Chapter 21: The Lymphatic System and Immunity PDF

CHAPTER TWENTY-ONE The Lymphatic System and Immunity The immune system is the complex collection of cells and organs that destroys or neutralizes pathogens that would otherwise cause disease or death. The lymphatic system is the system of vessels, cells, and organs tha...

CHAPTER TWENTY-ONE The Lymphatic System and Immunity The immune system is the complex collection of cells and organs that destroys or neutralizes pathogens that would otherwise cause disease or death. The lymphatic system is the system of vessels, cells, and organs that carries excess fluids to the bloodstream and filters pathogens from the blood. 21.1 Functional Anatomy of the Lymphatic and Immune Systems A. Functions of the Lymphatic System: 1. The lymphatic system drains excess interstitial fluid from the interstitial space and transports it to the bloodstream. Once this tissue fluid enters into the lymphatic vessels, it is no longer called interstitial fluid; it is now referred to as lymph. Any blockage in the normal drainage of lymph produces lymphedema. 2. The lymphatic system houses the phagocytic cells and lymphocytes that clean the tissue fluid before it is dumped into circulation. 3. The lymphatic system absorbs digested fats from the intestine by specialized lymph vessels called lacteals. The fatty lymph is known as chyle. B. Structure of the lymphatic system 1. The lymphatic system includes the vessels, cells, tissues, and organs responsible for defending the body against both environmental hazards (such as various pathogens) and internal threats (such as cancer cells). 2. Lymph Vessels: carry lymph from the peripheral tissues to the venous system. The lymphatic network begins with lymphatic capillaries, which merge to form progressively larger vessels as they make their way towards circulation. a. Lymph capillaries: present in almost every tissue and organ in the body; are believed to be as abundant as blood capillaries. i. Lymph capillaries are absent, however, in areas of the body that lack a blood supply, such as the cornea of the eye, and are also absent from the central nervous system and bone marrow. ii. Lymphatic capillaries differ from blood capillaries in that they 1) are blind-end tubes, 2) have larger diameters with lower resistance and pressure, 3) have thinner walls that are more permeable, and 4) typically have a flattened or irregular shaped lumen. iii. Although lymphatic capillaries are lined by simple squamous epithelium, the basal lamina is incomplete or absent. Furthermore, the endothelial cells overlap forming a type of one-way valve called a mini-valve. The mini-valves permit the entry of fluids and solutes (such as proteins) as well as viruses, bacteria, and cell debris, but prevent their return to the intercellular spaces. b. Lymph collecting vessels: from the lymph capillaries, lymph flows into larger lymph collecting vessels with valves that lead toward the body’s trunk. c. Lymph trunks: the superficial and deep lymph collecting vessels converge to form larger vessels known as lymphatic trunks and are named by the areas of body they drain: i. The jugular trunks are located in the neck and drain the head. ii. The subclavian trunks are located in the shoulders and drain the arms. iii. The bronchomediastinal trunks are located in the chest and drain the thoracic cavity and lungs. iv. The lumbar trunks are located in the lower back and drain the pelvis and lower limbs.  v. The intestinal trunk is located in the abdomen and drains the walls of the digestive organs. vi. Blockage of the lumbar trunks or subclavian trunks by a filarial worm, such as Wuchereria bancrofti, causes severe lymphedema known as Elephantiasis. d. Lymph ducts: the lymph trunks merge to form the two largest lymphatic vessels called the right lymphatic duct and thoracic duct. i. The right lymphatic duct forms from the merger of the right jugular trunk, the right subclavian trunk and the right bronchomediastinal trunk. The right lymphatic duct drains the right side of the head, right arm, right shoulder, and right side of the thoracic cavity. The right lymphatic duct empties into the right subclavian vein. ii. The thoracic duct ascends along the left side of the vertebral column, collecting lymph from the left bronchomediastinal trunk, the left subclavian trunk, the left jugular trunk. At the base of the thoracic duct is an enlarged sac-like chamber called the cisterna chyli which receives lymph from the lumbar trunk and intestinal trunk. The thoracic duct drains the left side of the head, the left arm, the left shoulder, and the left side of the thoracic cavity, all of the abdomen, pelvic region and both legs. It empties into the left subclavian vein. C. The Organization of Immune Function 1. Barrier defenses such as the skin and mucous membranes, which act instantaneously to prevent pathogenic invasion into the body tissues 2. Innate immune response – rapid, non-specific response consists of a variety of specialized cells and soluble factors 3. Adaptive immune response – slower, specific and effective, involves many cell types and soluble factors, but is primarily controlled by white blood cells (leukocytes) known as lymphocytes, which help control immune responses 4. In adults, erythropoiesis is normally confined to red bone marrow, but lymphocyte production, called lymphopoiesis, involves the red bone marrow, thymus, and peripheral lymphoid tissues. WBCs can be divided into three classes based on function: a. Phagocytic cells - ingest pathogens to destroy them b. Lymphocytes - specifically coordinate the activities of adaptive immunity c. Granular WBCs - help mediate immune responses against parasites and intracellular pathogens such as viruses D. Lymphocytes: B Cells, T cells, Plasma cells and Natural Killer cells 1. Although lymphocytes account for 20-30 percent of the circulating leukocyte populations, circulating lymphocytes are only a small fraction of the total lymphocyte population. The majority of these reside within the lymph organs of the body such as the lymph nodes, spleen, tonsils, thymus, etc. 2. Three classes of lymphocytes circulate in blood and are sensitive to specific antigens: a. B cells – account for 10-15 of circulating lymphocytes. B cells are said to be responsible for antibody-mediated immunity (aka humoral immunity) because antibodies circulate widely within body fluids and attack targets with foreign antigens. When stimulated by an antigen, B cells differentiate into plasma cells. b. Plasma cells, which produce and secrete antibodies. Plasma cells differ in morphology from standard B and T cells in that they contain a large amount of cytoplasm packed with the protein-synthesizing machinery known as rough endoplasmic reticulum. c. T cells – approximately 80 percent of the circulating lymphocytes are classified as T cells. T cells are diverse and provide cell-mediated immunity (discussed later).  d. Natural Killer (NK) cells – only about 5-10 percent of circulating lymphocytes are Natural Killer cells. This particular group of lymphocytes is part of the body’s non- specific defenses and they using cytotoxic granules to attack foreign cells, body cells infected with viruses, and cancer cells that appear in normal tissues. Their continuous monitoring of peripheral tissues has been called immunological surveillance. E. Primary Lymphoid Organs and Lymphocyte Development 1. Red bone marrow. Blood cells are made in the yolk sac in an embryo. This function is taken over by the spleen, lymph nodes, and liver as the embryo develops. Later, the bone marrow takes over most hematopoietic functions, although the final stages of the differentiation of some cells may take place in other organs. Thymocytes - immature T cells leave the bone marrow and mature largely in the thymus gland. 2. Thymus – produces several hormones, collectively called the thymosins, that are important to the development of functional T cells, and thus to the maintenance of normal body defenses. a. The thymus is large when a person is born and continues to grow through childhood as the individual is exposed to infection. By puberty, the thymus weighs 40 g. However, after puberty, it gradually diminishes in size and becomes increasingly fibrous in a process known as involution. By the time an individual reaches age 50, the thymus may weigh less than 12 g and is correlated with an increase in susceptibility to infection and disease. b. The thymus is surrounded by a capsule that divides it into left and right lobes. Fibrous partitions called septa originate at the capsule and divide the lobes into lobules averaging 2 mm in diameter. c. Each lobule consists of a dark outer cortex and a lighter central medulla. The medulla is dominated by thymic corpuscles not present in the cortex. F. Secondary Lymphoid Organs and their Roles in Active Immune Responses. 1. Naïve lymphocyte - one that has left the primary organ and entered a secondary lymphoid organ. Naïve lymphocytes are fully functional immunologically, but have yet to encounter an antigen to respond to. 2. Lymph nodes – are small lymphoid organs ranging in diameter from 1 mm to 25 mm. The shape of a typical lymph node resembles that of a kidney bean. The largest collections of lymph nodes are located in the cervical region, axillary region, and inguinal region. As lymph flows through a lymph node, at least 99% of the antigens in the lymph are removed and the immune response is stimulated as needed. Swollen lymph nodes are called buboes. The path of lymph flow through a lymph node is as follows: a. Afferent lymphatic vessels – transport “dirty” lymph into the lymph node from the peripheral tissues. The afferent lymphatic vessels penetrate the capsule of the lymph node on the side opposite the hilum (a shallow depression where the blood vessels and nerves enter and leave the organ). b. The afferent vessels deliver the lymph to the subcapsular space, a meshwork of reticular fibers, macrophages, and dendritic cells. Dendritic cells are involved in the initiation of the immune response. c. Lymph next flows in the outer cortex which contains B cells within germinal centers that resemble those of lymphoid nodules. d. Lymph then flows through the lymph sinuses to the deep cortex which is dominated by T cells. e. Lymph continues into the medullary sinuses at the core of the lymph node. This region contains B cells and plasma cells. f. Efferent lymphatic vessels – drain the “cleaned” lymph out of the lymph node and exit at the hilum.  