Blood Physiology and Immunity
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This document summarizes key concepts about blood physiology. It describes the components of blood, including red blood cells and hemoglobin, which transports oxygen. It discusses blood groups and reasons for transfusion reactions. It also outlines the process of hemostasis that restricts blood loss from damaged vessels, and the consequences of thrombosis. Additionally, it covers immunity and defense against microbes, the roles of hematopoietic growth factors and cytokines, and the mechanisms of innate, acquired, humoral, and cellular immunity.
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Blood Physiology and Immunity
- 1. Blood Physiology Demuel Dee L. Berto
- 2. • Describe the components of blood and their origins, and the role of hemoglobin in transporting oxygen in red blood cells. • Understand the molecular basis of blood groups and the reasons for transfusion reactions. • Delineate the process of hemostasis that restricts blood loss when vessels are damaged, and the adverse consequences of intravascular thrombosis.
- 3. • Understand the significance of immunity, particularly with respect to defending the body against microbial invaders. • Identify the functions of hematopoietic growth factors, cytokines, and chemokines. • Delineate the roles and mechanisms of innate, acquired, humoral, and cellular immunity.
- 4. References • Medical Physiology by Guyton 12th Edition • Review of Medical Physiology by Ganong 23rd Edition • Basic Pathology by Kumar 8th Edition • Clinical Physiology by Ashis Banerjee , 2005
- 5. General Functions • Delivery of substances needed for cellular metabolism in the tissues • Defense against invading microorganisms and injury • Acid-base balance
- 12. Transport Hemoglobin Transport CO2 Acid Base Buffer Erythrocytes Functions
- 14. Shape and Size of Red Blood Cells Concentration of Red Blood Cells in the Blood Quantity of Hemoglobin in the Cells
- 20. Maxwell et al: Renal erythropoietin- producing cells
- 23. Vitamin B12 MATURATION OF RED BLOOD CELLS Folic acid
- 45. THE RH GROUP
- 51. HEMOSTASIS
- 61. Immunity
- 62. Inflammation Immuno- competence Innate Acquired Immunity Immunity
- 63. INNATE IMMUNITY
- 72. Nucleated Cells
- 82. Gregersen and Behrens Nature Reviews Genetics 7, 917–928 (December 2006) | doi:10.1038/nrg1944
Editor's Notes
- http://www.pc.maricopa.edu/Biology/pfinkenstadt/BIO202/202LessonBuilder/Hematology/index.htmlI. Composition of Blood: 1. Formed elements (45%) + plasma (55%) 2. Approximately. 90% water and 10% solutes 3. Normal blood volume = 5.5L (adult)Blood consists of a protein-rich fluid known as plasma, in which are suspended cellular elements: white blood cells,red blood cells, and platelets. The normal total circulating blood volume is about 8% of the body weight (5600 mL in a70-kg man). About 55% of this volume is plasma.
- In the adult, red blood cells, many white blood cells, and platelets are formed in the bone marrow. The bone marrow is actually one of the largest organs in the body, approaching the size and weight of the liver. It isalso one of the most active.Normally, 75% of the cells in the marrow belong to the white blood cell-producing myeloid series and only 25% are maturing red cells, even though there are over 500 times as many red cells in the circulation as there are white cells. This difference in the marrow reflects the fact that the average life span of white cells is short, whereas that of red cells is long.The average lifespan of (non-activated human) neutrophils in the circulation is about 5.4 days.[12] Upon activation, they marginate (position themselves adjacent to the blood vessel endothelium), and undergo selectin-dependent capture followed by integrin-dependent adhesion in most cases, after which they migrate into tissues, where they survive for 1–2 days.[
- Right on cue, blood and blood vessel formation begin at the end of the second week in both the embryo and developing placenta. Heart tubes (the precursor to the heart) form and start pumping within seven days. The cardiovascular system is the first organ system to become functional--an important factor, since every cell depends on blood to survive. The embryo makes RBCs first, his most necessary blood component. These distinctive cells are made by the inner lining of blood vessels in a temporary structure outside the embryo called the yolk sac, which in people is actually a "blood forming sac" that never contains yolk. This misguided name was given because it was believed to have "arisen" in a pre-human animal ancestor and because it initially contains a yellow substance.The progenitor RBCs eventually migrate from the yolk sac to the liver and spleen, which become the lead cell-forming sites by the mid-second month of gestation. By the fifth month, bone marrow is sufficiently formed to take over for nonstop lifelong production. Interestingly, even in adulthood if the body is stressed by a shortage of RBCs, the spleen and liver can resume production as emergency backup sites. http://www.icr.org/article/4823/
- Figure 1. Ontogeny of hematopoiesis in humans. In the early weeks of embryonic life, primitive, nucleated red blood cells are produced in the yolk sac. During the middle trimester of gestation, the liver is the main organ for production of red blood cells, but reasonable numbers are also produced in the spleen and lymph nodes.Then, during the last month or so of gestation and after birth, red blood cells are produced exclusively in the bone marrow.
- Active cellular marrow is called red marrow; inactive marrow that is infiltrated with fat is called yellow marrow.Red marrow is found mainly in the flat bones, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and in the cancellous ("spongy") material at the epiphyseal ends of long bones such as the femur and humerus. Yellow marrow is found in the medullary cavity, the hollow interior of the middle portion of long bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow to increase blood cell production.
- The bone marrow of essentially all bones produces red blood cells until a person is 5 years old. The marrow of the long bones,except for the proximal portions of the humeri and tibiae, becomes quite fatty and produces no more red blood cells after about age 20 years. Beyond this age, most red cells continue to be produced in the marrow of the membranous bones, such as the vertebrae, sternum, ribs, and ilia. Even in these bones, the marrow becomes less productive as age increases.In children, blood cells are actively produced in the marrow cavities of all the bones. By age 20, the marrow in the cavities of the long bones, except for the upper humerus and femur, has become inactive (Figure 32–2).
- The major function of red blood cells:1.Transport hemoglobin, which in turn carries oxygen from the lungs to the tissues. Insome lower animals, hemoglobin circulates as free protein in the plasma, notenclosed in red blood cells. When it is free in the plasma of the human being,about 3 per cent of it leaks through the capillary membrane into the tissuespaces or through the glomerular membrane of the kidney into the glomerularfiltrate each time the blood passes through the capillaries. Therefore, for hemoglobinto remain in the human blood stream, it must exist inside red blood cells.2. For instance, they contain a large quantity of carbonic anhydrase, an enzymethat catalyzes the reversible reaction between carbon dioxide (CO2) and waterto form carbonic acid (H2CO3), increasing the rate of this reaction several thousand fold.The rapidity of this reaction makes it possible for the water of theblood to transport enormous quantities of CO2 in the form of bicarbonate ion(HCO3 –) from the tissues to the lungs, where it is reconverted to CO2 andexpelled into the atmosphere as a body waste product. 3. The hemoglobin in the cells is an excellent acid-base buffer (as is true of most proteins), so that the red blood cells are responsible for most of the acid-base buffering power of whole blood.
- The Haldane Effect: The Haldane effect states that deoxygenated Hb has a greater affinity for CO2 than does oxyHb. Thus, O2 release at the tissues facilitates CO2 pickup while O2 pickup at the lungs facilitates CO2 release. Likewise, CO2 pickup at the tissues facilitates O2 release while CO2 release at the lungs promotes O2 pickup The Bohr Effect: The Bohr effect states that deoxygenated Hb has a greater affinity for H+ than does oxyhemoglobin. Thus, O2 release at the tissues facilitates H+ pickup while O2 pickup at the lungs facilitates H+ release. Likewise, H+ pickup at the tissues facilitates O2 release while H+ release at the lungs promotes O2 pickup
- Shape and Size of Red Blood Cells. biconcave discs having a mean diameter of about 7.8 micrometers and thickness of 2.5 micrometers at the thickest point and 1 micrometer or lessin the center. 3. The average volume of the red blood cell is 90 to 95 cubic micrometers.The shapes of red blood cells can change remarkably as the cells squeeze through capillaries. Actually, the red blood cell is a “bag” that can be deformed into almost any shape. Furthermore, because the normal cell has a great excess of cell membrane for the quantity of material inside, deformation does not stretch the membrane greatly and, consequently, does not rupture the cell, aswould be the case with many other cells.Concentration of Red Blood Cells in the Blood. In normal men, the average number of red blood cells per cubic millimeter is 5,200,000 (±300,000); in normal women, it is 4,700,000 (±300,000).Quantity of Hemoglobin in the Cells. Red blood cells have the ability to concentrate hemoglobin in the cell fluid up to about 34 grams in each 100 milliliters of cells. The concentration does not rise above this value, because this is the metabolic limit of the cell’s hemoglobin- forming mechanism.Whole blood of men contains an average of 15 grams of hemoglobin per 100 milliliters of cells; for women, it contains an average of 14 grams per 100 milliliters.Each gram of pure hemoglobin is capable of combining with 1.34 milliliters of oxygen.A maximum of about 20 milliliters of oxygen can be carried in combination with hemoglobin in each 100 milliliters of blood. In a normal woman, 19 milliliters of oxygen can be carried.
