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Chapter 10

  1. 1. Rhoades/Bell 3e Chapter 10, page 1 First draft Insert date of submission Chapter 10 Immunology, Organ Interaction and Homeostasis Gabi Nindl Waite, Ph.D. Active Learning Objectives Upon mastering the material in this chapter you should be able to: Explain what triggers an immune response and where in the body the immune response occurs Understand how the immune system handles exogenous and endogenous antigen differently Define the differences between innate and adaptive immunity and their complementary activities Discuss how antigen specificity is achieved in the immune system Understand the different roles of immune cells and their communication Describe the structure and functions of different antibodies Outline the functions of acute inflammation and separate them from chronic inflammation Explain the immune-related requirements for organ transplantation Present an overview of immune system disorders Explain the immune system’s role in allergic and immune system disorders Portray how the immune system interacts with other systems to maintain homeostasis Talk about some novel immune topics in clinics and research The immune system is the body’s primary defense system against all harmful agents. Harmful agents might be living matter such as bacteria, parasites, fungi and viruses, or non-living matter such as toxins, chemicals, drugs or foreign particles. The immune system is composed of a complex system of organs, tissues, specialized cells and a circulatory system. It tries to prevent the agents from entering the body, and if they do enter, attacks them. When the immune system functions optimally, the substances are
  2. 2. Rhoades/Bell 3e Chapter 10, page 2 First draft Insert date of submission eliminated before the host shows disease symptoms. The immune system is also involved in detecting aberrant cellular structures such as tumor cells. A body without an immune system would not be able to survive more than a few days. Understanding the immune system is of crucial importance to understanding how the body functions, and hence is an important part of physiology. However, one chapter about the immune system cannot do justice to such a fascinating aspect of our body. The aim of the current chapter is to place the functioning of the immune system within the framework of the whole human organism and its homeostasis, and to provide the foundation on which one can expand in the specialty courses immunology, microbiology and pathophysiology.
ACTIVATION AND LOCATION OF THE IMMUNE SYSTEM The ultimate function of the immune system is to recognize and to destroy foreign substances in the body. Any substance that provokes the immune system is called an immunogen. Organisms that might cause diseases are called pathogens. They may enter the body through a cut in the skin, as in the case of the hepatitis B virus, through membranes of the respiratory tract, as in the case of the measles virus, or through membranes of the digestive tract, as in the case of salmonella bacteria. Pathogens may further be transmitted by insect bites, as in the case of malaria, or by sexual encounter, as in the case of the HIV virus. Antigens are substances that bind to receptors on T and B cells or antibodies. Haptens are similar to antigens, but are only immunogenic when linked to a carrier molecule. In addition to pathogens, a large number of other foreign substances can be antigenic. Pesticides, cosmetics and exhaust particles are examples of such substances, whose number increases with the advancement of technology in our society. Exogenous antigens such as bacteria and foreign particles are most accessible to immune elimination. They first activate the innate immunity (see Innate Immune System below). As part of it, immune cells
  3. 3. Rhoades/Bell 3e Chapter 10, page 3 First draft Insert date of submission might engulf the antigen or destroy it with enzymes and oxygen radicals. Complement proteins might lyse the organism and promote inflammation (see Inflammation below). If the pathogen evades the innate immune system, the adaptive immunity response is triggered, where cells and antibodies work together to eliminate the antigen (see Adaptive Immune System below). Endogenous (intracellular) antigens such as viruses, protozoan parasites, and intracellular bacteria are eliminated together with the infected host cell. Antibodies can bind directly to the infected cell and activate complement, if some immunogenic parts of the microorganism are present on the plasma membrane of the host cell (see humoral immunity below). If the antigen cannot immediately be recognized on the surface of the cell, it is degraded intracellularly into smaller pieces. These are then incorporated into the host cells’ plasma membranes and together with major histocompatibility complex (MHC) proteins presented to T cells (see T cell mediated immunity below).