3. Spleen – is the largest lymphoid organ and performs the same functions for blood that the lymph nodes perform for lymph. The spleen removes abnormal red blood cells, stores iron from recycled RBCs, and initiates immune response by B cells and T cells to antigens in the bloodstream. a. The spleen lies along the curving lateral border of the stomach. It is attached to the lateral border of the stomach by the gastrosplenic ligament, a broad band of mesentery. The outer surface, called the diaphragmatic surface, is smooth and convex, conforming to the shape of the diaphragm and body wall. b. The spleen is surrounded by a capsule containing collagen and elastin fibers. The spleen tears so easily that a seemingly minor impact to the left side of the abdomen can rupture the capsule. Because it is so fragile, it is difficult to repair and is instead typically removed in a process called a splenectomy. c. Splenic blood vessels and lymphatic vessels communicate with the spleen on the medial surface (also called visceral surface) at the hilum. The medial surface also has two shallow depressions that conform to the shape of the stomach (gastric area) and that of the kidney (renal area). d. Fibrous partitions, called trabeculae, radiate outward toward the capsule through the interior from the hilum. Blood vessels travel within the trabeculae. e. The cellular components within the spleen constitute the pulp. The red pulp contains large quantities of red blood cells, whereas the white pulp resembles lymphoid nodules and contains lymphocytes. f. The unusual circulatory arrangement within the spleen gives the phagocytes of the spleen an opportunity to identify and engulf any damaged or infected cells in circulating blood. G. Lymph nodules - areas of densely packed lymph tissue or lymphocytes. Houses a specialized form of connective tissue called reticular connective tissue which resembles areolar tissue but contains larger numbers of collagen, elastin, and reticular fibers. Their boundaries are not distinct because although they may cluster together and form large masses, there is no fibrous capsule surrounding them. 1. Tonsils are large lymphoid nodules in the walls of the pharynx. Left and right palatine tonsils are located at the posterior, inferior margin of the oral cavity. A single pharyngeal tonsil (often called the adenoid) lies in the posterior superior wall of the nasopharynx, and a pair of lingual tonsils lies deep to the mucous epithelium covering the base of the tongue. A final pair of tonsils, called the tubal tonsils, is found in the base of each of the pharyngotympanic tubes. Most of the time, our tonsils go unnoticed unless they are infected and swollen, a condition known as tonsillitis. 2. Mucosa-associated lymphoid tissue (MALT) protects the rest of the epithelia of the digestive, respiratory, urinary, and reproductive tracts from pathogens and toxins. a. A variety of clinical disorders can result from infection and/or inflammation of the MALT components such as appendicitis (inflammation of lymphoid tissue from the appendix). b. Aggregated lymphoid nodules, or Peyer’s patches, are a type of MALT, found clustered deep in the epithelial linings of the distal small intestine. Each nodule has a central zone, called the germinal center, which contains rapidly-dividing lymphocytes. c. Bronchus-associated lymphoid tissue (BALT) consists of lymphoid follicular structures with an overlying epithelial layer found along the bifurcations of the bronchi, and between bronchi and arteries. 3. Cancer originating in any lymphoid cells or tissues is called lymphoma. Hodgkin’s lymphoma is characterized by the presence of Reed-Sternberg cells and has been associated with the Epstein-Barr virus in 70% of cases. All other types of lymphoma are called Non-Hodgkin’s lymphoma of which there are at least 61 types. 21.2 Barrier Defenses and the Innate Immune Response A. Characteristics of the innate body defenses: 1. Innate defenses are present and functioning at birth. 2. Innate defenses are non-specific, that is, they do not distinguish one threat from another and respond the same way regardless of the invading agent. 