- THE red cell, as it continuously circulates, must be able to undergo extensive passive deformation and to resist fragmentation. These two essential qualities require a highly deformable yet remarkably stable membrane.Geometry of erythrocytes; the biconcave-discoid shape provides an extra surface area for the cell, enabling shape change without increasing surface area. This type of shape change requires significantly smaller forces than those required for shape change with surface area expansion.Cytolasmic viscosity; reflecting the cytoplasmichemoglobin concentration of erythrocytes. Visco-elastic properties of erythrocyte membrane, mainly determined by the special membrane skeletal network of erythrocytes.The red cell membrane has been well characterized biochemically and is composed of a lipid bilayer, integral proteins, and a skeletal protein network of spectrin, actin, ankyrin, tropomyosin, and proteins 4.1 and 4.9.
- Hereditary spherocytosis is a relatively common disorder (as far as hematologic disorders go): 1 in 5,000 people of Northern European descent have it (the incidence is lower in other racial groups). Though it is a hereditary disorder, the age of onset of clinical symptoms – and their severity – is variable. The clinical symptoms are usually described as a triad of mild anemia, intermittent jaundice, and splenomegaly. Most patients are able to make enough new red cells to replace the ones that are being prematurely destroyed – so most of the time, there is a mild anemia (or no anemia at all). The basic defect in hereditary spherocytosis involves spectrin, a component of the membrane cytoskeleton. Either there’s not enough spectrin around, or it doesn’t work properly, leading to membrane instability, and loss of bits of membrane (which means that the cells round up, making spherocytes, which are the darker, smaller red cells with no central pallor in the image above). The big problem in this disorder is that the macrophages in the spleen see these abnormal cells and eat them up! It’s not so much the spherocytes themselves (though they are more fragile than normal biconcave-disc-shaped red cells) – it’s the removal of red cells by the spleen that is the main cause of the anemia.Four abnormalities in red cell membrane proteins have been identified and include (1) spectrin deficiency alone, (2) combined spectrin and ankyrin deficiency, (3) band 3 deficiency, and (4) protein 4.2 defects. Spectrin deficiency is the most common defect.Hereditary elliptocytosis is a genetic disorder in which there are abnormalities of the red cell cytoskeleton. Most patients have abnormalities in spectrin, but a few have abnormalities in protein 4.1 (which attaches spectrin to actin) or glycophorin C (which attaches protein 4.1 to the cell membrane). Normal red cells are able to temporarily deform themselves from a biconcave disk into an elliptical shape as they squeeze through tiny capillaries. The red cells in hereditary elliptocytosis can do this too, but afterwards, their cytoskeletal defects prevent them from reverting to normal biconcave disk form, and they remain stuck in the elliptical shape.
- Hematopoietic stem cells (HSCs) are bone marrow cells that are capable of producing all types of blood cells.The blood cells begin their lives in the bone marrow from a single type of cell called the pluripotential hematopoietic stem cell, from which all the cells of the circulating blood are eventually derived.A small portion of them remains exactly like the original pluripotential cells and is retained in the bone marrow to maintain a supply of these, although their numbers diminish with age.The intermediate stage cells are very much like the pluripotential stem cells, even though they have already become committed to a particular line of cells and are called committed stem cells.Growth and reproduction of the different stem cells are controlled by multiple proteins called growth inducers. Four major growth inducers have been described, each having different characteristics. One of these, interleukin-3, promotes growth and reproduction of virtually all the different types of committed stem cells, whereas the others induce growth of only specific types of cells.The growth inducers promote growth but not differentiation of the cells. This is the function of another set of proteins called differentiation inducers. Each of these causes one type of committed stem cell to differentiate one or more steps toward a final adult blood cell. They differentiate into one or another type of committed stem cells (progenitor cells). These in turn form the various differentiated types of blood cells. There are separate pools of progenitor cells for megakaryocytes, lymphocytes, erythrocytes, eosinophils, and basophils; neutrophils and monocytes arise from a common precursor.The bone marrow stem cells are also the source of osteoclasts (see Chapter 23), Kupffer cells (see Chapter 29), mastcells, dendritic cells, and Langerhans cells. The HSCs are few in number but are capable of completely replacing the bone marrow when injected into a host whose own bone marrow has been completely destroyed.The HSCs are derived from uncommitted, totipotent stem cells that can be stimulated to form any cell in the body.Adults have a few of these, but they are more readily obtained from the blastocysts of embryos.Development of various formed elements of the blood from bone marrow cells. Cells below the horizontal line arefound in normal peripheral blood. The principal sites of action of erythropoietin (erythro) and the various colonystimulatingfactors (CSF) that stimulate the differentiation of the components are indicated. G, granulocyte; M,macrophage; IL, interleukin; thrombo, thrombopoietin; SCF, stem cell factor.
- Stages of Differentiation of Red Blood CellsThe first cell that can be identified as belonging to the red blood cell series is the proerythroblast, shown at the starting point stimulation, large numbers of these cells are formed from the CFU-E stem cells.The first-generation cells are called basophil erythroblasts because they stain with basic dyes; the cell at this time has accumulated very little hemoglobin.The cells become filled with hemoglobin to a concentration of about 34 per cent, the nucleus condenses to a small size, and its final remnant is absorbed or extruded from the cell. At the same time, the endoplasmic reticulum is also reabsorbed. The cell at this stage is called a reticulocytebecause it still contains a small amount of basophilic material, consisting of remnants of the Golgi apparatus, mitochondria, and a few other cytoplasmic organelles. During this reticulocyte stage, the cells pass from the bone marrow into the blood capillaries by diapedesis (squeezing through the pores of the capillary membrane).The remaining basophilic material in the reticulocyte normally disappears within 1 to 2 days, and the cell is then a mature erythrocyte. Because of the short life of the reticulocytes, their concentration among all the red cells of the blood is normally slightly less than 1 per cent.
- Regulation of Red Blood Cell Production—Role of ErythropoietinTissue Oxygenation Is the Most Essential Regulator of Red Blood Cell Production.Erythropoietin Stimulates Red Cell Production, and Its Formation Increases in Response to Hypoxia.The principal stimulus for red blood cell production in low oxygen states is a circulating hormone called erythropoietin, a glycoprotein with a molecular weight of about 34,000Erythropoietin (Epo) is a glycoprotein hormone which stimulates erythropoiesis when oxygen delivery is reduced by anemia or hypoxemia [reviewed in 1, 2]. In most species the liver is the major site of production in fetal life [3]. The kidney is the dominant organ of production in adult life [4], and Epo deficiency is the most important component of the anemia which complicates chronic renal disease [5].Role of the Kidneys in Formation of ErythropoietinAbout 90 per cent of all erythropoietin is formed in the kidneys; the remainder is formed mainly in the liver.It is not known exactly where in the kidneys the erythropoietin is formed.One likely possibility is that the renal tubular epithelial cells secrete the erythropoietin, because anemic blood is unable to deliver enough oxygen from the peritubular capillaries to the highly oxygen-consuming tubular cells, thus stimulating erythropoietin production. Both norepinephrine and epinephrine and several of the prostaglandins stimulate erythropoietin production.Effect of Erythropoietin in ErythrogenesisWhen an animal or a person is placed in an atmosphere of low oxygen, erythropoietin begins to be formed within minutes to hours, and it reaches maximum production within 24 hours. Yet almost no new red blood cells appear in the circulating blood until about 5 days later. From this fact, as well as other studies, it has been determined that the important effect of erythropoietinis to stimulate the production of proerythroblasts from hematopoietic stem cells in the bone marrow. In addition, once the proerythroblasts are formed, the erythropoietin causes these cells to pass more rapidly through the different erythroblastic stages than they normally do, further speeding up the production of new red blood cells.
- In transgenic mice bearing Epo-TAg at homologous and heterologous insertion sites, renal expression was restricted to a population of cells in the interstitium of the cortex and outer medulla. Immunohistochemical characterization by light and electron microscopy shows that these are the fibroblast-like type I interstitial cells.Identification of the renal erythropoietin-producing cells using transgenic micePatrick H Maxwell, Mark K Osmond, Christopher W Pugh, Andrew Heryet, Lynn G Nicholls, Chorh C Tan, Brendan G Doe, David J P Ferguson, Martin H Johnson and Peter J Ratcliffehttp://www.nature.com/ki/journal/v44/n5/abs/ki1993362a.html
- Fig. 8. Immunoelectron microscopy for SV4O T Ag. A. Low power electron micrograph from the deep cortex showing a group of interstitial fibroblast-like cells (F) and a round monocyte-like cell (R) surrounded by proximal tubules (P) and capillaries (Ca). Bar is 5 m. B. Enlargement of the enclosed area in A showing numerous gold particles over the euchromatin of the nucleus (arrowheads) of the fibroblast-like cells (F). Note the absence of label over the endothelial cell (En) nucleus. Immunostained for SV4O T Ag. Bar is 0.5 m,
- When both kidneys are removed from a person or when the kidneys are destroyed by renal disease, the person invariably becomes very anemic because the 10 per cent of the normal erythropoietin formed in other tissues (mainly in the liver) is sufficient to cause only one third to one half the red blood cell formation needed by the body.