A Molecule Must Be Recognized as Foreign to Elicit a Physiological Immune Response Any antigen that is not recognized as being a normal part of the body is marked as being potentially dangerous to the body. This discrimination of self from non-self is one of the core tasks of the immune system. Body cells carry molecules that label them as “self” so that the immune system ignores them, a process called self-tolerance. Foreign molecules also carry distinctive markers, and the immune system recognizes many millions of them. There are some exemptions. We generally tolerate food-derived foreign particles; although some foods induce allergic reactions (see Immune Diseases below). A mother does not reject the fetal molecules that are derived from the father. Identical twins can accept skin grafts from each other without causing immune reactions (see Organ Transplantation below). On the other hand, when a body erroneously mounts an immune response against its own tissues, it leads to autoimmune diseases (see Immune Diseases below).
  4. 4. Rhoades/Bell 3e Chapter 10, page 4 First draft Insert date of submission Each part of the antigen bound by a unique antibody is called an epitope. Most protein antigens have several epitopes that are recognized by different B cells and induce a polyclonal antibody response. Antibodies of a single specificity (monoclonal) are used for immune diagnostic tests and immunotherapy. Epitopes may be shared by closely related antigens (cross-reactivity). For instance, the vaccine against tetanus disease contains tetanus toxoid, which makes the body produce antibodies that also recognize tetanus toxin, the poisonous substances produced by Clostridium tetani bacteria. Proteins are by far the best immunogens. Polysaccharides, lipids and nucleic acids by themselves induce either weak or no immune responses, but their antigenicity is greatly improved when attached to proteins. This principle is used for many vaccines. For instance, the vaccine targeting the carbohydrate capsule of Streptococcus pneumoniae is conjugated to protein carriers to enhance its effectiveness. The immunogenicity of substances increases with their complexity. For instance, polymers made of only one type of nucleotide are poor immunogens regardless of their size, while polymers made of more than one base are usually good immunogens. Nevertheless, size matters, and typically, only molecules with a molecular weight of 4000 Dalton or above elicit an immune response. Other factors that increase the likelihood of being recognized by the immune defenses are protein aggregation, protein charges and complex three-dimensional conformation.
Body Defenses After Injury Can Occur With or Without Immune Activation Immune responses are tied in with other body defenses and reactions. When the body sustains injury, whether from physical force, cellular breakdown, or biological infection, the decision for immune activation depends on the severity and type of the injury. If the cells are not too severely injured, cells may adapt to the event by changing their size, number and functions. For instance, skeletal muscle cells in a patient on bed rest respond with downsizing to the cellular stress of lack of physiological stimuli, an event that is usually not associated with immune responses. On the other hand, the replacement of
  5. 5. Rhoades/Bell 3e Chapter 10, page 5 First draft Insert date of submission glandular epithelium in the lungs of a smoker by a better protecting squamous epithelium goes along with inflammation of the airway cells, triggered by strongly irritating smoke particles. If the damage to a cell is too great to cope with, the cell will die by necrosis. The immune system is activated when the cells collapse and their cellular contents leak into the surrounding tissue. As a result, various types of immune cells are attracted by chemokines to the injury site and initiate the inflammatory response, which further activates the immune response. On the other hand, cell death by apoptosis will not cause immune activation. The cells die without bursting apart, and as a result, no damaging substances are released from the cells and an inflammatory response is avoided. Apoptosis is the body’s non-pathological process of removing cells. This is especially important for the role of the immune system in keeping homeostasis and regulating tolerance. Every day, several millions of B and T cells are generated and the majority of those dies apoptotically by processes called negative selection, or activation-induced-cell-death.
The Immune System Encompasses Distinct Immunological Organs As Well As Cells and Non-cellular Elements That Are Part of Every Tissue Thymus and bone marrow are primary (or central) lymphatic organs (Fig. 10.1). These are the organs where the cells mature to become immunocompetent. All immune cells derive from a common precursor stem cell in the bone marrow (see Chapter 9). While most immune cells including B lymphocytes begin a life of patrol once they are released from the bone marrow, T lymphocytes first undergo further maturation in the thymus. Lymph nodes, tonsils, lymph follicles of mucous membranes and the spleen belong to the list of secondary (or peripheral) lymphatic organs. These are the organs where mature immune cells participate in specific immune defense reactions. Figure 10.1 also shows the different types of immune cells. Their morphology was introduced in chapter 9. Their immune function is presented as part of the sections on innate and adaptive immunity (see below).