3. Innate defenses tend to be more localized and generally attack the infection where the invading agent is attempting to gain entry into the body. 4. Innate defenses have no memory. Regardless of the number of times the body encounters the invading agent, innate defenses do not improve their response to the infection. B. Innate immunity includes physical barriers, cellular defenses via phagocytes and NK cells, and chemical defenses via complement, inflammatory chemicals, interferon, and pyrogens. C. PHYSICAL BARRIERS – keep hazardous organisms and materials outside the body. 1. Skin – the integumentary system provides the major physical barrier to the external environment. a. The epidermis of the skin is composed of stratified squamous epithelium with keratinized cells and a network of desmosomes that lock adjacent cells together. b. Hairs found on most areas of the body’s surface provide some protection against mechanical abrasion (especially on the scalp), and they often prevent hazardous materials or insects from contacting the skin. c. The epidermal surfaces receive the secretions of sweat glands. These secretions, which flush the surfaces to wash away microorganisms and chemical agents, may also contain bactericidal chemicals called defensins, destructive enzymes called lysozymes, and antibodies. d. The epidermal surfaces receive secretions from sebaceous glands. Sebum not only lubricates the skin but also reduces the amount of free water on the surface of the skin, thereby creating an arid environment that most microorganisms find inhospitable. 2. Mucous membranes – the epithelial linings of the digestive, respiratory, urinary, and reproductive tracts provide a barrier that most organisms cannot cross. a. Mucus bathes the surfaces of the mucous membranes. The mucus captures most microorganisms and debris so that it cannot gain entry past the delicate internal passageways. b. Mucous membranes also secrete chemicals that reduce the growth of microorganisms: powerful acids, lysozymes, and defensins. c. The cells of mucous membranes are held together by numerous tight junctions and supported by a fibrous basal lamina. d. Mucous membranes often possess cilia that create an outward wave of movement that transports microorganisms up and out of the body. e. Mucous membranes possess MALT (mucosa-associated lymphatic tissue). D. CELLULAR DEFENSES – if the hazardous organism gains entry into the body, cells attack the infection at the site of entry. 1. Phagocytic cells – cells that engulf pathogens and cell debris should they make it past the physical barriers created by the skin and mucous membranes. a. Characteristics common to all phagocytes: i. Phagocytes can leave capillaries by squeezing between adjacent endothelial cells in a process known as diapedesis, or emigration. ii. Phagocytes are attracted to chemicals produced by infection in a phenomenon called positive chemotaxis.  iii. Phagocytosis always begins with the attachment of the phagocyte to its target cell. In this process, called adherence, receptors on the plasma membrane of the phagocyte bind to the surface of the target. iv. After attachment, the phagocyte may either destroy the target itself or promote its destruction by activating T cells and B cells. b. Different types of phagocytic cells: i. Neutrophils – the most abundant leukocytes; they are highly mobile and quick to phagocytize cellular debris or invading bacteria. They circulate in the bloodstream and roam through the peripheral tissues, especially at the sites of injury or infection. ii. Eosinophils – less abundant than neutrophils and have limited abilities to phagocytize compared to neutrophils; they engulf foreign pathogens only it they’ve been coated with antibodies. iii. Monocytes – less numerous than neutrophils but more numerous than eosinophils; give rise to types of macrophages: free and fixed. a) Free macrophages travel throughout the body, arriving at the site of injury by migrating through adjacent tissues or by recruitment from the circulating blood. An example of a free macrophage would be dendritic cells. b) Fixed macrophages are permanent residents of specific tissues and organs and are scattered among connective tissues. They normally do not move within these tissues. An example of a fixed macrophage would be the kupffer cells of the liver. 2. NK cells – detect and destroy abnormal body cells or virus infected cells. a. Generally the immune system ignores the body’s own cells unless they become abnormal in some way such as cancer cells. The constant monitoring of normal tissues by Natural Killer (NK) cells is called immunological surveillance. NK cells are also able to recognize bacteria, foreign cells, and cells infected by viruses. b. In each case, the steps leading to destruction of the target cell are similar: i. Step one: If a cells has unusual components in its plasma membrane, NK cells recognize the cell as abnormal and adhere to the cell. ii. Step two: Large numbers of secretory vesicles are produced by the golgi apparatus. These vesicles, which contain the proteins called perforins, travel through the cytoplasm toward the cell surface. iii. Step three: The perforins are released at the cell surface by exocytosis and diffuse across the narrow gap separating the NK cell from its target. iv. Step four: The perforins create holes or pores in the plasma membrane of the target cell so that it can no longer maintains its internal environment and it quickly disintegrates. E. CHEMICAL DEFENSES – substances that destroy the organism, label it as an invading cell, prevent it from reproducing in the body, or stimulate other immune system cells to respond. 