- Requirementfor Vitamin B12 (Cyanocobalamin) andFolic AcidThe vitamin folate (aka folic acid) affects the anemia symptoms of B12 deficiency. Folate is needed to turn uracil into thymidine, an essential building block of DNA (4). DNA is needed for new red blood cell production and division. B12 is involved in this process because in creating methylcobalamin (used in the HCY to methionine reaction), B12 produces a form of folate needed to make DNA. If there is no B12 available, this form of folate can become depleted (known as the methyl-folate trap) and DNA production slows (5). See Methionine-Homocysteine-Folate-B12 Cycle for an illustration of this pathwayEspecially important for final maturation of the red blood cells are two vitamins, vitamin B12 and folic acid.Both of these are essential for the synthesis of DNA, because each in a different way is required for the formation of thymidinetriphosphate, one of the essential building blocks of DNA. Therefore, lack of either vitamin B12 or folic acid causes abnormal and diminished DNA and, consequently, failure of nuclear maturation and cell division.CyanocobalaminCannot be produced in our body, produced microbially (bacteria): generated in the colon but unavailable for absorption; Most absorption occurs in the ileumDietary Sources: liver, meat, fish, meat products, eggParticipates in many biochemical reactionsPorphyrin like ring structure with Cobalt atom in center attached to a nucleotideDifferent organic compounds are attached to the Cobalt atom forming CobalamineCobalamines like Hydroxycobalamine and Cyanocobalamine are present in meatActive forms of Cobalamine are Methoxycobalamine and Deoxy-adenosilCobalamineAbsorptionEnteral absorption requires the so-called “intrinsic factor”Vit-B12 in food dissociates in the duodenum or jejunum and combines with the intrinsic factor (a glycoprotein) derived from the parietal cells of the stomach. (B12 is called the extrinsic factor).This complex is absorbed from the terminal parts of the ileum.DistributionBinds to Transcobalamine-II (a glycoprotein) for transport.Excess Vit-B12 is deposited in the liver.ExcretionSignificant amount excreted through the urine only when very large amounts are given parenterally, overcoming the binding capacity of transcobalamine.Failure of Maturation Caused by Deficiency of Folic Acid(Pteroylglutamic Acid).Folic acid is a normal constituent of green vegetables, some fruits, and meats (especially liver). However, it is easily destroyed during cooking. Also, people with gastrointestinal absorption abnormalities, such as the frequently occurring small intestinaldisease called sprue, often have serious difficulty absorbing both folic acid and vitamin B12. Therefore, in many instances of maturation failure, the cause is deficiency of intestinal absorption of both folic acid and vitamin B12.
- B12 from the Gastrointestinal Tract—Pernicious Anemia. A common cause of red blood cell maturation failure is failure to absorb vitamin B12 from the gastrointestinal tract. This often occurs in the disease pernicious anemia, in which the basic abnormality is an atrophic gastric mucosa that fails to produce normal gastric secretions. The parietal cells of the gastric glandssecrete a glycoprotein called intrinsic factor, which combines with vitamin B12 in food and makes the B12 available for absorption by the gut. It does this in the following way: (1) Intrinsic factor binds tightly with the vitamin B12. In this bound state, the B12 is protected from digestion by the gastrointestinal secretions. (2) Still in the bound state, intrinsic factor binds to specific receptor sites on the brush border membranes of the mucosal cells in the ileum. (3) Then, vitamin B12 is transported into the blood during the next few hours by the process of pinocytosis, carrying intrinsic factor and the vitamin together through the membrane. Lack of intrinsic factor, therefore, causes diminished availability of vitamin B12 because of faulty absorption of the vitamin.Once vitamin B12 has been absorbed from the gastrointestinal tract, it is first stored in large quantities in the liver, then released slowly as needed by the bone marrow. The minimum amount of vitamin B12 required each day to maintain normal red cell maturation is only 1 to 3 micrograms, and the normal storage in the liver and other body tissues is about 1000 times this amount. Therefore, 3 to 4 years of defective B12 absorption are usually required to cause maturation failure anemia.
- 2 essential enzymatic reactions in humans require Vitamin-B12:Methylcobalamine serves as an intermediate in the transfer of a methyl group from N5-Methyltetrahydrofolate to Methionin.Result of B12 deficiency: Depletion of tetrahydrofolate and deficiency of folate cofactor which is necessary for several biochemical reactions, e.g. DNA synthesis. (Go back to Figure 2); this can be counteracted by increasing the amount of folate intake.Isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methymalonyl-CoAmutase. (NEURO problems)In Vit-B12 deficiency, this conversion cannot take place and the substrate methylmalonyl-CoA accumulates leading to neurological manifestations, e.g. paresthesia, weakness in the peripheral nerves which progresses to spasticity, ataxia and other CNS disorders.Administration of folic acid in the setting of Vit-B12 deficiency will not prevent neurological manifestations but it can largely correct the anemia caused by Vit-B12 deficiency (folic acid dihydrofolate tetrahydrofolate).In Vit-B12 deficiency, this conversion cannot take place and the substrate methylmalonyl-CoA accumulates leading to neurological manifestations, e.g. paresthesia, weakness in the peripheral nerves which progresses to spasticity, ataxia and other CNS disorders.Administration of folic acid in the setting of Vit-B12 deficiency will not prevent neurological manifestations but it can largely correct the anemia caused by Vit-B12 deficiency (folic acid dihydrofolate tetrahydrofolate).Scientists believe, for various reasons, that RNA came first, and that there was an "RNA world" before DNA evolved. If this idea is correct, uracil was a component of nucleic acids before thymine. When DNA evolved, thymine may have proved a preferable material for storing genetic information because of its much greater stability; RNA breaks down relatively quickly, but DNA is stabilized by its double-stranded form. RNA is easily hydrolised than DNA. It is interesting to note that in our own bodies we can synthesize RNA from simpler compounds, but to make DNA we first build RNA nucleotides, then convert them. We remove one oxygen atom from the ribose component of the nucleotide, to form deoxyribose. Then, if the base is uracil, we add a methyl group to it to form thymine. But this leaves the question: what advantage does thymine have over uracil in DNA? One suggestion is this: cytosine (C) occasionally converts into uracil (U) by deamination. If this U is not removed, at the next replication it will act as a template for an adenine (A) on the new strand, and there will have been a mutation from G to A. Having thymine (T) as the regular base in DNA makes it easy for a cell to spot a deamination, because U should not be there at all. The cell then removes the U with a DNA repair enzyme (e.g. uracilglycosylase).Read more: http://wiki.answers.com/Q/Why_does_uracil_replace_thymine_in_RNA#ixzz22DS7AP8A
- The red, oxygen-carrying pigment in the red blood cells of vertebrates is hemoglobin, a protein with a molecularweight of 64,450. Hemoglobin is a globular molecule made up of four subunits (Figure 32–6). Each subunit contains aheme moiety conjugated to a polypeptide. Heme is an iron-containing porphyrin derivative (Figure 32–7). Thepolypeptides are referred to collectively as the globin portion of the hemoglobin molecule. There are two pairs ofpolypeptides in each hemoglobin molecule. In normal adult human hemoglobin(hemoglobin A), the twopolypeptides are called chains, each of which contains 141 amino acid residues, and chains, each of whichcontains 146 amino acid residues. Thus, hemoglobin A is designated 2 2. Not all the hemoglobin in the blood ofnormal adults is hemoglobin A. About 2.5% of the hemoglobin is hemoglobin A2, in which chains are replaced bychains ( 2 2). The chains also contain 146 amino acid residues, but 10 individual residues differ from those in thechains.There are small amounts of hemoglobin A derivatives closely associated with hemoglobin A that represent glycatedhemoglobins. One of these, hemoglobin A1c (HbA1c), has a glucose attached to the terminal valine in each chainand is of special interest because it increases in the blood of patients with poorly controlled diabetes mellitus (seeChapter 21).
- Formation of HemoglobinSynthesis of hemoglobin begins in the proerythroblastsand continues even into the reticulocyte stage ofthe red blood cells. Therefore, when reticulocytes leavethe bone marrow and pass into the blood stream, theycontinue to form minute quantities of hemoglobin foranother day or so until they become mature erythrocytes.Figure 32–5 shows the basic chemical steps in theformation of hemoglobin. First, succinyl-CoA, formedin the Krebs metabolic cycle (as explained in Chapter67), binds with glycine to form a pyrrole molecule. Inturn, four pyrroles combine to form protoporphyrinIX, which then combines with iron to form the hememolecule. Finally, each heme molecule combines witha long polypeptide chain, a globin synthesized byribosomes, forming a subunit of hemoglobin called ahemoglobin chain (Figure 32–6). Each chain has amolecular weight of about 16,000; four of these in turnbind together loosely to form the whole hemoglobinmolecule.
- As mentioned above, hemoglobin exists in two distinct states: the T-state and the R-state. The T-state of hemoglobin is the more "Tense" of the two; this is the deoxy form of hemoglobin (meaning that it lacks an oxygen species) and is also known as "deoxyhemoglobin. The unliganded (deoxy) form is called the "T" (for "tense") state because it contains extra stabilizing interactions between the subunitsThe R-state of hemoglobin is more "Relaxed" and is the fully oxygenated form; it is also known as"oxyhemoglobin."In the high-affinity R-state conformation the interactions which oppose oxygen binding and stabilize the tetramer are somewhat weaker or "relaxed".
