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BLOOD AND IMMUNE:! ! Lecture 21 the composition and feature of blood.! BLOOD CIRCULATION:! -the average person has 5 litres of blood! -14,0000 L circulates through the heart every 24 hours ! -large vessels = high volume but low flow! -small vessels = low volume but high flow ! -there is a vast network of tiny capillaries which require high pressures to force blood through ! -muscular arteries and valves provide pressurised directional flow from lungs to tissues and organs (tissue and organs need oxygen)! -four chambered heart in mammals (right and left ventricles and right and left atriums)! -pulmonary artery extends from the right ventricle to the lungs where unoxygenated blood is bathed in oxygen breathed in through the lungs and is drawn back into the left atrium through the pulmonary vein. The left ventricle then pumps blood out through the aorta through the arterial system to the tissues and organs ! -the heart itself doesn’t use much blood, along with bone, skin uses about 6% and brain is a major user of blood because it requires a great deal of oxygen, skeletal muscle uses 15%, kidneys use 20% because they filter the blood, and liver uses a great deal, others use 8%.! -arteries are muscular ! -valves are part of the Venus system to prevent back flow of blood (makes sure the blood is always flowing in one direction)! Pressure:! -pressure on arterial blood is quite high ! -capillaries have thick muscular walls so when the left atrium pumps those walls expand to carry the pressure of the heart! -measured as systolic pressure 120/80 is normal ! -systolic means the blood is at full compression that is when the left ventricle is squeezed at its tightest and the arteries are expanded at their greatest ! -120 mm of mercury means that the mercury on the stigma monitor is 120 mm high. The radial artery on the arm is compressed and the pressure is slowly released, with a stethoscope over the radial artery waiting to hear the pulsation. As soon as the sound starts to pulse that is the systolic pressure. As they release the cuff pressure even further diastolic pressure is signaled by the sound of pause of the blood and the arteries stopping (heart at rest)! Blood pressure ensures:! -even and efficient flow through the small capillaries ! -low enough to prevent capillary leakage but high enough to avoid coagulation ! -if the blood pressure is too high the arteries are not expanding and contracting effectively (they have hardened or there is some other disease associated with them (blocked))! -when the blood pressure raises above around 140-150 that signals that there is something very wrong and there is significant risk of fibrotic diseases such as blood clots and coronary heart disease ! -too low means not enough blood in veins to supply tissues (commonly causes fainting)! MAJOR COMPONENTS OF BLOOD:! 1. Cells- red blood cells which have haemoglobin (erythroid) and we also have myeloid (neutrophils, macrophages, monocytes, basophils) and lymphoid cells ( b cells (from bone marrow) and t cells (migrate to the thymus of the heart)) and are components of the innate immune system ! 2. Proteins: albumin (most abundant protein in the heart filling role such as osmotic presses and maintaining hypertonicity), haemoglobin (component of red blood cells which carries oxygen

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from the heart to the tissues, fibrinogen is a major protein which constitutes 7% of blood and is the major component that forms the blood clots (it is soluble and is cleaved with fibrin molecules which cross link together to form a clot which is hard a seals any leakage), immunoglobulins. ! Lipids bound in lipoproteins, when you eat a fatty meal the lipids are uptaken and form lipoproteins (they signal your susceptibility to different forms of coronary heart disease. LDL is a low density lipoprotein (bad lipoprotein), HDL is high density lipoprotein (good), VLDL. These are based on density because the only way to isolate them is to centrifuge them at high speeds.! Electrolytes. Includes salts and minerals to maintain isotonicities (HCO3, Na+, Cl-, Ca++, Mg+ +, K+, creatine and creatinine)- some of the major electrolytes and deviation from any of the normal levels could cause illness. The most tightly regulated is potassium because it regulates a lot of cellular functions e.g nerve potential and heart muscle acitivty is regulated by potassium.! Vitamins and hormones that are transported to various organs through blood (e.g insulin, glucagon)! Glucose. 6 carbon source that is used by tissues such as muscle through glycolysis which degrades down into two carbon fragments to form part of the Krebs cycle which is then used by mitochondria to generate energy allowing you to function and move !