1. Interferons – an example of a cytokine, interferons are secreted by lymphocytes, macrophages, and tissues infected with viruses. a. When a virus is in the body, interferons are secreted to protect healthy cells. On reaching the membrane of a normal cell, the interferon binds to surface receptors on the cell and via a second messenger, triggers the production of antiviral proteins within the cell’s cytoplasm. b. Antiviral proteins do not interfere with the entry of viruses but instead interfere with viral replication inside the cell thereby preventing the spread of the virus.  c. At least three types of interferons exist: i. Alpha interferons – produced by viral infected cells to attract NK cells and enhance resistance to viral infection. ii. Beta interferons – secreted by fibroblast to slow inflammation in a damaged area. iii. Gamma interferons – secreted by T cells and NK cells to stimulate macrophage activity. 2. Complement – a system of 11 circulating proteins that assist, or complements, antibodies in the destruction of pathogens. There are two pathways for complement action and both are described as an enzyme cascade leading to a series of common steps: a. Classical pathway: the most rapid and effective activation of the complement system also sometimes called the antigen-antibody complex. i. The classical pathway begins when one of the complement proteins attaches to antibody molecules already bound to their specific antigen. ii. The attached complement protein then acts as an enzyme, catalyzing a series of reactions involving other complement proteins. iii. Eventually an activated complement protein binds to the bacterial cell wall which then enhances lysis of the foreign cell, opsonization and phagocytosis of the foreign cell, or histamine release triggering the inflammatory response. b. Alternative pathway: most important in the defense against bacteria, some parasites, and virus infected cells. i. The alternative pathway begins when several complement proteins, notably factor B, factor D, and properdin, interact in the plasma. The interaction of these complement proteins can be triggered by exposure to foreign materials, such as the capsule of a bacterium. ii. The end result is the attachment of an activated complement protein to the bacterial cell wall which then enhances lysis of the foreign cell, opsonization and phagocytosis of the foreign cell, or histamine release triggering the inflammatory response. 3. Inflammatory chemicals – localized, tissue-level response that tends to limit the spread of an injury or infection. a. The inflammatory response follows a complex process: i. Step one: tissue damage (including impact, abrasion, distortion, chemical irritation, infection by pathogens, and extreme temperatures) can induce inflammation. ii. Step two: injured or infected tissues release prostaglandins, cytokines, potassium ions, pyrogens, and a host of other “alarm chemicals”. iii. Step three: mast cells and basophils are activated; these then release histamine and heparin iv. The flood of chemicals into the body fluids induce numerous changes: a) Vasodilation increases blood flow to the site of damage b) Increased permeability of the local blood vessels causes exudate to seep out of the bloodstream. c) Fibrin threads form a network that occludes lymph vessels which limit the removal of lymph which in turn, reduces the spread of infection. In combination with increased permeability of blood vessels, this causes swelling, or edema. d) Leukocytosis – stimulation of increased WBC production  e) Positive chemotaxis – activated phagocytes, especially neutrophils, are attracted to the site of injury where they begin phagocytizing foreign and injured cells. b. The four cardinal signs of inflammation: redness, heat, swelling, and pain. 4. Pyrogens – a fever-inducing chemical that elevates the body temperature which in turn, accelerates tissue metabolism, tissue repair, and the activity of immune defenses. a. Fever is defined as the maintenance of body temperature above 37.2o C (or 99oF). For each 1oC rise in body temperature, metabolic rate jumps by 10%. b. Within limits, an increase in body temperature may be beneficial because it can inhibit the growth and reproduction of bacteria and viruses and can stimulate increased metabolism and tissue repair. c. However, beyond a certain threshold, high body temperature can begin to denature proteins which could actually shut down normal immune response. 21.3 The Adaptive Immune Response: T lymphocytes and Their Functional Types A. Characteristics of the adaptive immune defenses: 1. Adaptive defenses are not present and functioning at birth and are instead developed as a result of exposure to infections and their antigens. 2. Adaptive defenses are specific, that is, they recognize and attack one infection with one specific antigen while ignoring all other infections with different antigens. 