- Advanced glycation end products (AGEs)Advanced glycation end products (AGEs) are modifications of proteins or lipids that become nonenzymaticallyglycated and oxidized after contact with aldose sugars. In other words, they are the result of a chain of chemical reactions which follow an initial glycation reaction. The intermediate products are known as Schiff base, Amadori, and Maillard products, after the researchers who first described them. Initially, glycation involves covalent reactions between free amino groups of amino acids, such as lysine, arginine, or protein terminal amino acids and sugars (glucose, fructose, ribose, etc), to create, first, the Schiff base and then Amadori products, of which the best known are HbA1c (Figure 1) and fructosamine (fructoselysine). Additional reactions occur successively.Accumulation of AGEs in the ECM occurs on proteins with a slow turnover rate, with the formation of cross-links that can trap other local macromolecules. In this way, AGEs alter the properties of the large matrix proteins collagen, vitronectin, and laminin. AGE cross-linking on type I collagen and elastin causes an increase in the area of ECM, resulting in increased stiffness of the vasculature. Glycation results in increased synthesis of type III collagen, type V collagen, type VI collagen, laminin, and fibronectin in the ECM, most likely via upregulation of transforming growth factor-â pathways. Formation of AGEs on laminin results in reduced binding to type IV collagen, reduced polymer elongation, and lower binding of heparansulfateproteoglycan. Glycation of laminin and type I and type IV collagens, key molecules in the basement membrane, causes inhibited adhesion to endothelial cells for both matrix glycoproteins. In addition, it has been suggested that AGE formation leads to a reduction in the binding of collagen and heparan to the adhesive matrix molecule vitronectin. AGE-induced alterations of vitronectin and laminin may explain the reduction in binding of heparansulfateproteoglycan, a stimulant of other matrix molecules in the vessel wall, to the diabetic basement membrane. As for the role of lipids, glycated low-density lipoprotein (LDL) reduces nitric oxide (NO) production and suppresses uptake and clearance of LDL through its receptor on endothelial cells.It must also be kept in mind that AGEs can be absorbed through diet.8 In this regard, foods high in protein and fat, such as meat, cheese, and egg yolk, are rich in AGEs, whereas those high in carbohydrates have the lowest amount of AGEs. In addition, increased cooking temperatures, through broiling and frying, and increased cooking times lead to an increased amount of AGEs. A diet heavy in AGEs results in proportional elevations in serum AGE levels and increased cross-linking in patients with diabetes, whereas, conversely, dietary AGE restriction causes a marked reduction in serum AGEs in healthy subjects.9-11
- RAGE is an approximately 45-kDa protein. It has an extracellular component, consisting of two Ctype (constant) domains preceded by one V-type (variable) immunoglobulin-like domain (Figure 3). RAGE has a single transmembrane domain followed by a cytosolic tail. The V domain in the N-terminus is important in ligand binding, and the cytosolic tail is critical for RAGE-induced intracellular signaling. RAGE is expressed in many tissues and is most abundant in the heart, lung, skeletal muscle, and vessel wall. In addition, it is present in monocytes/macrophages and lymphocytes. In vessels, it is located in the endothelium and in smooth muscle cells. Physiologically, the receptor might play a role in developmental processes, at least as shown in a few experimental models.The most important pathological consequence of RAGE interaction with its ligands is the activation of several intracellular pathways, leading to the induction of oxidative stress and a broad spectrum of signaling mechanismsThe interactions lead to prolonged inflammation, mainly as a result of the RAGE-dependent expression of proinflammatory cytokines and chemokines. In the vasculature, the first pathological consequence of RAGE interaction with its ligands is the induction of increased intracellular reactive oxygen species (ROS), the generation of which is linked, at least in part, to the activation of the NAD(P)H-oxidase system.AGE-RAGE interaction elicits and potentiates inflammatory responses through the enhanced generation of reactive oxygen species, proinflammatory adhesion molecules, and cytokines, causing continued amplification of inflammatory events.
- Oxygen does not combine with the two positive bonds of the iron in the hemoglobin molecule. Instead, it binds loosely with one of the so-called coordination bonds of the iron atom. This is an extremely loose bond, so that the combination is easily reversible. Furthermore, the oxygen does not become ionic oxygen but is carried as molecular oxygen (composed of two oxygen atoms) to the tissues, where, because of the loose, readily reversible combination, it is released into the tissue fluids still in the form of molecular oxygen rather than ionic oxygen.Because each hemoglobin chain has a heme prosthetic group containing an atom of iron, and because there are four hemoglobin chains in each hemoglobin molecule, one finds four iron atoms in each hemoglobin molecule; each of these can bind loosely with one molecule of oxygen, making a total of four molecules of oxygen (or eight oxygen atoms) that can be transported by each hemoglobin molecule.
- FACTORS AFFECTING THE AFFINITY OF HEMOGLOBIN FOR OXYGENThree important conditions affect the oxygen–hemoglobin dissociation curve: the pH, the temperature, and theconcentration of 2,3-biphosphoglycerate (BPG; 2,3-BPG). A rise in temperature or a fall in pH shifts the curve tothe right (Figure 36–3). When the curve is shifted in this direction, a higher PO2 is required for hemoglobin to bind agiven amount of O2. Conversely, a fall in temperature or a rise in pH shifts the curve to the left, and a lower PO2 isrequired to bind a given amount of O2. A convenient index for comparison of such shifts is the P50, the PO2 at whichhemoglobin is half saturated with O2. The higher the P50, the lower the affinity of hemoglobin for O2.The decrease in O2 affinity of hemoglobin when the pH of blood falls is called the Bohr effect and is closely related tothe fact that deoxygenated hemoglobin (deoxyhemoglobin) binds H+ more actively than does oxygenated hemoglobin(oxyhemoglobin). The pH of blood falls as its CO2 content increases, so that when the PCO2 rises, the curve shifts tothe right and the P50 rises. Most of the unsaturation of hemoglobin that occurs in the tissues is secondary to thedecline in the PO2, but an extra 1–2% unsaturation is due to the rise in PCO2 and consequent shift of the dissociationcurve to the right.
- 2,3-BPG is very plentiful in red cells. It is formed from 3-phosphoglyceraldehyde, which is a product of glycolysis via the Embden–Meyerhof pathway (Figure 36–4). It is a highly charged anion that binds to the B chains of deoxyhemoglobin. One mole of deoxyhemoglobin binds 1 mol of 2,3-BPG.
- In this equilibrium, an increase in the concentration of 2,3-BPG shifts the reaction to the right, causing more O2 to beliberated.Because acidosis inhibits red cell glycolysis, the 2,3-BPG concentration falls when the pH is low. Conversely, thyroidhormones, growth hormones, and androgens can all increase the concentration of 2,3-BPG and the P50.Exercise has been reported to produce an increase in 2,3-BPG within 60 min, although the rise may not occur intrained athletes. The P50 is also increased during exercise, because the temperature rises in active tissues and CO2and metabolites accumulate, lowering the pH. In addition, much more O2 is removed from each unit of blood flowingthrough active tissues because the tissues' PO2 declines. Finally, at low PO2 values, the oxygen–hemoglobindissociation curve is steep, and large amounts of O2 are liberated per unit drop in PO2.
- When 2,3-BPG binds to deoxyhemoglobin, it acts to stabilize the low oxygen affinity state (T state) of the oxygen carrier. It fits neatly into the cavity of the deoxy- conformation, exploiting the molecular symmetry and positive polarity by forming salt bridges with lysine and histidine residues in the four subunits of hemoglobin. By selectively binding to deoxyhemoglobin, 2,3-BPG stabilizes the T state conformation, making it harder for oxygen to bind hemoglobin and more likely to be released to adjacent tissues. 2,3-BPG is part of a feedback loop that can help prevent tissue hypoxia in conditions where it is most likely to occur. Conditions of low tissue oxygen concentration such as high altitude (2,3-BPG levels are higher in those acclimated to high altitudes), airway obstruction, or congestive heart failure will tend to cause RBCs to generate more 2,3-BPG in their effort to generate energy by allowing more oxygen to be released in tissues deprived of oxygen. Ultimately, this mechanism increases oxygen release from RBCs under circumstances where it is needed most.
