Blood Physiology PDF

Physiology Homeostasis, blood, coagulation and immunology Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio- molecules carry out the chemical or physical functions that exist in a...

Physiology Homeostasis, blood, coagulation and immunology Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio- molecules carry out the chemical or physical functions that exist in a living system. Homeostasis Homeostasis (from Greek hómoios, "similar", and stásis, "standing still") is the property of a system that regulates its internal environment and tends to maintain a stable, relatively constant condition of properties such as temperature or pH. An advantage of homeostatic regulation is that it allows an organism to function effectively in a broad range of environmental conditions. For example, ectotherms tend to become sluggish at low temperatures, whereas a co-located endotherm may be fully active. That thermal stability comes at a price since an automatic regulation system requires additional energy. One reason snakes may eat only once a week is that they use much less energy to maintain homeostasis. Most homeostatic regulation is controlled by the release of hormones into the bloodstream. However, other regulatory processes rely on simple diffusion to maintain a balance. Homeostasis includes regulation of the pH of the blood at 7.365. All animals also regulate their blood glucose, as well as the concentration of their blood. Mammals regulate their blood glucose with insulin and glucagon. The human body maintains glucose levels constant most of the day, even after a 24-hour fast. Even during long periods of fasting, glucose levels are reduced only very slightly. Insulin, secreted by the beta cells of the pancreas, effectively 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology transports glucose to the body's cells by instructing those cells to keep more of the glucose for their own use. If the glucose inside the cells is high, the cells will convert it to the insoluble glycogen to prevent the soluble glucose from interfering with cellular metabolism. Ultimately this lowers blood glucose levels, and insulin helps to prevent hyperglycemia. When insulin is deficient or cells become resistant to it, diabetes occurs. Glucagon, secreted by the alpha cells of the pancreas, encourages cells to break down stored glycogen or convert non-carbohydrate carbon sources to glucose via gluconeogenesis, thus preventing hypoglycemia. The kidneys are used to remove excess water and ions from the blood. These are then expelled as urine. The kidneys perform a vital role in homeostatic regulation in mammals, removing excess water, salt, and urea from the blood. These are the body's main waste products. Sleep timing depends upon a balance between homeostatic sleep propensity, the need for sleep as a function of the amount of time elapsed since the last adequate sleep episode, and circadian rhythms that determine the ideal timing of a correctly structured and restorative sleep episode. Control mechanisms of Homeostasis: All homeostatic control mechanisms have at least three interdependent components for the variable being regulated: The receptor is the sensing component that monitors and responds to changes in the environment. When the receptor senses a stimulus, it sends information to a "control center", the component that sets the range at which a variable is maintained. The control center determines an appropriate response to the stimulus. In most 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology homeostatic mechanisms, the control center is the brain. The control center then sends signals to an effector, which can be muscles, organs or other structures that receive signals from the control center. After receiving the signal, a change occurs to correct the deviation by either enhancing it with positive feedback or depressing it with negative feedback. Positive feedback: Positive feedback is a mechanism by which an output is enhanced, such as protein levels. Positive feedback mechanisms are designed to accelerate or enhance the output created by a stimulus that has already been activated. Unlike negative feedback mechanisms that initiate to maintain or regulate physiological functions within a set and narrow range, the positive feedback mechanisms are designed to push levels out of normal ranges. To achieve this purpose, a series of events initiates a cascading process that builds to increase the effect of the stimulus. This process can be beneficial but is rarely used by the body due to risks of the acceleration's becoming uncontrollable. One positive feedback example event in the body is blood platelet accumulation, which, in turn, causes blood clotting in response to a break or tear in the lining of blood vessels. Another example is the release of oxytocin to intensify the contractions that take place during childbirth. Negative feedback: Negative feedback mechanisms consist of reducing the output or activity of any organ or system back to its normal range of functioning. A good example of this is regulating blood pressure. 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology Blood vessels can sense resistance of blood flow against the walls when blood pressure increases. The blood vessels act as the receptors and they relay this message to the brain. The brain then sends a message to the heart and blood vessels, both of which are the effectors. The heart rate would decrease as the blood vessels increase in diameter (known as vasodilation). This change would cause the blood pressure to fall back to its normal range. The opposite would happen when blood pressure decreases, and would cause vasoconstriction. Another important example is seen when the body is deprived of food. The body would then reset the metabolic set point to a lower than normal value. This would allow the body to continue to function, at a slower rate, even though the body is starving. Therefore, people who deprive themselves of food while trying to lose weight would find it easy to shed weight initially and much harder to lose more after. This is due to the body readjusting itself to a lower metabolic set point to allow the body to survive with its low supply of energy. Exercise can change this effect by increasing the metabolic demand. Another good example of negative feedback mechanism is temperature control. The hypothalamus, which monitors the body temperature, is capable of determining even the slightest variation of normal body temperature (37 degrees Celsius). Response to such variation could be stimulation of glands that produce sweat to reduce the