CENTRIFUGATION OF BLOOD WITH ANTI COAGULANT ! -simplest form of separation of blood is centrifugation ! -2 tubes of blood taken, one will be left to clot in the glass tube, the clot will go to the bottom of the tube containing the fibrinogen. About 30 mins later they will remove the clot from the Bottom of the tube to leave behind a yellow coloured solution that is called serum (blood within frinogen)! -they will add an anti-coagulant called heparin to the other tube which will stop the blood clotting and then they will spin in a centrifuge to get the plasma which still fibrinogen in it (55% of blood volume is plasma ) and the red blood cells (45% of blood volume). There is also a layer of white cells called the Buffy coat which is composed of white blood cells (lymphocyutes and myeloid cells) and platelets! -often there are conditions where you don’t make enough red cells which makes you anaemic, too many can cause blood to become extremely viscous which can happen at high altitudes and is called cerebral edema ! -typical way people separate out blood components for testing ! BLOOD CELLS: MAIN! Erythrocytes:! -5-6 million per ml ! -largest majority of cells in the blood ! -anucelated (they don’t have a nucleus)! -sole purpose is to carry oxygen to tissue ! -their protein is haemoglobin ! -red blood cells ! Leukocytes ! -immune defence ! -10,000 per ml of blood ! -neutrophil is the most abundant (they migrate very quickly from e.g capillary tissue through the tissue to the sight of infection and begin to engulf ! Platlets:! -coagulation and tissue repair ! -400,000 per ml! -20th of the size of leukocytes ! -platlets respond by linking together as part of the blood clot to form a plug to prevent leakage from the damaged tissue ! -responsible for releasing a number of mechanisms that maintain homeostasis of tissue repair !

BLOOD PROTEIN SEPARATION (ELECTROPHORESIS) - IMAGE SHOWS NORMAL READING! Plasma:! -the viscous liquid fraction of blood without cells. Contains fibrinogen that is removed with coagulation ! -does not electrophoresis very well because fibrinogen tends to cause problems with the process! - for electrophoresis you need to remove fibrinogen by first clotting the blood ! Serum:! -less viscous yellow liquid remaining after removal of the clot ! -you mix It with a buffer solution to keep the PH ! -typically you dab some onto a piece of paper and apply an electric field across the paper (positive electron and a negative electron)! -proteins nature is charged so they will migrate in the electric field ! -if they are negatively charged they will migrate to the cathode (positive election)! -if they are positively charged they will migrate toward the negative electron ! Serum electrophoresis:! -Using an electric current to separate proteins ! -serum proteins are exposed to an electric field ! -separates into 5 distinct bands! -we have albumin which is about 50% of the total ! -globulin is 405 of total ! -a1, a2, beta and Y fraction which contains immunoglobulins / antibodies which are quite positively charged so they will migrate furthest to the negative electrode ! - the gamma globulin faction ! -you get a spread of blood proteins ! -uses a stain ! Multiple myeloma:! -a form of leukaemia where a malignant lymphocyte produces monoclonal immunoglobulins/ antibodies ! -serum electrophoresis is used to diagnose this condition ! -b cell malignancy meaning too many antibodies are produced ! -a single band will appear in the gamma globulin faction which indicates that one b cell is over producing a monoclonal antibody! -typically these reside in the bone marrow, not the blood but when the patient becomes quite advanced the antibody is in such high density that you can urinate it into your urine so you have this protein in your urine which is almost entirely antibody which is called bento jones proteins ! ! MAJOR BLOOD PROTIENS:! Albumin ! -50% of total blood proteins ! -maintians colloidal osmotic pressure ! -it absorbs a lot of the fluid in the blood and allows the fluid to be balanced to avoid fluid leaking out of capillaries (they are very weak walls), the osmotic pressure on either side of the capillaries has to be balanced very carefully ! -binds and transports many small molecules and hormones (you find very large amounts of proteins bound associated to albumin to use as a transport to tissue) !