  6. 6. Rhoades/Bell 3e Chapter 10, page 6 First draft Insert date of submission Lymph nodes are the sites through which blood, lymph and immune cells are filtered. These encapsulated organs are located throughout the body at junctions of lymphatic vessels and are optimized for interaction between antigen-presenting cells and T and B lymphocytes. During a bacterial infection, lymph nodes swell due to proliferation of immune cells. Palpation of lymph nodes to give an indication of the activity level of the immune system is part of most orderly clinical examinations. The movement of lymph through lymph vessels and lymph nodes is supported by skeletal muscle movement, but is otherwise passive. There is no organ similar to the heart to pressurize the lymph flow. There is an abundance of non-cellular immune elements in blood and lymph. They include, but are not limited to, antibodies (see Table 10.4), communication molecules (see Table 10.5), and complement. Additionally, the innate immune system encompasses a variety of fluids and other non-cellular components with antimicrobial character (see Innate Immunity below).
THE INNATE IMMUNE SYSTEM: The ability of cells and tissues to respond to and to get rid of environmental challenges is an ancient evolutionary development that has persisted through vertebrate development as innate immunity (Table 10.1). It is also called nonspecific or natural immunity. In humans it is present at birth. It is always in place throughout life, can be rapidly mobilized, and it acts quickly. All antigens are attacked pretty much equally and there is no long-term change in the quantity or quality of the response.
Elements of the Innate Immune System Include Anatomic and Physiologic Barriers and Antibacterial Agents Our skin is a good anatomical and physiological barrier against microorganisms. The cells of the epidermal layers are dry and densely packed making it an inhospitable environment to many bacteria. Salty secretions from sweat glands and oily secretions from the sebaceous glands associated with hair
  7. 7. Rhoades/Bell 3e Chapter 10, page 7 First draft Insert date of submission follicles create a hyperosmotic and slightly acidic skin environment, which dehydrates bacteria and discourages those that prefer a neutral pH for colonization. Additionally, the continuous desquamation of skin cells eliminates bacteria adhering to epithelial cells. Lastly, a large number of non-invasive, non- pathogenic commensal (part of normal flora) microorganisms on the skin prevent growth of harmful microorganisms in a process called competitive exclusion. Acidity is also used in other places of the body as an antimicrobial tool. For example, natural microflora alters the fluids of the vaginal and urinary tract to an acidic pH below 4.5, so that yeast and other microorganisms cannot grow. Parietal cells of the stomach create highly acidic gastric juice below pH 3. Other factors such as low oxygen tension and fever are said to contribute to the innate barrier defenses, but their physiologic impact is still under discussion. For instance, the role of fever is thought to have a direct negative effect on certain microorganisms. It may also be helpful to enhance the efficiency of phagocytosis. Various types of cellular secretions destroy and eliminate germs. Mucus prevents microorganisms from adhering to epithelial cells and contains antibacterial components. The mucus of the gut blocks, inactivates, or destroys pathogens associated with food before they can enter the body. A thin layer of mucus covering the airway from the nose to the bronchioles traps inhaled viruses, bacteria, pollens and other particles and facilitates their removal before they can damage the airway lining cells. The flow of saliva helps to wash away bacteria attached to food particles, while attacking them with thiocyanates and lysozymes. Saliva can also contain antibodies that destroy oral bacteria in certain people. Tears and nasal secretions contain similar antibacterial components. The list of chemical factors with antimicrobial character is long and includes pepsin in the stomach, defensins produced by immunological cells, and surfactant proteins of the lung, to name a few. Interferons are a group of proteins that are produced by cells following viral infection. Complement is a group of serum proteins that circulate in an inactive state and can be activated by a variety of specific
  8. 8. Rhoades/Bell 3e Chapter 10, page 8 First draft Insert date of submission and non-specific immunologic mechanisms. It is sometimes called the humoral component of the innate immune system. Its action is discussed again below. These chemical factors often connect the innate immune system with the adaptive immune system, the system that comes into play when the innate system is overwhelmed by the invaders or unable to detect them.
