PHS 212 Blood Physiology - Part III PDF

**PHS 212: BLOOD PHYSIOLOGY Continued......Part III** **BLOOD GROUP**\ There are certain molecules on the membrane surfaces of all cells in the body that can be recognized as foreign by the immune system of another individual. These molecules are known as ***antigens**.* As part of the immune syste...

**PHS 212: BLOOD PHYSIOLOGY Continued......Part III** **BLOOD GROUP**\ There are certain molecules on the membrane surfaces of all cells in the body that can be recognized as foreign by the immune system of another individual. These molecules are known as ***antigens**.* As part of the immune system response in the body, particular lymphocytes secrete a class of proteins called ***antibodies*** that bond in a specific fashion with antigens. The specificity of antibodies for antigens is analogous to the specificity of enzymes for their substrates, and of receptor proteins for neurotransmitters and hormones. **Blood Groups -- ABO System** Blood groups refer to the presence of certain types of ***antigens*** on the red blood cells that elicit a specific immune response when introduced into the body of another animal. There are several types of blood groups, but the best known are the ABO and Rhesus blood groups. Others of less importance are the M,N,S,P and Lewis groups. These membrane surface antigens are mucopolysaccharides of molecular weight of 200,000 and 300,000 and the *specificity* depends on the carbohydrate portion of the molecule. Antigens are present on tissues as well; e.g., majority of people secrete some ABO and Lewis blood group substances in the saliva and other body fluids. Because the antigens on the cells make the cells of the recipients to be susceptible to agglutination (clumping together), antigens are also called ***agglutinogens***. Blood group antibodies (agglutinins) are mostly found in the γ-globulin fraction of the serum. These antibodies are formed after birth when the foreign antigens enter the human body through food, bacteria or other means. In terms of the antigens present on the red blood cell surface, a person may be *type A* (with only A antigens), *type B* (with only B antigens), *type AB* (with both A and B antigens), or *type O* (with neither A nor B antigens). Each person's blood type - A, B, or O---denotes the antigens present on the red blood cell surface, which are the products of the genes (located on chromosome number 9) that code for these antigens. The immune system exhibits ***tolerance*** to its own red blood cell antigens. So people who are type A, for example, do not produce anti-A antibodies. Surprisingly, however, they do make antibodies against the B antigen and, conversely, people with blood type B make antibodies against the A antigen ( fig. 13.5 ). This is believed to result from the fact that antibodies made in response to some common bacteria cross-react with the A or B antigens. People who are type A, therefore, acquire antibodies that can react with B antigens by exposure to these bacteria, but they do not develop antibodies that can react with A antigens because tolerance mechanisms prevent this. People who are type AB develop tolerance to both of these antigens, and thus do not produce either anti-A or anti-B antibodies. Those who are type O (i.e. they have no antigens), by contrast, do not develop tolerance to either antigen; therefore, they have both anti-A and anti-B antibodies in their plasma (see Table below). GROUP GENOTYPE ANTIGEN on RBCs ANTIBODIES in SERUM Relative Frequency, % ------- ---------- ----------------- --------------------- ----------------------- AB AB A and B 48 A OA or AA A Anti -- B 25 B OB or BB B Anti-A 22 O OO \-- Anti-A and Anti- B 4 Blood groups are important in: - transfusion reactions, - in inheritance of genes, and therefore, - of medico-legal and anthropological importance, - in transplantation reactions. **Blood Typing** In blood typing, the donor's blood cells are matched with the serum of the recipient as shown in the table below. If there is agglutination reaction, the blood samples are said to be ***mismatched*** and no transfusion of the blood should take place. Blood typing also takes care of the less important blood groups that may cause reaction. The donor's antibodies do not cause much reaction because they are effectively diluted by the recipient's larger plasma volume. Note that blood group O is, normally, referred to as the ***Universal Donor*** because it contains no antigens that can react with the recipient's antibody; while blood group AB is called the ***Universal Recipient*** there are no antibodies that can react with the donor's antigens. **Blood Transfusion and Transfusion Reactions**\ In conditions when there is severe decrease in blood volume, there will be need for blood transfusion -- of usually, whole blood; though blood cells or plasma alone may sometimes be transfused. Before transfusions are performed, a *major cross-match* is made by mixing serum from the recipient with blood cells from the donor. If the types do not match---if the donor is type A, for example, and the recipient is type B---the recipient's antibodies attach to the donor's red blood cells and form bridges that cause the cells to clump together, or **agglutinate** (figs. 13.5 and13.6). Because of this agglutination reaction, the A and B antigens are sometimes called ***agglutinogens,*** and the antibodies against them are called ***agglutinins.