- The total quantity of iron in the body averages 4 to 5 grams, about 65 per cent of which is in the form of hemoglobin. About 4 per cent is in the form of myoglobin, 1 per cent is in the form of the various heme compounds that promote intracellular oxidation, 0.1per cent is combined with the protein transferrin in the blood plasma, and 15 to 30 per cent is stored for later use, mainly in the reticuloendothelial system and liver parenchymal cells, principally in the form of ferritin.When iron is absorbed from the small intestine, it immediately combines in the blood plasma with a beta globulin, apotransferrin, to form transferrin, which is then transported in the plasma. The iron is loosely bound in the transferrin and, consequently, can bereleased to any tissue cell at any point in the body. Excess iron in the blood is deposited especially in the liver hepatocytes and less in the reticuloendothelial cells of the bone marrow. In the cell cytoplasm, iron combines mainly with a protein, apoferritin, to form ferritin. Apoferritinhas a molecular weight of about 460,000, and varying quantities of iron can combine in clusters ofiron radicals with this large molecule; therefore, ferritin may contain only a small amount of iron or a large amount. This iron stored as ferritin is called storage iron.Smaller quantities of the iron in the storage pool are in an extremely insoluble form called hemosiderin. This is especially true when the total quantity of iron in the body is more than the apoferritin storage pool can accommodate. Hemosiderin collects in cells in the form of large clusters that can be observed microscopically as large particles. In contrast, ferritinparticlesare so small and dispersed that they usually can be seen in the cell cytoplasm only with the electron microscope.When the quantity of iron in the plasma falls low, some of the iron in the ferritin storage pool is removed easily and transported in the form of transferrin in the plasma to the areas of the body where it is needed. A unique characteristic of the transferrin molecule is that it binds strongly with receptors in the cell membranes of erythroblasts in the bone marrow. Then, along withits bound iron, it is ingested into the erythroblasts by endocytosis. There the transferrin delivers the iron directly to the mitochondria, where heme is synthesized.In people who do not have adequate quantities of transferrin in their blood, failure to transport iron to the erythroblasts in this manner can cause severe hypochromicanemia—that is, red cells that contain much less hemoglobin than normal.When red blood cells have lived their life span and are destroyed, the hemoglobin released from the cells is ingested by monocyte-macrophage cells. There, iron is liberated and is stored mainly in the ferritin pool to be used as needed for the formation of new hemoglobin.Daily Loss of Iron. A man excretes about 0.6 milligram of iron each day, mainly into the feces. Additional quantities of iron are lost when bleeding occurs. For a woman, additional menstrual loss of blood brings longterm iron loss to an average of about 1.3 mg/day.
- When red blood cells are delivered from the bone marrow into the circulatory system, they normally circulate an average of 120 days before being destroyed. Even though mature red cells do not have a nucleus, mitochondria, or endoplasmic reticulum, they do have cytoplasmic enzymes that are capable of metabolizing glucose and forming small amounts of adenosine triphosphate.These enzymes also (1) maintain pliability of the cell membrane, (2) maintain membrane transport of ions, (3) keep the iron of the cells’ hemoglobin in the ferrous form rather than ferric form, and (4) prevent oxidation of the proteins in the red cells. Even so, the metabolic systems of old red cells become progressively less active, and the cells become more and more fragile, presumably because their life processes wear out. Once the red cell membrane becomes fragile, the cell ruptures during passage through some tight spot of the circulation. Many of the red cells self-destruct in the spleen, where they squeeze through the red pulp of the spleen.There, the spaces between the structural trabeculae of the red pulp, through which most of the cells must pass, are only 3 micrometers wide, in comparison with the 8-micrometer diameter of the red cell. When the spleen is removed, the number of old abnormal red cells circulating in the blood increases considerably.Briefly, when the red blood cells have lived out theirlife span (on average, 120 days) and have become toofragile to exist in the circulatory system, their cellmembranes rupture, and the released hemoglobin isphagocytized by tissue macrophages (also called thereticuloendothelial system) throughout the body. Thehemoglobin is first split into globin and heme, andthe heme ring is opened to give (1) free iron, which istransported in the blood by transferrin, and (2) astraight chain of four pyrrole nuclei, which is the substratefrom which bilirubin will eventually be formed.The first substance formed is biliverdin, but this israpidly reduced to free bilirubin, which is graduallyreleased from the macrophages into the plasma. Thefree bilirubin immediately combines strongly withplasma albumin and is transported in this combinationthroughout the blood and interstitial fluids. Even whenbound with plasma protein, this bilirubin is still called“free bilirubin” to distinguish it from “conjugated bilirubin,”which is discussed later.Within hours, the free bilirubin is absorbed throughthe hepatic cell membrane. In passing to the inside ofthe liver cells, it is released from the plasma albumin andsoon thereafter conjugated about 80 per cent with glucuronicacid to form bilirubinglucuronide, about 10 percent with sulfate to form bilirubinsulfate, and about 10per cent with a multitude of other substances. In theseforms, the bilirubin is excreted from the hepatocytes byan active transport process into the bile canaliculi andthen into the intestines.Formation and Fate of Urobilinogen. Once in the intestine,about half of the “conjugated” bilirubin is converted bybacterial action into the substance urobilinogen, whichis highly soluble. Some of the urobilinogen is reabsorbedthrough the intestinal mucosa back into theblood. Most of this is re-excreted by the liver back intothe gut, but about 5 per cent is excreted by the kidneysinto the urine.After exposure to air in the urine, the urobilinogenbecomes oxidized to urobilin; alternatively, inthe feces, it becomes altered and oxidized to form stercobilin.These interrelations of bilirubin and the otherbilirubin products are shown in Figure 70–2.
- An H gene codes for a fucosetransferase that adds a terminal fucose, forming the H antigen that is usually present in individuals of all blood types (Figure 32–10). Individuals who are type A also express a second transferase that catalyzes placement of a terminal N-acetylgalactosamine on the H antigen, whereas individuals who are type B express a transferase that places aterminal galactose. Individuals who are type AB have both transferases. Individuals who are type O have neither, so the H antigen persists.
- Now that we understand the biochemistry behind the ABO blood types [ABO Blood Types] it's time to look at the genetics. Recall that the human ABO gene on chromosome 9 has three common variants of the gene. Different variants are called alleles. The A allele encodes N-acetylaminogalactosyltransferase and this enzyme makes the A antigen that confers blood type A. The B allele encodes a variant enzyme that makes B antigen and gives rise to blood type B. The O allele encodes a defective enzyme that doesn't make either antigen. In the absence of both A antigen and B antigen your blood type will be O.Everyone has two copies of chromosome 9 so you have two ABO genes. If both of them are the A alleles then your genotype (genetic makeup) will be AA. Your blood type will be A. If one of your ABO genes is the A allele and the other is the O allele then your genotype will be AO. In this case your blood type will be A as well since there are only three possibilities: (1) you have A antigen, (2) you have B antigen, (3) you have no antigen (you can have both antigens, see below). As long as you have one A allele, you will produce the A antigen on the surface of your blood cells.Now let's look at the possibilities for inheritance of blood types. If someone has blood type A then their genotype might be AA or AO. Imagine that they mate with someone having blood type O. That person must have genotype OO. The manifestation of the genes is called the phenotype. The phenotype is related to the genotype but you can't always predict the genotype from the phenotype.We can examine the possible genotypes and phenotypes of the children by constructing a Punnett Square where the alleles from one parent are listed on the side and the alleles from the other parent are listed on the top. You can think of this as being two different kinds of sperm or two different kinds of eggs; keeping in mind that sperm and eggs have only one copy of chromosome 9. The results for the AA parent are shown on the left. All four of the possible combinations are shown in the matrix. There is only one genotype that will show up in the children (AO). All of the children will have blood type A, shown as purple boxes.If the blood type A parent has the AO genotype then the Punnett square calculations look like the diagram on the right. In this case, there are two possible combinations; AO and OO. Half the children will have blood type A and half will have blood type O.Since the O phenotype is masked by the presence of the A phenotype, we say that O is recessive to A and A is dominant with respect to O. The only way to see the O phenotype is when the genotype is OO. We refer to this as the homozygous recessive state. AO individuals are heterozygous because they have two different alleles.
- http://www.google.com/imgres?imgurl=http://www.biologycorner.com/anatomy/blood/images/bloodtype_chart.gif&imgrefurl=http://www.biologycorner.com/anatomy/blood/notes_bloodtype.html&usg=__bpDzuQxz3C4QTbUHv4MdCs20qyc=&h=363&w=355&sz=8&hl=en&start=16&zoom=1&tbnid=xLM0lbEjUjUSMM:&tbnh=121&tbnw=118&ei=NesTUIPWLsrHrQe7nIDYCg&itbs=1TRANSFUSION REACTIONSDangerous hemolytic transfusion reactions occur when blood is transfused into an individual with an incompatibleblood type; that is, an individual who has agglutinins against the red cells in the transfusion. The plasma in thetransfusion is usually so diluted in the recipient that it rarely causes agglutination even when the titer of agglutininsagainst the recipient's cells is high. However, when the recipient's plasma has agglutinins against the donor's redcells, the cells agglutinate and hemolyze. Free hemoglobin is liberated into the plasma. The severity of the resultingtransfusion reaction may vary from an asymptomatic minor rise in the plasma bilirubin level to severe jaundice andrenal tubular damage leading to anuria and death.Incompatibilities in the ABO blood group system are summarized in Table 32–4. Persons with type AB blood are"universal recipients" because they have no circulating agglutinins and can be given blood of any type withoutdeveloping a transfusion reaction due to ABO incompatibility. Type O individuals are "universal donors" because they lack A and B antigens, and type O blood can be given to anyone without producing a transfusion reaction due to ABOincompatibility. This does not mean, however, that blood should ever be transfused without being cross-matchedexcept in the most extreme emergencies, since the possibility of reactions or sensitization due to incompatibilities insystems other than ABO systems always exists. In cross-matching, donor red cells are mixed with recipient plasmaon a slide and checked for agglutination. It is advisable to check the action of the donor's plasma on the recipient cellsin addition, even though, as noted above, this is rarely a source of trouble.A procedure that has recently become popular is to withdraw the patient's own blood in advance of elective surgeryand then infuse this blood back (autologous transfusion) if a transfusion is needed during the surgery. With irontreatment, 1000 to 1500 mL can be withdrawn over a 3-wk period. The popularity of banking one's own blood is dueprimarily to fear of transmission of infectious diseases by heterologous transfusions, but of course another advantageis elimination of the risk of transfusion reactions.