Cellular Elements of the Innate Immune System Involve Phagocytes, Killer Cells, Eosinophils, and Mast Cells Figure 10.1 illustrates the cells of the immune system. Table 10.2 identifies neutrophils, macrophages and dendritic cells as the main cells capable of phagocytosis, an ongoing process of the innate immunity. Phagocytes are activated by T cell cytokines, and can directly sense the pathogens through a group of transmembrane receptors, Toll-like receptors. Upon activation, phagocytes engulf the microorganism, particle, or cell debris. The engulfed matter is enclosed within vacuoles and enzymatically digested, after fusion with lysosomes. Some pathogens have been coated with opsonins in a process called opsonization to render them more attractive to phagocytosis. Examples of opsonins are IgG antibody and the C3b molecule of the complement system. Neutrophils (or polymorphonuclear leukocytes) recognize chemicals produced by bacteria in a cut or scratch and migrate towards them. Once arrived, they ingest bacteria and kill them. For killing, neutrophils use proteolytic enzymes and reactive oxygen species as part of the respiratory burst (see Chapter 9). Macrophages are derived from circulating monocytes. Macrophages, like neutrophils, kill by using the respiratory burst and proteolytic enzymes. Macrophages secrete various cytokines that attract leukocytes to the infection site and initiate the acute phase inflammatory response. Finally, macrophages act as antigen-presenting cells to T cells and are hence an important bridge to the adaptive immune response.
  9. 9. Rhoades/Bell 3e Chapter 10, page 9 First draft Insert date of submission Macrophages can circulate in lymph vessels (wandering, non-fixed macrophages), or they can reside in connective tissue, lymph nodules, along the digestive tract, in the lungs, in the spleen and other places (mature, fixed macrophages). Fixed macrophages are part of the reticuloendothelial system (RES), which, in addition to removing pathogens, also remove old cells and cellular debris from the bloodstream. Some of these macrophages have their own names. For instance, the macrophages along certain blood vessels in the liver are called Kupffer cells, while the macrophages of the joints are called synovial A-cells. Microglial cells are macrophages located in the brain. Dendritic cells are, similar to macrophages, a critical link between the innate and adaptive immune systems. They exist in an immature form throughout the epithelium of the skin (Langerhans’ cells), the respiratory tract and the gastrointestinal tract. After phagocytosis of pathogens, the cells mature and travel to regional lymph nodes, where they activate T cells, which then activate B cells to produce antibodies against the pathogen. Natural killer (NK) cells attack aberrant body cells such as virus-infected cells and malignant cells. They release the cytolytic protein perforin, which forms a pore in the plasma membrane of the target cell. Proteolytic enzymes such as granzyme enter through the pore and induce apoptosis. Upon exposure to lymphocyte secretions such as interleukin-2 and interferon-gamma, NK cells become lymphokine-activated killer (LAK) cells, which are even more efficient in killing than NK cells. Eosinophils are best known as participants in allergic reactions where they might detoxify some of the inflammation-inducing substances. But they are also able to secrete factors that punch small holes in worms and certain other parasites causing them to die. Mast cells are present in most tissues in the vicinity of blood vessels. They are especially prominent under coverings, lining the body surfaces such as skin, mouth, nose, lung mucosa and digestive tract. Although best known for their roles in allergy and anaphylaxis of the adaptive immune system, mast cells play an important role in the innate system as well. They release factors that increase blood flow
  10. 10. Rhoades/Bell 3e Chapter 10, page 10 First draft Insert date of submission and vascular permeability bringing components of immunity to the site of infection. In combination with IgE antibody from B cells, mast cells can also target parasites which are too large to be phagocytosed, such as intestinal worms.
THE ADAPTIVE IMMUNE SYSTEM: Microbes that escape the onslaught of cells and molecules of the innate immune system face attack by T cells and B cell products of the adaptive immune system (Table 10.1), also called the acquired immune system. Adaptive immunity is a relatively recent evolutionary development and characteristic of jawed vertebrates. The adaptive immune system is induced by hundreds of thousands of diverse antigens, which are presented as glycoproteins on the surface of bacteria, as coat proteins of viruses, as microbial toxins, or as membranes of infected cells. It responds with the generation of antibodies and cells that specifically assault the invading pathogen. The adaptive immune response is slow, being fullly activated about four days after the immunological threat. Adaptive immune responses exhibit immunological memory, so that repeated exposure to the same infectious agent results in improved resistance against it (anamnestic response). Although innate and adaptive immune system are characterized by contrasting functions and timing (Table 10.1), they work together in ways that obscure their differences. For instance, the initiation and the adequate functioning of the innate system often depends on the presence of elements of the adaptive immune system such as small amounts of specific antibody in blood plasma. The reverse is true as well. Antibodies and other mediators of the adaptive immune system depend on elements that are typically associated with the innate immune system such as neutrophils. Only when working together can the innate and adaptive immune system provide a considerable obstacle to the establishment and long-term survival of infectious agents.