temperature or signaling various muscles to shiver to increase body temperature. Both feedbacks are equally important for the healthy functioning of one's body. Complications can arise if any of the two 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology feedbacks are affected or altered in any way. Homeostatic imbalance: Many diseases are a result of disturbance of homeostasis, a condition known as homeostatic imbalance. As it ages, every organism will lose efficiency in its control systems. The inefficiencies gradually result in an unstable internal environment that increases the risk for illness. In addition, homeostatic imbalance is also responsible for the physical changes associated with aging. Even more serious than illness and other characteristics of aging is death. Heart failure has been seen where nominal negative feedback mechanisms become overwhelmed, and destructive positive feedback mechanisms then take over. Diseases that result from a homeostatic imbalance include diabetes, dehydration, hypoglycemia, hyperglycemia, gout, and any disease caused by a toxin present in the bloodstream. All of these conditions result from the presence of an increased amount of a particular substance. In ideal circumstances, homeostatic control mechanisms should prevent this imbalance from occurring, but, in some people, the mechanisms do not work efficiently enough or the quantity of the substance exceeds the levels at which it can be managed. In these cases, medical intervention is necessary to restore the balance, or permanent damage to the organs may result. Every illness has aspects to it that are a result of lost homeostasis. Just as we live in a constantly changing world, so do the cells and tissues survive in a constantly changing microenvironment. The 'normal' or 'physiologic' state then is achieved by adaptive responses to the ebb and flow of various stimuli 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology permitting the cells and tissues to adapt and to live in harmony within their microenvironment. Thus, homeostasis is preserved. It is only when the stimuli become more severe, or the response of the organism breaks down, that disease results - a generalization as true for the whole organism as it is for the individual cell. ================= Blood Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells. In vertebrates, it is composed of blood cells suspended in a liquid called blood plasma. Plasma, which constitutes 55% of blood fluid, is mostly water (92% by volume), and contains dissipated proteins, glucose, mineral ions, hormones, carbon dioxide (plasma being the main medium for excretory product transportation), and blood cells themselves. Albumin is the main protein in plasma, and it functions to regulate the colloidal osmotic pressure of blood. The blood cells are mainly red blood cells (also called RBCs or erythrocytes), white blood cells(leukocytes) and platelets. The most abundant cells in vertebrate blood are red blood cells. These contain hemoglobin, an iron-containing protein, which facilitates transportation of oxygen by reversibly binding to this respiratory gas and greatly increasing its solubility in blood. In contrast, carbon dioxide is almost entirely transported extracellularly dissolved in 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology plasma as bicarbonate ion. Blood is circulated around the body through blood vessels by the pumping action of the heart. In animals with lungs, arterial blood carries oxygen from inhaled air to the tissues of the body, and venous blood carries carbon dioxide, a waste product of metabolism produced by cells, from the tissues to the lungs to be exhaled. Functions of blood: Blood performs many important functions within the body including: Supply of oxygen to tissues (bound to hemoglobin, which is carried in red cells) Supply of nutrients such as glucose, amino acids, and fatty acids (dissolved in the blood or bound to plasma proteins (e.g., blood lipids)) Removal of waste such as carbon dioxide, urea, and lactic acid Immunological functions, including circulation of white blood cells, and detection of foreign material by antibodies Coagulation, which is one part of the body's self-repair mechanism (blood clotting after an open wound in order to stop bleeding) Messenger functions, including the transport of hormones and the signaling of tissue damage Regulation of body pH Regulation of core body temperature Hydraulic functions 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology Constituents of blood: A) Cells: One microliter of blood contains: 4.7 to 6.1 million (male), 4.2 to 5.4 million (female) Erythrocytes. Red blood cells contain the blood's hemoglobin and distribute oxygen. 4,000–11,000 Leukocytes: White blood cells are part of the body's immune system; they destroy and remove old or aberrant cells and cellular debris, as well as attack infectious agents (pathogens) and foreign substances. The cancer of leukocytes is called leukemia. 200,000–500,000 Thrombocytes: Also called platelets, thrombocytes are responsible for blood clotting (coagulation). They change fibrinogen into fibrin. This fibrin creates a mesh onto which red blood cells collect and clot, which then stops more blood from leaving the body and also helps to prevent bacteria from entering the body. B) Plasma About 55% of blood is blood plasma, a fluid that is the blood's liquid medium, which by itself is straw-yellow in color. The blood plasma volume totals of 2.7–3.0 liters (2.8–3.2 quarts) in an average human. It is essentially an aqueous solution containing 92% water, 8% blood plasma proteins, and trace amounts of other materials. Plasma circulates dissolved nutrients, such as glucose, amino acids, and fatty acids (dissolved in the blood or bound to plasma proteins), and removes waste products, such as carbon dioxide, urea, and lactic 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology acid. C) Other important components include: Serum albumin Blood-clotting factors (to facilitate coagulation) Immunoglobulins (antibodies) lipoprotein particles Various other proteins Various electrolytes (mainly sodium and chloride) The term serum refers to plasma from which the clotting proteins have been removed. Most of the proteins remaining are albumin and immunoglobulins. Blood pH is regulated to stay within the narrow range of 7.35 to 7.45, making it slightly alkaline.Blood that has a pH below 7.35 is too acidic, whereas blood pH above 7.45 is too alkaline. Blood pH, partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), − and HCO3 are carefully regulated by a number of homeostatic mechanisms, which