- The Rh factor, named for the rhesus monkey because it was first studied using the blood of this animal, is a systemcomposed primarily of the C, D, and E antigens, although it actually contains many more. Unlike the ABO antigens,the system has not been detected in tissues other than red cells. D is by far the most antigenic component, and theterm Rh-positive as it is generally used means that the individual has agglutinogen D. The D protein is notglycosylated, and its function is unknown. The Rh-negative individual has no D antigen and forms the anti-Dagglutinin when injected with D-positive cells. The Rh typing serum used in routine blood typing is anti-D serum.Eighty-five percent of Caucasians are D-positive and 15% are D-negative; over 99% of Asians are D-positive. Unlikethe antibodies of the ABO system, anti-D antibodies do not develop without exposure of a D-negative individual toD-positive red cells by transfusion or entrance of fetal blood into the maternal circulation.
- Another complication due to Rh incompatibility arises when an Rh-negative mother carries an Rh-positive fetus. Smallamounts of fetal blood leak into the maternal circulation at the time of delivery, and some mothers developsignificant titers of anti-Rh agglutinins during the postpartum period. During the next pregnancy, the mother'sagglutinins cross the placenta to the fetus. In addition, there are some cases of fetal–maternal hemorrhage duringpregnancy, and sensitization can occur during pregnancy. In any case, when anti-Rh agglutinins cross the placenta toan Rh-positive fetus, they can cause hemolysis and various forms of hemolytic disease of the newborn(erythroblastosisfetalis). If hemolysis in the fetus is severe, the infant may die in utero or may develop anemia,severe jaundice, and edema(hydropsfetalis).
- Kernicterus, a neurologic syndrome in which unconjugatedbilirubin is deposited in the basal ganglia, may also develop, especially if birth is complicated by a period of hypoxia.Bilirubin rarely penetrates the brain in adults, but it does in infants with erythroblastosis, possibly in part because theblood–brain barrier is more permeable in infancy. However, the main reasons that the concentration of unconjugatedbilirubin is very high in this condition are that production is increased and the bilirubin-conjugating system is not yetmature.
- Hemostasis is the process of forming clots in the walls of damaged blood vessels and preventing blood loss whilemaintaining blood in a fluid state within the vascular system. A collection of complex interrelated systemic mechanisms operates to maintain a balance between coagulation and anticoagulation.
- THE CLOTTING MECHANISMThe loose aggregation of platelets in the temporary plug is bound together and converted into the definitive clot byfibrin. Fibrin formation involves a cascade of enzymatic reactions and a series of numbered clotting factors (Table32–5). The fundamental reaction is conversion of the soluble plasma protein fibrinogen to insoluble fibrin (Figure32–13). The process involves the release of two pairs of polypeptides from each fibrinogen molecule. The remainingportion, fibrin monomer, then polymerizes with other monomer molecules to form fibrin. The fibrin is initially aloose mesh of interlacing strands. It is converted by the formation of covalent cross-linkages to a dense, tightaggregate (stabilization). This latter reaction is catalyzed by activated factor XIII and requires Ca2+.The conversion of fibrinogen to fibrin is catalyzed by thrombin. Thrombin is a serine protease that is formed from itscirculating precursor, prothrombin, by the action of activated factor X. It has additional actions, including activation ofplatelets, endothelial cells, and leukocytes via so-called proteinase activated receptors, which are G protein-coupled.Factor X can be activated by either of two systems, known as intrinsic and extrinsic (Figure 32–13). The initialreaction in the intrinsic system is conversion of inactive factor XII to active factor XII (XIIa). This activation, whichis catalyzed by high-molecular-weight kininogen and kallikrein (see Chapter 33), can be brought about in vitro byexposing the blood to glass, or in vivo by collagen fibers underlying the endothelium. Active factor XII then activatesfactor XI, and active factor XI activates factor IX. Activated factor IX forms a complex with active factor VIII, which isactivated when it is separated from von Willebrand factor. The complex of IXa and VIIIa activate factor X.Phospholipids from aggregated platelets (PL) and Ca2+ are necessary for full activation of factor X. The extrinsicsystem is triggered by the release of tissue thromboplastin, a protein–phospholipid mixture that activates factor VII.Tissue thromboplastin and factor VII activate factors IX and X. In the presence of PL, Ca2+, and factor V, activatedfactor X catalyzes the conversion of prothrombin to thrombin. The extrinsic pathway is inhibited by a tissue factorpathway inhibitor that forms a quaternary structure with tissue thromboplastin (TPL), factor VIIa, and factor Xa.
- Antithrombin III is a circulating protease inhibitor that binds to serine proteases in the coagulation system,blocking their activity as clotting factors. This binding is facilitated by heparin, a naturally occurring anticoagulantthat is a mixture of sulfated polysaccharides with molecular weights averaging 15,000–18,000. The clotting factorsthat are inhibited are the active forms of factors IX, X, XI, and XII.The endothelium of the blood vessels also plays an active role in preventing the extension of clots. All endothelial cellsexcept those in the cerebral microcirculation produce thrombomodulin, a thrombin-binding protein, on theirsurfaces. In circulating blood, thrombin is a procoagulant that activates factors V and VIII, but when it binds tothrombomodulin, it becomes an anticoagulant in that the thrombomodulin–thrombin complex activates protein C(Figure 32–14). Activated protein C (APC), along with its cofactor protein S, inactivates factors V and VIII andinactivates an inhibitor of tissue plasminogen activator, increasing the formation of plasmin.
- Structure of human plasminogen. Note the Glu at the amino terminal, the Asn at the carboxyl terminal, and fiveuniquely shaped loop structures (kringles). Hydrolysis by t-PA at the arrow separates the carboxyl terminal light chainfrom the amino terminal heavy chain but leaves the disulfide bonds intact. This activates the molecule.Plasmin (fibrinolysin) is the active component of the plasminogen (fibrinolytic) system (Figure 32–14). Thisenzyme lyses fibrin and fibrinogen, with the production of fibrinogen degradation products (FDP) that inhibit thrombin.Plasmin is formed from its inactive precursor, plasminogen, by the action of thrombin and tissue-typeplasminogen activator (t-PA). It is also activated by urokinase-type plasminogen activator (u-PA). If thet-PA gene or the u-PA gene is knocked out in mice, some fibrin deposition occurs and clot lysis is slowed. However,when both are knocked out, spontaneous fibrin deposition is extensive.Human plasminogen consists of a 560-amino-acid heavy chain and a 241-amino-acid light chain. The heavy chain,with glutamate at its amino terminal, is folded into five loop structures, each held together by three disulfide bonds(Figure 32–15). These loops are called kringles because of their resemblance to a Danish pastry of the same name.The kringles are lysine-binding sites by which the molecule attaches to fibrin and other clot proteins, and they arealso found in prothrombin. Plasminogen is converted to active plasmin when t-PA hydrolyzes the bond between Arg560 and Val 561.
- General ProcessesPhagocytosis of bacteriaDestruction of swallowed organisms by the acid secretions of the stomach and the digestive enzymes.Resistance of the skin to invasion by organismsPresence in the blood of certain chemical compounds that attach to foreign organisms or toxins and destroy them. Some of these compounds are lysozyme, a mucolytic polysaccharide that attacks bacteria and causes them to dissolute; basic polypeptides, which react with and inactivate certain types of gram-positive bacteria; the complement complex that is described later, a system of about 20 proteins that can be activated in various ways to destroy bacteria; and natural killer lymphocytes that can recognize and destroy foreign cells, tumor cells, and even some infected cells.
- In vertebrates, including humans, innate immunity provides the first line of defense against infections, but it alsotriggers the slower but more specific acquired immune response (Figure 3–3). In vertebrates, natural andacquired immune mechanisms also attack tumors and tissue transplanted from other animals. Once activated, immune cells communicate by means of cytokines and chemokines. They kill viruses, bacteria, and other foreign cells by secreting other cytokines and activating the complement system.