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The Three Most Important Features of Adaptive Immune Responses Are Specificity, Diversity and Memory The specificity of the adaptive immune system is created by antigen-recognition molecules which are synthesized prior to the exposure to antigen and are then modified during the immune response to make them more specific to the antigen. Three types of molecules participate in this anticipatory defense system: Specific receptors on T and B lymphocytes, molecules encoded in the major histocompatibility complex (MHC), and antibodies. All three types of molecules show an extreme diversity so that each molecule can specifically detect a particular antigen. The T cell receptor (TCR) resembles the Fab fragment of an immunoglobulin (Fig. 10. 4). There are two forms of TCRs known. Over 90 percent of peripheral T cells express one of them, the alpha/beta form. TCRs are antigen-specific. In an individual, there are about 1018 different TCRs, but each T cell has only one type of it. The B cell receptor (BCR) is a membrane-bound form of immunoglobulin. There are about 1014 BCRs, again one type of immunoglobulin per B cell. There is a similarly high number of antigen-specific MHC molecules per individual. The molecule diversity is achieved by multiple genes encoding for the molecules (polygeny) as well as variable recombination and mutation of the molecules during cell differentiation (polymorphy). The MHC genes are known as the most polymorphic genes of the human genome. The binding of an antigen to the lymphocyte with the best fitting receptor occurs mainly in the local lymph node and induces the proliferation of the responsive cell, a process known as clonal selection (Fig. 10.2). However, in the case of T cells, T cell proliferation is only induced if a co-stimulatory signal, secondary to TCR binding, occurs. Clonal selection amplifies the number of T or B lymphocytes that are programmed to specifically respond to the inciting stimulus. While all of the cells that were generated after a single clone has expanded, are specific for the inducing antigen (and hence have the same TCR or BCR), they may not all possess the same functional characteristics. For instance, clonal
  12. 12. Rhoades/Bell 3e Chapter 10, page 12 First draft Insert date of submission proliferation of T cells leads to the generation of more antigen-specific T cells and to the production of effector T cells, such as T helper (TH) cells and cytotoxic T cells (CTL). Antigen-binding to the BCR of B cells induces their development into plasma cells, which are capable of generating antibodies, first IgM antibodies and later IgG, IgA and/or IgE antibodies. The antibody can be found in a variety of body fluids, including saliva, other secretions, and plasma. Other progeny in the expanded B cell clone may function as memory cells, which account for one of the primary tenets of immunity. These cells mimic the reactive specificity of the original lymphocytes that responded to the antigen and accelerate the responsiveness of the immune system when the antigen is encountered again. It leads to increased resistance after initial exposure to the infectious agent and is the basis for vaccination (see Clinical Box 3).
T Cell Mediated Immunity is One of the Two Fundamental Mechanisms of Adaptive Immunity Cell-mediated immunity (or cellular immunity) is accomplished by activated T cells (Fig. 10.3). T cells continuously patrol the body and check the virulence of antigen in a process called immune surveillance. T cells are activated by binding of antigen to the specific TCR plus a co-stimulatory event. Antigen can only bind to the TCR when presented by antigen presenting cells (APC) in combination with MHC. The complex interaction between the T cell and the APC is called immunological synapse. Almost every cell in the body can present antigen to the TCR of CD8+ cytotoxic T cells. In this case, the antigen is a cytosolic pathogen, which was degraded in the cytosol and associated with MHC class I molecules (Table 10.3). In the case that the antigen stems from intra- or extracellular bacteria or toxins, it is associated with MHC class II molecules and presented to the TCR of CD4+ T helper cells. Only macrophages, dendritic cells, and B cells can do that. Macrophages become APCs when they upregulate their MHC-II molecules in response to infection and stimulation of specific lipopolysaccharide (LPS)