exert their influence principally through the respiratory system and the urinary system in order to control the acid- base balance and respiration. An arterial blood gas will measure these. Plasma also circulates hormones transmitting their messages to various tissues. The list of normal reference ranges for various blood electrolytes is extensive. Blood is circulated around the body through blood vessels by the pumping action of the heart. In humans, blood is pumped from the strong left ventricle of the heart through arteries to peripheral tissues and returns to the right atrium of the heart through veins. It 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology then enters the right ventricle and is pumped through the pulmonary artery to the lungs and returns to the left atrium through the pulmonary veins. Blood then enters the left ventricle to be circulated again. Arterial blood carries oxygen from inhaled air to all of the cells of the body, and venous blood carries carbon dioxide, a waste product of metabolism by cells, to the lungs to be exhaled. However, one exception includes pulmonary arteries, which contain the most deoxygenated blood in the body, while the pulmonary veins contain oxygenated blood. Additional return flow may be generated by the movement of skeletal muscles, which can compress veins and push blood through the valves in veins toward the right atrium. Production and degradation of blood cells: In vertebrates, the various cells of blood are made in the bone marrow in a process called hematopoiesis, which includes erythropoiesis, the production of red blood cells; and myelopoiesis, the production of white blood cells and platelets. During childhood, almost every human bone produces red blood cells; as adults, red blood cell production is limited to the larger bones: the bodies of the vertebrae, the breastbone (sternum), the ribcage, the pelvic bones, and the bones of the upper arms and legs. In addition, during childhood, the thymus gland, found in the mediastinum, is an important source of lymphocytes. The proteinaceous component of blood (including clotting proteins) is produced predominantly by the liver, while hormones are produced by the endocrine glands and the watery fraction is regulated by the hypothalamus and maintained by the kidney. 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology Healthy erythrocytes have a plasma life of about 120 days before they are degraded by the spleen, and the Kupffer cells in the liver. The liver also clears some proteins, lipids, and amino acids. The kidney actively secretes waste products into the urine. Hematological disorders: Anemia oInsufficient red cell mass (anemia) can be the result of bleeding, blood disorders like thalassemia, or nutritional deficiencies; and may require blood transfusion. Several countries have blood banks to fill the demand for transfusable blood. A person receiving a blood transfusion must have a blood type compatible with that of the donor. oSickle-cell anemia Disorders of cell proliferation oLeukemia is a group of cancers of the blood-forming tissues. oNon-cancerous overproduction of red cells (polycythemia vera) or platelets (essential thrombocytosis) may be premalignant. oMyelodysplastic syndromes involve ineffective production of one or more cell lines. Disorders of coagulation oHemophilia is a genetic illness that causes dysfunction in one of the blood's clotting mechanisms. This can allow otherwise inconsequential wounds to be life-threatening, 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology but more commonly results in hemarthrosis, or bleeding into joint spaces, which can be crippling. oIneffective or insufficient platelets can also result in coagulopathy (bleeding disorders). oHypercoagulable state (thrombophilia) results from defects in regulation of platelet or clotting factor function, and can cause thrombosis. Infectious disorders of blood oBlood is an important vector of infection. HIV, the virus that causes AIDS, is transmitted through contact with blood, semen or other body secretions of an infected person. Hepatitis B and C are transmitted primarily through blood contact. Owing to blood-borne infections, bloodstained objects are treated as a biohazard. oBacterial infection of the blood is bacteremia or sepsis. Viral Infection is viremia. Malaria and trypanosomiasis are blood-borne parasitic infections. Coagulation Coagulation is the process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or obstructive clotting (thrombosis). Coagulation is highly conserved throughout biology; in all 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. The system in humans has been the most extensively researched and is therefore the best understood. Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium lining the vessel. Exposure of the blood to proteins such as tissue factor initiates changes to blood platelets and the plasma protein fibrinogen, a clotting factor. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: Proteins in the blood plasma, called coagulation factors or clotting factors, respond in a complex cascade to form fibrin strands, which strengthen the platelet plug. Platelet activation: When endothelium is damaged, the normally isolated, underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific glycoprotein Ia/IIa surface receptors. This adhesion is strengthened further by von Willebrand factor (vWF), which is released from the endothelium and from platelets; vWF forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils. These adhesions also activate the platelets. Activated platelets release the contents of stored granules into the blood plasma. The granules include ADP, serotonin, platelet- activating factor (PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2), which, in turn, activate additional platelets. The granules' contents activate a Gq-linked protein receptor cascade, resulting in 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology increased calcium concentration in the platelets' cytosol. The calcium activates protein kinase C, which, in turn, activates phospholipase A2 (PLA2). PLA2 then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen. The activated platelets change shape from spherical to stellate, and the fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets (completing primary hemostasis). The coagulation cascade: This is the classical blood coagulation pathway. The coagulation cascade of secondary hemostasis has two pathways which lead to fibrin formation. These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic pathway). It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form. The coagulation factors are generally serine proteases (enzymes). There are some exceptions. For example, FVIII and FV are glycoproteins, and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific serine residues. 