3. Adaptive defenses tend to be more systemic and can attack the infection anywhere and everywhere in the body not just where it got in. 4. Adaptive defenses have memory. With each exposure to the infection, the adaptive defenses modify and improve their response to the infection so that the response is faster, stronger, and longer-lasting. 5. Adaptive defenses are versatile. Because exposure to the infection causes the adaptive cells to multiply, clones that are all specific to the infection are produced. Each clone can then take on a different role in the immune response to the infection. 6. Adaptive defenses exhibit tolerance. The immune system ignores normal body tissues (recognized as “self”) while it targets abnormal body tissues (recognized as “non-self”). B. There are two main types of adaptive defenses: cell mediated immunity and antibody-mediated immunity: C. CELL MEDIATED IMMUNITY 1. Properties of Cell Mediated Immunity: a. Provided by the action of T-lymphocytes which are produced in the red bone marrow but mature in the thymus gland. b. T-lymphocytes cannot recognize antigen directly, instead the antigen must be processed and presented to the T-lymphocyte by either specialized Antigen Presenting Cells (APCs) or infected body cells. c. Antigen presentation occurs when glycoproteins on the surface of APCs or body cells display an antigen or a piece of the antigen. These membrane glycoproteins are called major histocompatibility complexes or MHC proteins. d. There are two classes of MHC proteins: i. Class I MHC proteins – found on every body cell to allow body cells infected with virus to alert the immune system that they’ve been attacked by infection and reveal the identity of their attacker. ii. Class II MHC proteins – found only on the membranes of APCs (which may be macrophages, other phagocytic cells such as neutrophils or eosinophils, and dendritic cells). Class II proteins allow APCs to alert the body that infection has  been discovered and stimulate other immune system cells to rush to the site of infection to help with the attack. 2. Stimulation and Clonal expansion of T cells a. When macrophages patrolling the body tissues encounter foreign organisms, they engulf them by phagocytosis. Once the organism is inside the macrophage, the macrophage processes the antigen and exposes it on the surface of its own cell in combination with the Class II MCH protein. The antigen - class II MHC complex can only be recognized by the cell that possesses a special CD4 marker. The only cells that possess the CD4 marker are the CD4 T cells that differentiate to form TH cells and memory TH cells. The TH cells begin secreting cytokines which now alert other B and T lymphocytes that an infection has been located and guides these cells to the site of infection by positive chemotaxis. b. On the other hand, if a body cell becomes infected by a virus, it can alert the body that it has been attacked. Once the virus is inside the body cell, the body cell takes pieces of the abnormal peptides of the virus and incorporates them with MCH proteins on their surface. Typical body cells however do not possess the Class II MCH proteins that macrophages possess. Instead, they possess the Class I MHC proteins that bind to the foreign antigen and stimulate only cells that possess the CD8 makers. CD8 T cells differentiate to form TC cells, TS cells and Memory TC cells. When the TC cell recognizes the antigen-MHC Class I complex, the cytotoxic T cells destroy the “sick” body cell by perforins, by activation of genes within the body cell which trigger apoptosis of the body cell, and disruption of the cell’s metabolism through the release of lymphotoxins. 3. Four types of T-cell clones are produced during infection: a. Helper T cells – TH cells or CD4 T-cells, produce cytokines that stimulate the proliferation of all other immune cell types (including more phagocytic cells, T-cells, and B-cells) to join the attack against the infection. b. Cytotoxic T cells – TC cells, also called killer T cells; stimulated by infected body cells and helper T cells to attack virus-infected body cells and cancer cells. c. Suppressor T cells – TS cells, shut down the activity of T cells and B cells once the infection has been conquered by the secretion of suppression factors. d. Memory T cells – cells that remain in circulation long after the infection is over to respond to future infections by the same pathogen. 21.4 Adaptive Immune Response: B-lymphocytes and Antibodies A. Properties of Antibody Mediated Immunity: 1. Provided by the action of B-lymphocytes which are produced in the red bone marrow and remain there to mature. 2. Also called Humoral Immunity because B-lymphocytes attack the infection or their antigens while in the body fluids (blood, lymph, interstitial fluid, etc.) 3. Although B-lymphocytes reside in the spleen and lymph nodes many are also circulating in the body fluids where they can directly recognize infection or their antigens and then undergo clonal expansion. B. Antibody Structure 1. An antibody molecule consists of four polypeptide chains: one pair of heavy chains on the interior and one pair of light chains on the exterior. The four chains are held together by disulfide bonds. 