*** Transfusion errors that result in such agglutination can lead to blockage of small blood vessels and cause hemolysis (rupture of red blood cells), which may damage the kidneys and other organs.  In emergencies, however, type O blood has been given to people who are type A, B, AB, or O. Because type O red blood cells lack A and B antigens, the recipient's antibodies cannot cause agglutination of the donor red blood cells. Type O is, therefore, a ***universal donor***---but only as long as the volume of plasma donated is small, since plasma from a type O person would agglutinate type A, type B, and type AB red blood cells. Likewise, type AB people are ***universal recipients*** because they lack anti-A and anti-B antibodies, and thus cannot agglutinate donor red blood cells. (Donor plasma could agglutinate recipient red blood cells if the transfusion volume were too large.) Because of the dangers involved, use of the universal donor and recipient concept is strongly discouraged in practice. The typical types of ***transfusion reactions*** from mis-match blood transfusion are : 1. ABO group mis-match. 2. Rh factor mis-match. 3. Pyrogenic reaction -- feverish condition only due to contaminated blood. 4. Reaction resulting from anticoagulants -- citrate is the usual anticoagulant of choice. But if large quantity is used and the blood is given rapidly, it may result in ***tetany*** due to reduced plasma Ca^++^ as a result of ***chelating*** action of the citrate. A low Ca^++^ concentration increases the excitability of nerve and muscle cell membranes resulting in ***hypocalcaemic tetany***, which is characterized by skeletal muscle spasms. N/B: If there is transfusion reaction, the main trust of the remedy is to prevent kidney shut down. Therefore, rapid infusion of dilute intravenous fluids and /or administration of diuretics may be of help. **Rhesus System (Rh Factor)** Another group of antigens found on the red blood cells of most people is the **Rh factor** (named after the Rhesus monkey in which these antigens were first discovered). There are a number of different antigens in this group, but one stands out because of its medical significance. This Rh antigen is termed D, and is often indicated as Rho(D). If this Rh antigen is present on a person's red blood cells, the person is **Rh positive;** if it is absent, the person is **Rh negative.** The Rh-positive condition is by far the more common (with a frequency of 85% in the Caucasian population, for example). The Rh factor is of particular significance when Rh- negative mothers give birth to Rh-positive babies. The fetal and maternal bloods are normally kept separate across the placenta during pregnancy, and so the Rh-negative mother is not usually exposed to the Rh positive antigen of the fetus during the pregnancy. At the ***time of birth***, however, a variable degree of exposure may occur, and the mother's immune system may become sensitized and produce antibodies against the Rh positive antigen. This does not always occur, however, because the exposure may be minimal and because Rh-negative women vary in their sensitivity to the Rh factor. If the woman does produce antibodies against the Rh factor, these antibodies could cross the placenta ***in subsequent pregnancies*** and cause hemolysis of the Rh-positive red blood cells of the fetus. Therefore, the baby could be born anemic due to a condition called ***erythroblastosis fetalis,* or *hemolytic disease of the newborn --*** *in which the babies RBCs are hemolyzed by the mother's antibodies.* Erythroblastosis fetalis can be prevented by injecting the Rh-negative mother with an antibody preparation against the Rh factor (a trade name for this preparation is RhoGAM---the GAM is short for gamma globulin, the class of plasma proteins in which antibodies are found) within 72 hours after the birth of each Rh-positive baby. This is a type of passive immunization in which the injected antibodies inactivate the Rh antigens and thus prevent the mother from becoming actively immunized to them. Some physicians now give RhoGAM throughout the Rh-positive pregnancy of any Rh-negative woman. The hemolytic disease of the new born, or ***erythroblastosis fetalis,*** is a classical example of immune response. The mother is Rh negative, the father is Rh positive, and the 1st baby in the womb is Rh positive by inheritance from the father. The mother then develops anti-Rh antibodies by exposure during parturition, which is then directed against the 2^nd^ baby, causing agglutination and clumping of the fetal RBCs, followed by hemolysis of the RBC and resulting into *hemolytic disease of the newborn. In severe cases, it leads to what is known as **Icterus gravis neonatorum** (severe jaundice of the new born), and other consequences like precipitation of bilirubin in the neuronal cells (**kernicterus**), and death if untreated.* *The standard treatment is the immediate replacement of the baby's blood with Rh negative blood by transfusion (**exchange transfusion**)* *Only one male in seven is Rh positive (i.e. males are heterozygous) and therefore, there is greater chance that the baby is Rh negative, and hence there will be no immune reaction.