Fibrinogen:! -fibrous protein, a large protein ! -that gets cleaved through the coagulation cascade to form and cross-linked fibrin ! -7% of total blood protein ! -imoportant in a large number of medical conditions that are associated with clotting such as coronary thrombosis, cerebral thrombosis or deep vein thrombosis ! OTHER MAJOR BLOOD COMPONENTS: ! Immunoglobulins:! -antibodies which provide a repertoire of antigen binding molecules which are there to provide defence ! -diverse repertoire of antigen binding proteins ! -produced by B lymphocytes ! Compliment proteins: ! -series of compliment proteins that contribute to your innate immune response ! -9 proteins that coat bacteria targeting for phagocytosis ! -coating process is opsonisation ! -9 major complement proteins ! -C3 is the major component ! -tag things that do not look like self ! -if you have an infection one of the first things that will happen is that the capillaries leak and blood will leak out and compliment proteins will react with the surface of the bacteria and coat it, they will coat it irreversibly in a process called opsonisation. That then signals the white cells to migrate to that sight and use phagocytosis. Neutrophils are the first cells that arrive at a sight of inflection, they are driven to migrate from the capillaries to the infection by the activation of complement ! Coagulation:! -13 proteins that are cleaved in an ordered cascade resulting in the cleavage of fibrinogen to fibrin for clotting ! -calcium is an essential component, it is tightly regulated ! -all coagulation factors are proteases, which means that they all cleave other proteins in the cascade ! -coagulation factors are very dependent on calcium for their regulation ! -diseases of coagulation are haemophilia caused by a missing component! -factor VIII deficiency is the most common form of haemophilia ! -haemophilia is a clotting disorder, they only need to cut or bruise themselves and they can bleed to death! Electrolytes:! -isotonicity and buffering! -blood PH tightly regulated at 7.4! -free Ca ++ and K + which are tightly maintained and critical for regulation of cell membrane channels, ion pumps and normal nerve and muscle function such as the heart ! -hearts are stopped during leathal injection with 1 mol of potassium chloride which effectively stops the heart ! ! ORIGIN OF BLOOD CELLS:! -all come from a single, multi potent stem cell which resides in bone marrow ! -bone marrow is the source of all blood cells! -the multi-potential haemopoetic stem cell is relatively rare! !

-extremely important because it is a stem cell that has the capacity to grow or differentiate into any other one of the mature haemopoetic cells that populate the body! -this stem cell is in high concentration in umbilical chord blood, very rich in haemopoetic stem cell! Cancer! -umbilical chords blood are stored in liquid nitrogen on the off chance that the child will develop leukaemia! -leukaemia is treated using radio oblation and chemical oblation, the haemopoetic stem cells from the umbilical blood is then transplanted in to re populate the bone marrow and regenerate a normal blood system! -before they are transplanted in the patient Is extremely susseptible to infection ! -3-4 weeks in isolation to prevent infection! -autologous bone marrow transplant ! ! Another technique with cancer….! -adults can use a technique which isolates the multi potent stem cells using a monoclonal antibody which recognises the CD34 antigen! -monoclonal antibody is manufactured commercially and usually has a fluorescent tag or a magnetic bead attached to it ! -you add the antibody to the patients blood and you hold a magnet to the side of the tube. All the CD34 cells will bind to the side of the tube and you wash away the other cells including the leukaemia cells which you do not want to transplant into the patient ! -gives a relatively purified population of CD34, you take the patient, treat them with radiation which destroys your white cells and the leukaemic cells too. Once that is done you transplant back the isolated CD34 cell !

FACTORS THAT DRIVE HAEMATOPOIESIS (stem cell factors):! -when cancer leukaemia patients are given their CD34 cells they are also given these to reduce chance of infection ! GM-CSF:! -granulocyte macrophage colony-stimulating factor! -produced by macrophages, T-cells, endothelial cells and fibroblasts! -it means when you add it to blood you get a massive surge in granulocytes such as eosinophils, neutrophils, basophils and monocytes! -major driver of the myeloid lineage ! -receptors on the myeloid progenitive cells bind GM-CSF to stimulate cells to further differentiate into various myeloid cells ! EPO:! -erythropoietin ! -produced mainly by the kidney during adult hood and in the liver in perinatal ! -drives the production of erythrocytes ! -most famous user is Lance Armstrong ! -favourite drug of endurance athletes! -quickest and easiest way of enhancing performance by at least 2 fold ! -more red blood cells = more oxygen to tissues ! -high altitude training will mean more erythrocytes are produced by the body ! $

G-CSF:! -Granulocyte colony stimulating factor! -used in radio oblation and autologous bone marrow transplant ! -drives the production of mature neutrophil !