  13. 13. Rhoades/Bell 3e Chapter 10, page 13 First draft Insert date of submission receptors by bacterial ligand. Dendritic cells are mostly found in peripheral tissue where they ingest, accumulate and process antigens. B cells are the least efficient APCs. They become activated by ligand binding to the BCR and ingest soluble proteins by pinocytosis. The CD4+ and CD8+ cells develop in the thymus. CD stands for Cluster of Differentiation. There are more than one hundred and sixty clusters that coat the lymphocyte surface. CD4 and CD8 are two that are used to identify T cell subsets. When the cells coming from the bone marrow reach the thymus they have neither CD4 nor CD8 (double negative T cells), but they then start expressing both markers (double positive T cells). During development in the thymus they differentiate into either CD4 or CD8 cells. At the same time, they develop their ability to distinguish self from non-self peptides as explained in the following. First, cells that do not bind MHC/antigen complexes within 3-4 days will die. This happens to over 95 percent of the cells. The rest of the cells undergo positive selection. This means that T cells that bind antigen (self or non-self) complexed with MHC, class I or II, proliferate. This happens in the cortex of the thymus. At this time, cells with TCRs specific for MHC II retain CD4 and lose CD8 and become T helper cells. T cells that are specific for MHC I retain CD8 and lose CD4 and become cytotoxic T cells. After positive selection, cells undergo negative selection in the medulla of the thymus. During this process cells that bind with high affinity to MHC/self antigen complexes will die by apoptosis. This is important since these cells would later react with self peptides and cause autoimmune diseases. Cells that bind with low affinity to MHC/ self antigen are allowed to leave the thymus. They will later only be activated by high affinity binding to MHC/ foreign antigen complex, the adequate signal for immune activation. Cytotoxic CD8+ T cells release lymphotoxins which cause cell apoptosis of virus-infected cells (Fig. 10.3). Suppressor T cells inhibit the production of cytotoxic T cells when they are no longer needed. Helper CD4+ T cells direct the immune response by secreting lymphokines. They stimulate proliferation
  14. 14. Rhoades/Bell 3e Chapter 10, page 14 First draft Insert date of submission of cytotoxic T cells and B cells, attract neutrophils, and activate macrophages. The differentiation of CD4+ T helper cells into helper 1 and helper 2 cells occurs only after they have been activated during an immune response in the peripheral lymphoid system. Each type of effector T cell produces a distinct set of effector molecules. For instance, T helper 1 cells release the macrophage-activating effector molecules interferon-gamma and tumor necrosis factor-alpha, while T helper 2 cells produce B cell activating effector molecules such as interleukin 4, 5, and 15, among numerous other cytokines. Research shows that the dual T helper cell model, although still widely be used, is too simple and might soon need to be expanded. For instance, many T cells express cytokines from both profiles. They are often named T helper zero cells. Additionally, many T cell cytokines are expressed by other immune cells as well. Lastly, memory T cells recognize a previously encountered pathogen. T cells and their products may act directly or exert their effects in concert with other effector cells, such as neutrophils and macrophages. The secretion of T cell factors that recruit and activate other cells takes time, and thus, the consequences of T cell activation are not noticeable until 24 to 48 hours after antigen challenge. An example illustrating this time delay is the delayed-type hypersensitivity reaction (see also Immune Diseases below) to purified protein derivative (PPD), a response used to assess prior exposure to the bacteria that cause tuberculosis. Injected under the skin of sensitive individuals, PPD elicits the familiar inflammatory reaction characterized by local erythema and edema 1 to 2 days later. Cell-mediated immune responses, while slow to develop, are potent and versatile. These delayed responses provide the main defense against many pathogens. T cells are also responsible for the rejection of transplanted tissue grafts (see Organ Transplantation below) and containment of the growth of neoplastic cells (see Immune Disorders below). A deficiency in T cell immunity, such as that associated with AIDS, predisposes the affected patient to a wide array of serious, life-threatening infections.
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Humoral Immunity is the Second Fundamental Mechanism of Adaptive Immunity Humoral immunity consists of defense mechanisms carried out by soluble mediators in the blood plasma (Fig. 10.3). Binding of antigen to the BCR activates B lymphocytes, which then start proliferating and maturing in the presence of T helper cytokines. Most new cells become plasma cells which produce antibodies for four to five days, resulting in a high level of antibodies in plasma and other body fluids. These antibodies can specifically bind to the antigenic determinant that induced their secretion. Other B cell clones become long-lived memory B cells. In general, antibodies are known to induce immediate responses to antigens and, thereby, provoke immediate hypersensitivity reactions (see Immune Disorders below).