* **IMMUNITY** Immunity refers to the ability of the body to defend itself from foreign organisms. There are two types of immunity in the body, namely: a. ***natural (innate***) and b. ***acquired*** (developed) immunity. There are several substances in the body that are used to defend against foreign invading organisms or toxins, e.g. ***Lysozymes, Polypeptides, Interferon*** (proteins released from virus-infected cells, which blocks replication of the virus) and ***Complement*** (series of enzymes in the serum which when activated, produce widespread inflammatory effects and lysis of cells). In addition, the body may use ***phagocytes*** and polymorphonuclear ***leucocytes (neutrophils***) in its response to foreign invasion by infectious agents. The use of these measures by the body is referred to as ***natural immunity***, which is not specific to any disease or invading organism (compared with acquired immunity). In ***acquired immunity***, the immune process is initiated by the entrance of the foreign organism into the body. This is particularly important if the foreign organisms have overcome the natural immune system. In this situation, the lymphoid systems of the body are, therefore, stimulated to develop specific globular molecules, or sensitize lymphocytes that are capable of reacting with and destroying the invading organism or agents now and even later when similar infection occurs (using ***immunological memory***). This type of immunity takes several weeks or months to develop or sensitize new lymphocytes production, and by that time, harm may have been done. Thus, there are two types of response using acquired immunity. 1. ***Humoral immunity*** -- in which antibodies are developed against the antigen of the invading organism, and B lymphocytes are involved. An antibody is a specialized protein (immunoglobulins, Ig) capable of combining with specific foreign antigen which stimulated its production. The antibodies are formed by the ***plasma cells*** in the ***lymph nodes, spleen, GIT,*** and other tissues. Depending on the type of amino acid chains that make up the Ig, there are ***five classes of Igs***, namely, ***IgG, IgM, IgA, IgD, and IgE.*** However, majority of the Igs are ***gamma*** globulin (IgG) fraction, of about 160,000 molecular weight in size. The properties of some human antibodies are shown on the table below. +-----------------------+-----------------------+-----------------------+ | **S/No** | **Name of Antibody** | **Function of | | | | Antibody** | +=======================+=======================+=======================+ | 1 | IgG -- Half life of | Antiviral, | | | about 25 days. | antibacterial and | | | | antitoxin activity. | | | | | | | | Can cross the | | | | placenta. | +-----------------------+-----------------------+-----------------------+ | 2 | IgA -- Serum; Half | Usually in body | | | life of about 6 days. | secretions like: | | | | tears, saliva, milk, | | | | mucus, etc. Has | | | | antiviral and | | | | antibacterial | | | | activity. | +-----------------------+-----------------------+-----------------------+ | 3 | IgM -- Half life of | Antibacterial and | | | about 5 days | anti polysaccharide | | | | activity. Produced | | | | early in immune | | | | response. | +-----------------------+-----------------------+-----------------------+ | 4 | IgD -- Half life of | Present on the | | | about 3 days. | lymphocyte. | +-----------------------+-----------------------+-----------------------+ | 5 | IgE -- Half life of | Important in allergic | | | about 2 days. | reactions and, | | | | therefore, binds | | | | mostly to mast cells. | +-----------------------+-----------------------+-----------------------+ 2. **Cellular Immunity --** In cellular immunity, lymphocytes become specifically sensitized against the foreign antigen. This type of immunity is characterized by the sensitization of the T- lymphocytes (usually the small lymphocytes), which continue to circulate in blood and even divide and multiply. That is, they stay in circulation longer than that of humoral immunity. Secondly, it requires very small amount of the foreign antigen to stimulate T-lymphocytes system, and it ***does not*** involve the production of antibodies as in humoral immunity. Basically, the available dormant lymphoblasts (immature forms), on exposure to the foreign antigen, proliferate to form several committed similar lymphocytes. These lymphocytes then attack the invading organism by attaching to the cell membrane and causing lysis of the cell membrane of the invading organism. **THE LYMPHATIC SYSTEM** The lymphatic system is a closed system of vessels which drains tissue fluid from the interstitial (or tissue) spaces to return the fluid to the circulation, by way of the vena cava. The lymphatic system consists of the **lymphatic vessels,** and the ***lymphoid tissues*** within the ***spleen, thymus, tonsils*** and ***lymph nodes*** (see fig. 13.8 below) ***--*** all of which produce lymphocytes, the white blood cells involved in cellular immunity. The lymphatic system has three basic functions: \(1) it transports interstitial (tissue) fluid, initially formed as blood filtrate through capillaries, back to the blood; \(2) it transports absorbed fat from the small intestine to the blood; and \(3) its cells---called lymphocytes ---help provide immunological defenses against disease-causing agents (pathogens). The smallest vessels of the lymphatic system are the ***lymphatic capillaries*** ( fig. 13.36 ). Lymphatic capillaries are microscopic closed-ended tubes that form vast networks in the ***intercellular spaces*** within most organs. Because the walls of lymphatic capillaries are composed of endothelial cells, like those of blood capillaries with porous junctions, interstitial fluid, proteins, extravasated white blood cells, microorganisms, and absorbed fat (in the intestine) can easily enter into the lymphatic vessels. Once fluid enters the lymphatic capillaries, it is referred to as ***lymph.