrophages) • or can use non-specific attachment to microorganisms (neutrophils) • Phagocytosis enhanced if the microorganism has been coated with complement protein

41. Cells of Innate and Adaptive Immunity: Neutrophils (Polymorphonuclear Granulocytes) • are over 90% of the circulating granulocytes • Nuclei = 2 to 5 lobes connected by thin strands • older cells have more lobes • young cells called band cells because of horseshoe shaped nucleus (band) • Fine, pale lilac practically invisible granules • Diameter is 10-12 microns • Fastest response of all WBC to bacteria • Direct actions against bacteria • release lysozymes which destroy/digest bacteria • release defensin proteins that act like antibiotics & poke holes in bacterial cell walls destroying them • release strong oxidants (bleach-like, strong chemicals ) that destroy bacteria

42. Cells of Innate and Adaptive Immunity: Monocyte (Agranulocyte) • two main functions • 1. “professional” phagocytic macrophages – derived from monocytes • 2. antigen-presenting cells • Nucleus is kidney or horse-shoe shaped • Largest WBC in circulating blood • does not remain in blood long before migrating to the tissues • differentiate into macrophages • form the reticuloendothelial system (RES) • Destroy microbes and clean up dead tissue following an infection • fixed group found in specific tissues • Or as “wandering cells” gathers at sites of infection • express an Fc receptor on their surface – important for recognizing the foreign microorganism • Diameter is 12 - 20 microns • Cytoplasm is a foamy blue-gray • 3 to 8% of circulating WBCs – form a circulating pool of monocytes • Take longer to get to site of infection, but arrive in larger numbers

43. Cells of Innate and Adaptive Immunity: Eosinophils (Granulocyte) • Nucleus with 2 or 3 lobes connected by a thin strand • Large, uniform-sized granules stain orange-red with acidic dyes • do not obscure the nucleus • Diameter is 10 to 12 microns • 2 to 4% of circulating WBCs • Leave capillaries to enter tissue fluid • Release histaminase • slows down inflammation caused by basophils • Attack parasitic worms • Phagocytize antibody-antigen complexes

44. Cells of Innate and Adaptive Immunity: Basophils (Granulocyte) • Large, dark purple, variable-sized granules stain with basic dyes • obscure the nucleus • Irregular, s-shaped, bilobed nuclei • Diameter is 8 to 10 microns • Less than 1% of circulating WBCs • Involved in inflammatory and allergy reactions • Leave capillaries & enter connective tissue as mast cells • Release heparin, histamine & serotonin • heighten the inflammatory response and account for hypersensitivity (allergic) reaction

45. Cells of Adaptive Immunity: Lymphocytes (Agranulocyte) • Dark, oval to round nucleus • Cytoplasm sky blue in color • amount varies from rim of blue to normal amount • Small cells 6 - 9 microns in diameter • Large cells 10 - 14 microns in diameter • increase in number during viral infections • 20 to 25% of circulating WBCs • produced in the primary lymphoid tissues – thymus and adult bone marrow • B cells • destroy bacteria and their toxins • turn into plasma cells that produces antibodies • T cells • attack viruses, fungi, transplanted organs, cancer cells & some bacteria • Natural killer cells = sometimes classified as large granular lymphocytes • attack many different microbes & some tumor cells • destroy foreign invaders by direct attack • kill by binding directly to the target = cytotoxicity

46. 2) Specific Defenses (Cell-mediated Immunity) Antigens: -before birth, the body takes an “inventory” of all self proteins = antigens -lymphocytes develop receptors that allow them to distinguish between self and foreign -non-self antigens combine with T and B cell receptors and stimulate an immune reaction T Cell-mediated immunity:/Cell-mediated immunity -T = thymus derived -respond to antigens by cell-cell contact - attach to foreign cells directly -antigens are processed before interacting with T cells -antigen-presenting cells (B cells, macrophages)

47. Antigen Presenting Cell (APC) • Foreign antigen in body fluid is phagocytized by APC • macrophage, B cell, dendritic cell (communicates with the B cell in the lymph node and spleen) • Antigen is digested and fragments are bound to MHC-II molecules stuck into antigen presenting cell membrane • APC migrates to lymphatic tissue to find T cells • found primarily in skin, lymph nodes, spleen and the thymus • typical APC – Langerhans cell in the skin • migrate out of the skin • enter into the lymph node where they interdigitate with the T lymphocytes

48. APC displays the foreign antigen to the T cell • this requires cell-cell contact between the APC and T cell in order to activate the T cell • both T helper and cytotoxic T cells can be activated by an APC • interaction between the MHC complex with the Ag and a complex of proteins on the T cell called the T cell receptor • TCR = multiple proteins associated with a co-receptor (CD4 for a T helper or CD8 for a cytotoxic T cells) - Activated T cells synthesize specific soluble chemicals called cytokines -also “decide” to become either helper or cytotoxic T cells -if the foreign Ag is bacterial = T helper -if the foreign Ag is viral = T cytotoxic

49. -T cells secrete chemicals called cytokines - enhance other cell responses to antigens • -cytokine = secreted signaling molecules • -cytokines made by lymphocytes may be called lymphokines • e.g. interleukins, interferons • -interleukins - over 23 made by various WBCs • -several made by T cells • -play various roles in activating the many components of the immune system • -interferons: play a role in viral infections • -released by virally-infected cells or by activated T cells in response to • the infection • -three types of IFNs are made naturally by T cells – alpha, beta and gamma IFN • -also made synthetically

50. T cell types • 1. Cytotoxic T cells (Tc cells) destroy virally infected cells and tumor cells • also implicated in transplant rejection. • are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface. • secrete perforin which punches holes in the foreign membrane • 2. Helper T cells, (Th cells) participate in bacterial infections • need to be activated by an APC • once activated - divide rapidly (clonal expansion) and secrete small proteins called cytokines that regulate or "help" the immune response. • also called CD4+ T cells • are a target of HIV infection - virus infects the cell by using the CD4 protein to gain entry. The loss of Th cells . • 3. Memory T cells - T cells that persist long-term after an infection has resolved. • quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, • provide the immune system with "memory" against past infections. • comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). • may be either CD4+ or CD8+. • 4) Regulatory T cells (Treg cells), formerly known as suppressor T cells • 5) Natural Killer T cells (NKT cells) – also called natural killer (NK) cells