OXYGEN TRANSPORT AND EXCHANGE:! -we need oxygen for oxidative phosphorylation to generate high energy ATP! -muscles are contracting and expanding because they are using high energy phosphate to drive that motion ! -the lung provides vast surface area for efficient exchange of O2 and CO2 through alveolus ! -the membrane of the alveoli is very thin and allows oxygen to diffuse across that membrane ! -alveoli are wrapped in tiny capillaries! -blood comes through the arterial (pulmonary arterial) through the capillary matrix where it picks up oxygen and becomes oxygenated! -colour of blood changes when it becomes oxygenated, typically Venus blood (you see it when you cut yourself) is dark red and pulmonary blood is a very bright red frothy which is under pressure (usually means that they have an arterial injury)! Haemoglobin and oxygen transport:! -molecule responsible for collecting oxygen is haemoglobin ! -haemoglobin has 4 lobes and each lobe has a heme molecule which have 4 mitisol nitrogens which complex the ion in its FE2 which allows the oxygen to bind and dissociate under pressures that are normally found at atmospheric pressure ! -each haemoglobin can carry 4 molecules of oxygen ! -raises the potential to carry oxygen 7 fold compared to if oxygen was diffused in your blood normally ! -oxygen is loaded into haemoglobin which then transports it to the tissue and it then dissociates because the partial pressure of oxygen has reduced significantly down to 20-40! -the haemoglobin then picks of carbon dioxide (by product of oxidative phosphorylation and respiration)! Displacement of oxygen:$ -carbon monoxide because it binds to iron (you can tell because the blood changes colour)! -cyanide binds to iron very tightly and displaces oxygen very readily ! -cyanide is most lethal to cytochrome coxydase ! COMPLEMENT AND INNATE IMMUNITY:$ -complenet proteins know that the bacterial surface is different enough (antigens and such on the surface of the bacteria) that it is recognised ! -three pathways that activate complement, we refer to them as classical activation (antibody), lectin activation (carbohydrate binding molecules) and alternative activation ! -complement C1 recognises antibodies bound to the surface of the bacteria which creates a proteolytic enzyme which then cleaves C4 and C2 which then go on to cleave the major component C3! -A components are released from the complement proteins on activation e.g C5a comes from C5, C4a comes from C4 and C3a comes from C3, these are called anaphylatoxins and the macrophage is sensing the anaphylatoxins being released from the bacteria. Mainly the C5a receptor is telling the macrophage that it needs to move because it is sensing a concentration of C5a! -these proteins bind irreversibly to the surface to form convertase complexes (stuck irreverably, covalent interaction)! -the bacteria cant be recognised by macrophages such as neutrophils until it is covered in these complement proteins which is called opsonisation ! -the later stage of complement go on to form what is called the lytic pore which can insert in some types of bacteria and immediately kill the bacteria !

CLASSICAL ACTIVATION OF COMPLEMENT:!

COAGULATION PATHWAY:! -three pathways ! -intrinsic pathway (Contact with surface)! -common! -extrinsic pathway (tissue damage)! -key element is thrombin which is an enzyme, exists as an inactive enzyme until activated by factor 10! -most of the anticoagulants that we use all interact with thrombin and prevent it from cleaving this fibrinogen molecule to fibrin ! -there are enzymes in the blood which cleave the clot, the main one is plasminogen, this is important in medicine for people who have had a thrombosis who are treated with molecules which activate plasminogen to form plasmin which releases the clot and saves the patient from severe tissue damage !

INATE IMMUNITY DEFENCE AGAINST PATHOGENS ! -immune response is loosely defined in three different areas! -anatomical and physiological! -innate immunity ! -adaptive immunity ! Anatomical and physiological barriers:! -skin, designed to resist the invasion of micro organisms ! -one of the most common skin pathogens is staphylococcus epidermis or another one called staphorious (very common to get from hospital)! -it is only until the anatomic barriers are broken or there is a disfunction in your immune response ! -ciliary clearance ! -low stomach PH (most bacteria don’t inhabit the stomach, only few can)! -lysozyme enzyme in tears and saliva for bacterial surface disruption! Innate immunity ! -your response that doesn’t change with time ! -two main components being cellular and humoral ! -complement falls into the humoral components of innate immunity because it is soluble ! -another form of humoral immunity is the lectin binding proteins that activates compliment, recognising unique carbohydrates found on the surface of bacteria, mannoes being one (typically found on primitive organisms prokaryotes and in higher organisms eukaryotes. Does not terminate glycoproteins it is usually sialic acid ! -one of the reasons we have terminal sialic acid is to be able to determine self cells from our non self cells ! -anti microbial peptide in humoral response, so in the gut, saliva and other parts of the body that have contact with the environment there are these small peptides produced that bind to the surface of bacteria and cause them to lyse ! -myeloid lineage gives rise of all of the white blood cells in the cellular component of innate immunity ! -most common and most important is neutrophil (most abundant)! -macrophages which are an activated form of monocytes is the second most abundant ! -natural killer cells, dendritic cells! INNATE IMMUNITY AND SELF/NON-SELF DISCRIMINATION ! -innate immunity is the way we distinguish self from non self ! -in both innate and adaptive immune response the immune system is said to be tolerant of...