*** From merging lymphatic capillaries, the lymph is carried into larger lymphatic vessels called ***lymph ducts***. The walls of lymph ducts are similar to those of veins. They have the same three layers and also contain valves to prevent backflow and maintain unidirectional flow of the lymph from the lymphatic capillaries to the veins. Fluid movement within these lymphatic vessels occurs as a result of peristaltic waves of contraction. The smooth muscle within the walls of lymph ducts contains a pacemaker (nerve tissue) that initiates action potentials associated with the entry of Ca 2 +, which stimulates the contraction of the lymphatic vessels. The activity of the pacemaker, and hence the peristaltic waves of contraction, are increased in response to stretch of the vessel, even by body movements. N/B: *Read the legends and descriptions below the diagrams carefully to understand them well.* The lymph ducts eventually empty into one of two principal vessels: the thoracic duct or the right lymphatic duct. These ducts drain the lymph into the left and right subclavian veins, respectively. Thus, interstitial fluid, which is formed by filtration of plasma out of blood capillaries, is ultimately returned to the circulating blood (fig. 13.37 ). Before the lymph is returned to the cardiovascular system, it is filtered through lymph nodes ( fig. 13.38 ). Lymph nodes contain: (a) phagocytic cells, which help remove pathogens, and \(b) germinal centers, which are sites of lymphocyte production.  **ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)** AIDS is caused by the human immunodeficiency virus (HIV), after it has overwhelmed the body's immune system. The virus, HIV, belongs to the ***retrovirus family***, whose nucleic acid core is RNA rather than DNA. Retroviruses possess an enzyme, ***reverse transcriptase***, that, once the virus is inside a host cell (e.g. human cell), transcribes the virus's RNA into DNA, which is then integrated into the host cell's chromosomes. Replication of the virus inside the cells causes the cells' death. Unfortunately, the cells that HIV preferentially (but not exclusively) enters are ***helper T cells,*** one of the most important immune cells that helps the B cells and cytotoxic T cells. HIV infects these cells because the ***CD4 protein*** on the plasma membrane of helper T cells acts as a ***high-affinity receptor*** for one of the HIV's surface proteins (gp120). Thus, the helper T cell binds the virus, making it possible for the virus to then enter the cell. Very importantly, this binding of the HIV gp120 protein to CD4 is not sufficient to grant the HIV entry into the helper T cell. In addition, another surface protein on the helper T cell, one that serves normally as a receptor for certain chemokines, must serve as a co-receptor for the gp120. It has been found that persons who have a mutation in this chemokine receptor are highly resistant to infection with HIV, and much research is now focused on the possible therapeutic use of chemicals that can interact with and block this receptor. Once in the helper T cell, the replicating virus directly kills the helper T cell and also indirectly causes its death via the body's usual immune attack of infected cells, mediated in this case mainly by cytotoxic T cells, against virus-infected cells. In addition, by still poorly understood mechanisms, the HIV also causes the death of many uninfected helper T cells by apoptosis. Without adequate numbers of helper T cells, neither B cells nor cytotoxic T cells can function normally. Thus, the AIDS patient dies from infections and cancers that ordinarily would be readily handled by the immune system. AIDS was first described in 1981, and it has since reached epidemic proportions worldwide. The great majority of persons presently infected with HIV have no symptoms of AIDS as yet. This is an important point: One must distinguish between the presence of the symptomatic disease---AIDS---and asymptomatic infection with HIV. (***HIV is diagnosed by the presence of anti-HIV antibodies in the blood***.) It is thought, however, that all infected persons will eventually develop AIDS, although at highly varying rates. The path from HIV infection to AIDS commonly takes about 10 years in untreated persons. Typically, during the first five years the rapidly replicating viruses continually kill large numbers of helper T cells in lymphoid tissues, but these are replaced by new cells. Therefore, the number of helper T cells stays normal (about 1000 cells/mm^3^ of blood), and the person is asymptomatic. During the next 5 years, this balance is lost; the number of helper T cells, as measured in blood, drops to about half the normal level, but many people still remain asymptomatic. As the helper T cell count continues to fall, however, the symptoms of AIDS begin to manifest, through infections with bacteria, viruses, fungi, and parasites. These are called ***opportunistic infections***. These are accompanied by systemic symptoms of weight loss, lethargy, and fever--- all caused by high levels of the cytokines that induce the ***acute phase response***. Certain cancers also occur with high frequency. In untreated persons, death usually ensues within two years after the onset of AIDS symptoms. **HIV Transmission** The transmission of HIV is known to occur only through 1. ) transfer of contaminated blood or blood products from one person to another;