- Members of one of the cytokine receptor superfamilies, showing shared structural elements. Note that all the subunits except the Alpha subunit in subfamily 3 have four conserved cysteine residues (open boxes at top) and a Trp-Ser-X-Trp-Ser motif (pink). Many subunits also contain a critical regulatory domain in their cytoplasmic portions (green). CNTF, ciliaryneurotrophic factor; LIF, leukemia inhibitory factor; OSM, oncostatin M; PRL, prolactin.(Modified from D'Andrea AD: Cytokine receptors in congenital hematopoietic disease. N Engl J Med 1994;330:839.)Many of the receptors for cytokines and hematopoietic growth factors (see above), as well as the receptors forprolactin (see Chapter 25), and growth hormone (see Chapter 24) are members of a cytokine-receptorsuperfamily that has three subfamilies (Figure 3–4). The members of subfamily 1, which includes the receptorsfor IL-4 and IL-7, are homodimers. The members of subfamily 2, which includes the receptors for IL-3, IL-5, andIL-6, are heterodimers. The receptor for IL-2 and several other cytokines is unique in that it consists of aheterodimer plus an unrelated protein, the so-called Tac antigen. The other members of subfamily 3 have thesame chain as IL-2R. The extracellular domain of the homodimer and heterodimer subunits all contain fourconserved cysteine residues plus a conserved Trp-Ser-X-Trp-Ser domain, and although the intracellular portionsdo not contain tyrosine kinase catalytic domains, they activate cytoplasmic tyrosine kinases when ligand binds tothe receptors.Another superfamily of cytokines is the chemokine family. Chemokines are substances that attract neutrophils(see previous text) and other white blood cells to areas of inflammation or immune response. Over 40 have nowbeen identified, and it is clear that they also play a role in the regulation of cell growth and angiogenesis. Thechemokine receptors are G protein-coupled receptors that cause, among other things, extension of pseudopodiawith migration of the cell toward the source of the chemokine.THE COMPLEMENT
- THE COMPLEMENT SYSTEMThe cell-killing effects of innate and acquired immunity are mediated in part by a system of more than 30 plasma proteins originally named the complement system because they "complemented" the effects of antibodies. Three different pathways or enzyme cascades activate the system: the classic pathway, triggered by immune complexes; the mannose-binding lectin pathway, triggered when this lectin binds mannose groups in bacteria; and the alternative or properdin pathway, triggered by contact with various viruses, bacteria, fungi, and tumor cells. The proteins that are produced have three functions: They help kill invading organisms by opsonization, chemotaxis, and eventual lysis of the cells; they serve in part as a bridge frominnate to acquired immunity by activating B cells and aiding immune memory; and they help dispose of wasteproducts after apoptosis. Cell lysis, one of the principal ways the complement system kills cells, is brought aboutby inserting proteins called perforins into their cell membranes. These create holes, which permit free flow ofions and thus disruption of membrane polarity.
- DEVELOPMENT OF THE IMMUNE SYSTEMDuring fetal development, and to a much lesser extent during adult life, lymphocyte precursors come from thebone marrow. Those that populate the thymus (Figure 3–5) become transformed by the environment in thisorgan into T lymphocytes. In birds, the precursors that populate the bursa of Fabricius, a lymphoid structurenear the cloaca, become transformed into B lymphocytes. There is no bursa in mammals, and thetransformation to B lymphocytes occurs in bursal equivalents, that is, the fetal liver and, after birth, the bonemarrow. After residence in the thymus or liver, many of the T and B lymphocytes migrate to the lymph nodes.T and B lymphocytes are morphologically indistinguishable but can be identified by markers on their cellmembranes. B cells differentiate into plasma cells and memory B cells. There are three major types of Tcells: cytotoxic T cells, helper T cells, and memory T cells. There are two subtypes of helper T cells: Thelper 1 (TH1) cells secrete IL-2 and -interferon and are concerned primarily with cellular immunity; T helper 2(TH2) cells secrete IL-4 and IL-5 and interact primarily with B cells in relation to humoral immunity. Cytotoxic Tcells destroy transplanted and other foreign cells, with their development aided and directed by helper T cells.Markers on the surface of lymphocytes are assigned CD (clusters of differentiation) numbers on the basis of theirreactions to a panel of monoclonal antibodies. Most cytotoxic T cells display the glycoprotein CD8, and helper Tcells display the glycoprotein CD4. These proteins are closely associated with the T cell receptors and mayfunction as coreceptors. On the basis of differences in their receptors and functions, cytotoxic T cells are dividedinto and types (see below). Natural killer cells (see above) are also cytotoxic lymphocytes, though theyare not T cells. Thus, there are three main types of cytotoxic lymphocytes in the body: T cells, T cells, andNK cells. MEMORY B CELLS & T CELLSAfter exposure to a given antigen, a small number of activated B and T cells persist as memory B and T cells.These cells are readily converted to effector cells by a later encounter with the same antigen. This ability toproduce an accelerated response to a second exposure to an antigen is a key characteristic of acquiredimmunity. The ability persists for long periods of time, and in some instances (eg, immunity to measles) it canbe lifelong.After activation in lymph nodes, lymphocytes disperse widely throughout the body and are especially plentiful inareas where invading organisms enter the body, for example, the mucosa of the respiratory and gastrointestinaltracts. This puts memory cells close to sites of reinfection and may account in part for the rapidity and strengthof their response. Chemokines are involved in guiding activated lymphocytes to these locations.
- 1. Antigen recognitionAntigen recognition by naïve T cells induced IL-2 secretion which help T cell proliferation and differentiation to effector CD4+ and CD8+ T cells. They have different functions to get rid Ag.- Antigen recognition by naive T cells in lymphoid organs initiates proliferate and differentiate into effector cells- Antigen recognition by effector T cells at peripheral site of antigen triggers effector functions that eliminate the antigen 2. T cell activation2.1 Helper T lymphocyte: Major Histocompatibility Complex (MHC) class II restricted peptides: processing from exogenous proteins2.2 Cytotoxic T lymphocyte: MHC class I restricted peptide: processing from endogenous proteinsSpecific interaction between specific T lymphocyte and APC, involves 1. The interaction between T cell receptor (TCR) and MHC-peptide complex, called Signal I. This signal is required for the activation of antigen-specific T lymphocyte. All TCRs on the surface of a T lymphocyte are identical and bind to only one type of peptide, therefore, a T lymphocyte is activated only by its specific antigen.2. In addition to Signal I, an interaction between costimulatory molecules on APC and T cells is required, this interaction is called Signal II. B7 is a costimulatory molecule expressed on APC upon activation by foreign antigen, this molecule interacts with CD28 molecule on activated T cell.3. Antigen elimination3.1 Helper T lymphocyte- Peptide MHC class II interact with TCR- Helper T lymphocyte mainly expresses TCR, CD3 and CD4 molecules on the surface - Biochemical process within activated T lymphocyte results in the proliferation of activated cells and secretion of cytokines3.2 Cytotoxic T lymphocyte- Peptide-MHC class I interact with TCR- Cytotoxic T lymphocyte mainly expresses TCR, CD3 and CD8 molecules on the surface- Require participation of CD4+ T cells- Clonal expansion phase: massive increase in antigen specific CD8+ activated T cells- Differentiation of CD8+ activated T cell into cytotoxic T lymphocytes (CTLs): acquire the machinery to perform target cell killing
- The genes for the MHC molecules are found in one region of chromosome 6 that contains more than 100 genesThe MHC moleculesThe MHC molecules are glycoproteins and are part of the immunoglobulin superfamily. There are two classes of MHC that have a slightly different function. They have very different amino acids sequences but very similar three-dimensional structure. They are known as MHC-I and MHC-II.MHC-I is made up of four domains. Three of these domains are formed by one peptide - the a-chain (an MHC glycoprotein) - and the fourth domain is provided by a non-MHC encoded molecule named b2-microglobulin. The three domains of the a-chain are named a1, a2, and a3. a1 and a2 form the peptide binding cleft where the antigen is presented to the T-cell receptor and a3 contains a trans-membrane region that binds the whole molecule to the cell membrane. (See diagram below).MHC-II is very similar and is made up of an a and a b chain, both of which are coded for by the MHC region in chromosome 6. Each chain has two domains; a1 and b1 form the peptide binding cleft and both a2 and b2 are membrane bound. The class I MHC proteins (MHC-I proteins) are coupled primarily to peptide fragments generated from proteins synthesized within cells. The peptides to which the host is not tolerant (eg, those from mutant or viral proteins) are recognized by T cells. The digestion of these proteins occurs in proteasomes, complexes of proteolyticenzymes that may be produced by genes in the MHC group, and the peptide fragments appear to bind to MHC proteins in the endoplasmic reticulum. The class II MHC proteins (MHC-II proteins) are concerned primarily with peptide products of extracellular antigens, such as bacteria, that enter the cell by endocytosis and are digested in the late endosomes.