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology The coagulation factors circulate as inactive zymogens. The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin. Coagulation Cascade: This takes place via extrinsic or intrinsic pathway, followed by common pathway (see the figure). Fibrinolysis: Eventually, blood clots are reorganised and resorbed by a process termed fibrinolysis. The main enzyme responsible for this process (plasmin) is regulated by various activators and inhibitors. Pathological thrombosis: Venous thromboembolism takes place in case of: 1. Vascular injury 2. Venous stasis 3. Pathological hypercoagulable state Risk factors of venous thromboembolism include surgery, trauma, immobility, malignancy, aging, pregnancy, obesity, smoking, varicose veins and inherited thrombophilia like antithrombin deficiency. 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology Coagulation Cascade ================ Immunology The immune system is a system of biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. Pathogens can rapidly evolve and adapt to avoid detection and neutralization by the immune system. As a result, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Components of the immune system: A-Innate immunity: This includes non-specific immunological mechanisms present from 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology time of birth. This includes surface barriers and cellular barriers. 1-Surface barriers: Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection. However, as organisms cannot be completely sealed against their environments, other systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms. Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β- defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens. Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH or available 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology iron. This reduces the probability that pathogens will reach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can lead to an "overgrowth" of fungi and cause conditions such as a vaginal candidiasis (a yeast infection). There is good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in unpasteurized yogurt, helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases, urinary tract infection and post-surgical infections. 2-Cellular barriers: Upon injury or microbial infection, there is a cascade of actions. a- Inflammation b-Complement activation c-Inflammatory infiltration Inflammation: Inflammation is one of the first responses of the immune system to infection. The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens. Complement activation: It is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates. In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane. 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology Inflammatory infiltration: Leukocytes (white blood cells) act like independent, single- celled organisms and are the second arm of the innate immune system. The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. Innate cells are also important mediators in the activation of the adaptive immune system. Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals. Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes. During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as interleukin 1. Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system. Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigen to T cells, one of the key cell types of the adaptive immune system. Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma. Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology been infected by viruses. B- Adaptive immune system: The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. Lymphocytes The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology MHC molecules (in all body cells), while helper T cells only recognize antigens coupled to Class II MHC molecules (in immune cells). These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture. Killer T cells Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. As with B cells, each type of T cell recognises a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Helper T cells Function of T helper cells: Antigen-presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their expression of CD4 co- receptor (CD4+). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells. Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology makes to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks. B lymphocytes and antibodies A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells. Immunological memory: When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory. Passive memory: Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum. The time-course of an immune response begins with the initial pathogen encounter, (or initial vaccination) and leads to the formation and maintenance of active immunological memory. Active memory and immunization: Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen in 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed. Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular components of micro- organisms, including harmless toxin components. Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity. Disorders of human immunity: The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities. Immunodeficiencies Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence. In developed countries, obesity, alcoholism, and drug use are common causes of 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology poor immune function. However, malnutrition is the most common cause of immunodeficiency in developing countries. Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection. Immunodeficiencies can also be inherited or 'acquired'. Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency. Autoimmunity Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides. One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity. Hypersensitivity Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the 14 Dr. Basim Anwar Shehata Messiha, Ph. D. Physiology Homeostasis, blood, coagulation and immunology hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen. Type II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are mediated by T cells, monocytes, and macrophages. ==================== 14 Dr. Basim Anwar Shehata Messiha, Ph. D.