2. Each of the four chains has a constant region where the amino acid sequence is the same and a variable region where the amino acid sequence is unique. The constant segments of the heavy chains form the base of the antibody molecule.  3. The free tips of the two variable segments form the antigen binding sites of the antibody molecule. These sites can interact with an antigen in the same way that the active site of an enzyme interacts with a substrate. Small differences in the amino acid sequence of the variable regions affect the precise shape of the antigen binding site so that each antibody can demonstrate specificity. 4. When an antibody molecule binds to its corresponding antigen molecules, an antigen-antibody complex is formed. a. Antibodies bind not to the entire antigen, but to specific portions of its exposed surface – regions called antigenic determinant sites. b. A complete antigen is an antigen with at least two antigenic determinant sites, one for each of the antigen binding sites on an antibody molecule. c. A partial antigen, or haptens, does not ordinarily cause B-cell activation. However, they may become attached to carrier molecules, forming combinations that can function as complete antigens. C. There are five different classes of antibodies, or immunoglobulins (Igs). The classes are determined by differences in the structure of the heavy-chain constant regions and so have no effect on the antibody’s specificity, which is determined by the antigen binding sites out on the variable region of the chains. 1. IgA – a dimer found primarily in glandular secretions such as mucus, tears, saliva, breast milk, sweat, and semen. These antibodies attack the pathogens before they gain access to internal tissues. 2. IgD – a monomer found on the surface of B-cells where it can bind antigens in the extracellular fluids. This binding plays a role in the sensitization of the B cell so that it proliferates to form the clone army. 3. IgE – a monomer that attaches as an individual molecule to the exposed surfaces of basophils and mast cells which initiate the inflammatory response via histamine and heparin. 4. IgG – account for 80% of all antibodies. IgG antibodies are responsible for resistance against many viruses, bacteria, and bacterial toxins. IgG are monomers and can cross the placenta. IgG antibodies cause the effects of HDN, hemolytic disease of the newborn, discussed in chapter 17. 5. IgM – a pentamer secreted after an antigen is encountered. IgM concentrations decline as IgG production accelerates. The anti-A and anti-B antibodies responsible for the agglutination of the incompatible blood types are IgM antibodies. D. Sensitization and Clonal Expansion of B-lymphocytes: 1. When a B-lymphocyte encounters its specific antigen in the body fluids, it prepares to undergo activation. This preparatory process is called sensitization. 2. The activated B-lymphocytes begin to proliferate rapidly forming a “clone” army. This initial response to exposure to an antigen is called the primary response. Because the antigen must activate the appropriate B-cells, the primary response takes time to develop. During the primary response, the antibody titer, or level of antibody activity in plasma, does not peak until one to two weeks after the initial exposure. 3. As the B-cell clones mature, they differentiate into two types of cells: a. Plasma B-cells – secrete free antibodies that attack the current infection and/or the antigens of the infection. After the infection is defeated, plasma cells undergo apoptosis, or programmed cell death. The antibodies secreted by the plasma cells (which can be as many as 100 million antibodies per hour) remain in circulation for an extend amount of time after the infection is over. b. Memory B-cells – remain in reserve and are primed to respond quickly to subsequent exposures to infections with the same antigens. The next time you encounter the same  infection, memory B-cells generate a faster and more efficient response. This is called the secondary response. In the secondary response, antibody titers increase more rapidly and reach levels many times greater than they did in the primary response. The secondary response is triggered even if the second exposure occurs years after the primary exposure. E. Humoral immunity can be actively or passively developed. 1. ACTIVE: a person makes their own antibodies giving them long-term immunity a. Naturally acquired active immunity – a person makes their own antibodies in response to a natural exposure to antigens in the environment. Example: getting chicken pox from your classmate. b. Artificially acquired active immunity – develops after administration of an antigen to purposely expose someone to antigen. Administration of the antigen stimulates the immune system to make antibodies against the infection. Example: vaccinations. 