- MHC-I is found on all nucleated cells and is central to anti-viral immunity.MHC-II, by contrast is found on a small number of specialist cells known collectively as antigen-presenting cells (APCs). Antigen presenting cells include macrophages, B-lymphocytes, cytotoxic T-lymphocytes and several others. Cytotoxic T-cells express the molecule CD8 with the T-cell receptor. CD8 binds to MHC-I and not MHC-II. For this reason Cytotoxic T-cells bind to MHC-I. T-helper cells do not express CD8 but do express CD4 which works in a similar but contrasting way – it binds to MHC-II only and thus T-helper cells only bind to MHC-II. Hence the molecules CD4 and CD8 are very important in defining the function of different T-lymphocytes. This is why T-helper cells are also know as CD4 cells and cytotoxic T-cells as CD8 cells.CD4 – binds to class II MHC molecules on APC’sFound in 60% of mature T cellsCD8 – binds to class I MHC molecules on APC’s30% of mature T cells*CD4/CD8 ratio = 2:1CD4 expressing T cells = “Helper T cells” Secretes cytokines that influence all other cells of the immune systemDestroyed by the HIV virusCD8 expressing T cells = “Cytotoxic T cells”Directly kills virus infected cells or tumor cells
- B CELLSAs noted above, B cells can bind antigens directly, but they must contact helper T cells to produce full activationand antibody formation. It is the TH2 subtype that is mainly involved. Helper T cells develop along the TH2lineage in response to IL-4 (see below). On the other hand, IL-2 promotes the TH1 phenotype. IL-2 acts in anautocrine fashion to cause activated T cells to proliferate. The role of various cytokines in B cell and T cellactivation is summarized in Figure 3–9.Summary of acquired immunity. (1) An antigen-presenting cell ingests and partially digests an antigen, thenpresents part of the antigen along with MHC peptides (in this case, MHC II peptides on the cell surface). (2) An"immune synapse" forms with a naive CD4 T cell, which is activated to produce IL-2. (3) IL-2 acts in an autocrinefashion to cause the cell to multiply, forming a clone. (4) The activated CD4 cell may promote B cell activation andproduction of plasma cells or it may activate a cytotoxic CD8 cell. The CD8 cell can also be activated by forming asynapse with an MCH I antigen-presenting cell.(Reproduced with permission from McPhee SJ, Lingappa VR, Ganong WF [editors]: Pathophysiology of Disease, 4thed. McGraw-Hill, 2003.)The activated B cells proliferate and transform into memory B cells (see above) and plasma cells. The plasmacells secrete large quantities of antibodies into the general circulation. The antibodies circulate in the globulinfraction of the plasma and, like antibodies elsewhere, are called immunoglobulins. The immunoglobulins areactually the secreted form of antigen-binding receptors on the B cell membrane.
- IMMUNOGLOBULINSCirculating antibodies protect their host by binding to and neutralizing some protein toxins, by blocking theattachment of some viruses and bacteria to cells, by opsonizing bacteria (see above), and by activatingcomplement. Five general types of immunoglobulin antibodies are produced by the lymphocyte–plasma cellsystem. The basic component of each is a symmetric unit containing four polypeptide chains (Figure 3–10). Thetwo long chains are called heavy chains, whereas the two short chains are called light chains. There are twotypes of light chains, k and , and eight types of heavy chains. The chains are joined by disulfide bridges thatpermit mobility, and there are intrachain disulfide bridges as well. In addition, the heavy chains are flexible in aregion called the hinge. Each heavy chain has a variable (V) segment in which the amino acid sequence is highlyvariable, a diversity (D) segment in which the amino acid segment is also highly variable, a joining (J) segmentin which the sequence is moderately variable, and a constant (C) segment in which the sequence is constant.Each light chain has a V, a J, and a C segment. The V segments form part of the antigen-binding sites (Fabportion of the molecule [Figure 3–10]). The Fc portion of the molecule is the effector portion, which mediates thereactions initiated by antibodies.Typical immunoglobulin G molecule. Fab, portion of the molecule that is concerned with antigen binding; Fc,effector portion of the molecule. The constant regions are pink and purple, and the variable regions are orange. Theconstant segment of the heavy chain is subdivided into CH1, CH2, and CH3. SS lines indicate intersegmentaldisulfide bonds. On the right side, the C labels are omitted to show regions JH, D, and JL.
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- Central toleranceCentral tolerance occurs during lymphocyte development and operates in the thymus and bone marrow. Here, T and B lymphocytes that recognize self antigens are deleted before they develop into fully immunocompetent cells, preventing autoimmunity. This process is most active in fetal life, but continues throughout life as immature lymphocytes are generated.In mammals the process occurs in the thymus (T cells)[2][3] and bone marrow (B cells), when maturing lymphocytes are exposed to self antigens. Self antigens are present in both organs due to endogenous expression within the organ and importation of antigen due to circulation from peripheral sites. In the case of T cell central tolerance, additional sources of antigen are made available in the thymus by the action of the transcription factor AIRE.Positive selection occurs first when naive T-cells are exposed to antigens in the thymus. T-cells which have receptors with sufficient affinity for self-MHC molecules are selected. Other cells that do not show sufficient affinity to self-antigens will undergo a deletion process known as death by neglect which involves apoptosis of the cells. The positive selection is a classical example of the importance of some degree of autorreactiveness. This does not occur in B cells.Negative selection of T-cells with a very high affinity of self-MHC molecules are induced to anergy, or lineage divergence to form T-regulatory cells. This proccess also occurs during B cell development.Peripheral tolerancePeripheral tolerance is immunological tolerance developed after T and B cells mature and enter the periphery. The T cells that leave the thymus are relatively but not completely safe. Some will have receptors(TCRs) that can respond to self antigens that:are present in such high concentration that they can bind to "weak" receptorsthe T cell did not encounter in the thymus (such as, tissue-specific molecules like those in the islets of Langerhans, brain or spinal cord)Peripheral tolerance is immunological tolerance developed after T and B cells mature and enter the periphery. These include the suppression of autoreactive cells by 'regulatory' T cells and the generation of hyporesponsiveness (anergy) in lymphocytes which encounter antigen in the absence of the co-stimulatory signals that accompany inflammation, or in the presence of co-inhibitory signals.IgnorancePotentially self-reactive T-cells are not activated at immunoprivileged sites, where antigens are expressed in non-surveillanced areas. This can occur in the testes, for instance. Anatomical barriers can separate the lymphocytes from the antigen, an example is the central nervous system (the blood-brain-barrier). Naive T-cells are not present in high numbers in peripheral tissue, but stay mainly in the circulation and lymphoid tissue.Some antigens are at too low a concentration to cause an immune response - a subthreshold stimulation will lead to apoptosis in a T cell.Induced anergyT-cells can be made non-responsive to antigens presented if the T-cell engages an MHC molecule without co-stimulatory molecules. This will occur if there is no acute inflammation, leading to no co-stimulator upregulation due to the low concentration of cytokines.
- AutoimmunitySometimes the processes that eliminate antibodies against self antigens fail and a variety of differentautoimmune diseases are produced. These can be B cell- or T cell-mediated and can be organ-specific orsystemic. They include type 1 diabetes mellitus (antibodies against pancreatic islet B cells), myasthenia gravis(antibodies against nicotinic cholinergic receptors), and multiple sclerosis (antibodies against myelin basicprotein and several other components of myelin). In some instances, the antibodies are against receptors andare capable of activating those receptors; for example, antibodies against TSH receptors increase thyroidactivity and cause Graves' disease (see Chapter 20). Other conditions are due to the production of antibodiesagainst invading organisms that cross-react with normal body constituents (molecular mimicry). An exampleis rheumatic fever following a streptococcal infection; a portion of cardiac myosin resembles a portion of thestreptococcal M protein, and antibodies induced by the latter attack the former and damage the heart. Someconditions may be due to bystander effects, in which inflammation sensitizes T cells in the neighborhood,causing them to become activated when otherwise they would not respond. However, much is still uncertainabout the pathogenesis of autoimmune disease
- Antigen-presenting cells (APCs) include specialized cells called dendritic cells in the lymph nodes andspleen and the Langerhansdendritic cells in the skin. Macrophages and B cells themselves, and likely manyother cell types, can also function as APCs. In APCs, polypeptide products of antigen digestion are coupled toprotein products of the major histocompatibility complex (MHC) genes and presented on the surface of thecell. The products of the MHC genes are called human leukocyte antigens (HLA).The genes of the MHC, which are located on the short arm of human chromosome 6, encode glycoproteins andare divided into two classes on the basis of structure and function. Class I antigens are composed of a 45-kDaheavy chain associated noncovalently with 2-microglobulin encoded by a gene outside the MHC (Figure 3–6).They are found on all nucleated cells. Class II antigens are heterodimers made up of a 29- to 34-kDa chainassociated noncovalently with a 25- to 28-kDa chain. They are present in antigen-presenting cells, including Bcells, and in activated T cells.
- 1. Ascorbate in the food reduces Fe3+ to Fe2+, and forms a soluble complex with iron, thereby effectively promoting the iron absorption. We normally ingest about 20 mg iron daily, and less than 1 mg is absorbed in healthy adults, because iron form insoluble salts and complexes in the gastrointestinal secretions.2. Iron is transported from the lumen of the upper jejunum, across the mucosa, and into the plasma by an iron-binding protein called gut transferrin. 3. Receptor proteins in the brush border membrane bind the transferrin-iron complex, and the complex is taken up into the cell by receptor-mediated endocytosis4. There is a free pool of iron in the cytosol. Iron exists in one of two states in the cytosol: The ferrous state (Fe2+) or the ferric state (Fe3+). The Fe2+ ions, after absorption into the mucosal cell, are oxidised to Fe3+ (Fig. 22-16). 5. When intracellular iron is available in excess, it is bound to apoferritin, an ubiquitous iron-binding protein, and stored within the mucosal cells as ferritin. The synthesis of apoferritin is stimulated by iron. This translational mechanism protects against excessive absorption. 6. At the basolateral membrane the Fe3+ are reduced to Fe2+ and passes from the interstitial space to the blood. Here Fe2+ are again oxidised to Fe3+ and binds to plasma transferrin. Cellular iron stores are mobilised by autophagocytosis of enterocyteferritin, when body stores of iron are deficient.