2. PASSIVE: antibodies are generated by someone or something else which provides short-term immunity. a. Naturally acquired passive immunity – a person receives antibodies from another person by participating in a natural activity. Example: an infant getting antibodies from their mother through breast milk. b. Artificially acquired passive immunity – antibodies produced by someone else are purposely given to the person to provide immunity. Example: anti-venom or gamma globulin, 21.5 The Immune Response Against Pathogens Antibodies use many different mechanisms to destroy target antigens. Because each antibody can perform a different function, they are said to be versatile. A. Complement activation – upon binding to antigen, portions of the antibody molecule change shape, exposing areas that bind complement proteins. The bound complement molecules then activate the complement system which destroys the antigen by lysis or enhancing phagocytosis. B. Opsonization – antibodies can coat the surface of pathogens so the pathogens become “sticky” and are more susceptible to phagocytosis. C. Phagocytosis – antigens covered with antibodies attract neutrophils, monocytes, and eosinophils – cells that phagocytize pathogens and destroy foreign or abnormal plasma membranes. D. Precipitation and Agglutination – if antigens are close together, an antibody can bind to antigenic determinant sites on two different antigens. In this way antibodies can clump large numbers of antigen together. When the target antigen is on the surface of a cell or virus, the process is called agglutination. When the target antigen is non-cellular, the clumping is called precipitation. E. Neutralization – both viruses and bacterial toxins must bind to the plasma membrane of body cells before they can enter or injure those cells. Antibodies can block the binding sites so the viruses or toxins cannot bind to the body cells. This is called neutralization. F. Prevents pathogen adhesion – antibodies dissolved in saliva, mucus, sweat, and tears coat epithelial cells, providing an additional layer of defense. A covering of antibodies makes it difficult for bacterial and viruses to adhere to penetrate body surfaces. G. Inflammation – antibodies may promote inflammation by stimulating the release of histamine and heparin from basophils and mast cells. 21.6 Immune System Disorders A. Immunodeficiency = deficient numbers of immune system cells 1. Severe combined immunodeficiency (SCID) syndrome is a congenital condition that results from a genetic disorder leading to deficits in both B and T cells.  2. Acquired immune deficiency syndrome (AIDS) is caused by the Human immunodeficiency virus (HIV) is a condition that destroys the helper T cells thus depressing cell-mediated immunity. Most patients die of opportunistic infections such as the flu or pneumonia. B. Allergies occur when the antibody response is so severe it causes tissue damage as it fights off a perceived infection, or allergen, that would otherwise be harmless to the body (such as pollen or pet dander). 1. Immediate hypersensitivity (Type I) = begins within seconds of exposure and lasts half to one hour. Example: anaphylactic shock and allergic rhinitis 2. Subacute hypersensitivity (Type II – III) =onset is 1-3 hours after exposure and the duration is 10-15 hours. Example: Type II = such as transfusion of mismatched blood and Type III = farmer’s lung. 3. Delayed hypersensitivity (Type IV) = occurs within 1-3 days and lasts for a week or more. Example: Contact dermatitis such as poison ivy and the tuberculosis skin test C. Autoimmune disease occurs B cells make antibodies against normal body tissues. These misguided antibodies are called autoantibodies. There are numerous autoimmune diseases: 1. Multiple sclerosis – autoantibodies attack white matter of the nervous system leading to demyelination of neurons which can cause weakness or even paralysis. 2. Rheumatoid arthritis – autoantibodies destroy the connective tissues associated with joints or the joint capsules. 3. Systemic lupus erythematosus – autoantibodies attack many organs 4. Grave's disease – autoantibodies attack thyroid tissue causing an excess production of thyroxine. 5. Type I diabetes mellitus – also known as insulin-dependent diabetes mellitus (or IDDM), autoantibodies attack the pancreatic cells that produce insulin. 6. Glomerulonephritis – autoantibodies attack the kidneys leading to renal dysfunction. 7. Myasthenia gravis – attack ACh receptor at neuromuscular junctions leading to debilitating muscle weakness 21.7 Transplantation and Cancer Immunology A. Graft Rejection 1. Result from tissues, organs, or blood transplants that are not compatible with the tissues of the recipient. They are recognized as non-self and attacked. 2. In order to reduce rejection, the best possible match is sought and immunosuppressive drugs are used. a. Autografts = tissues from the same person b. Isografts = tissues from genetically identical twins c. Allografts = tissues from non-genetically identical persons d. Xenografts = tissues from organisms of different species