Antibodies Consist of Four Protein Chains Arranged Like the Letter Y Antibodies, also called immunoglobulins or Igs, constitute the gamma globulin part of the blood proteins. The primary structure of an antibody is illustrated in Figure 10.4. Each antibody molecule consists of four polypeptide chains (two heavy chains and two light chains) held together as a Y- shaped molecule by one or more disulfide bridges. There are two classes (isotypes) of the light chain called kappa and lambda. Heavy chains have five different isotypes (gamma, alpha, mu, epsilon and delta), which consitute five different classes of antibody, each with different effector functions (see below). Each polypeptide chain possesses both a conserved constant region and a variable region, where considerable amino acid sequence heterogeneity is found. The amino terminal portions of the variable regions are known as the Fab regions. The hypervariable regions at the end of the Fab region, known as antibody idiotypes, are the antigen-binding regions. Each antibody unit possesses two identical antigen-binding sites, one at each end of the “Y.” The carboxy terminal end of the heavy chain is termed the Fc region. Fc fragments can bind to cells such as neutrophils, monocytes, and mast cells through their Fc receptors, which amplifies the biological
  16. 16. Rhoades/Bell 3e Chapter 10, page 16 First draft Insert date of submission activity of antigen-bound antibody. Antibodies are flexible in that the Fab arm can wave, bend and rotate and even the Fc region has some degree of freedom. This freedom of movement allows it to more easily conform to the shape of the antigen.
Antibodies Work in Three Ways to Destroy the Antigen 1. Neutralization. Antibodies can bind to toxins forming easily recognizable antibody-antigen complexes, which are removed by phagocytosis. Antibodies can also immobilize and agglutinate infectious agents with the effect that a virus cannot penetrate the host cell or a microbe cannot colonize mucosal tissue. In some cases the complexes may also settle out of solution and precipitate. 2. Opsonization. IgG antibodies bind to bacteria or virus-infected cells via the Fab region. That way, the pathogen is ‘tagged’ or ‘opsonized’ for phagocytosis or destruction by free radicals and enzymes. Some complement components can also act as opsonins. 3. Complement Fixation. Complement is a group of at least nine distinct proteins that circulate in plasma (Fig. 10.5). A cascade of events occurs when the first protein recognizes preformed immune complexes of antigen molecules bound to antibodies (classical pathway). These events include the recruitment of inflammatory cells. In addition, complement can be activated when one of the proteins is exposed to the cell wall of certain bacteria. Initiation of this system (alternate pathway) results in the lysis of the target by formation of the membrane attack complex (MAC). Because of its tubular structure and hydrophobic nature, the MAC inserts into the membrane of the cell and allows free passage of small molecules, ions and water resulting in the cell’s death. Complement fixation is the basis for various diagnostic tests to detect a specific antibody or a specific antigen in a patient’s serum
There Are Five Major Antibody Classes With Different Primary Functions Figure 10.4 and Table 10.4 summarize the shape and functions of the five major classes of antibodies. Figure 10.4 additionally shows the similarities of the TCR and the BCR with immunoglobulin.
  17. 17. Rhoades/Bell 3e Chapter 10, page 17 First draft Insert date of submission IgG is the major antibody produced in response to secondary and higher order antigen encounters. Secondary immune responses are faster and longer, and produce more antibody with higher affinity to the antigen compared to primary responses. Hence, IgG is the most prevalent antibody in serum and is responsible for adaptive immunity to bacteria and other microorganisms. It has a half-life of 23 days, the longest amongst the antibody classes. When bound to antigen, IgG can activate serum complement and cause opsonization. IgG exists in serum as a monomer. It can cross the placenta and is secreted into colostrum, protecting the fetus as well as the newborn from infection. IgA usually exist as polymers of the fundamental Y-shaped antibody unit. In most IgA molecules, two antibody units are held together by a secretory piece (J chain), a protein synthesized by epithelial cells. In this conformation, IgA is actively secreted into saliva, tears, colostrum, and mucus and hence is known as secretory immunoglobulin. IgA has a half-life of about 6 days. IgM consists of five Y units. Its size and large number of antigen-binding sites provide the molecule with an excellent capacity for agglutination of bacteria and blood cells. Such agglutinated antigens are efficiently and quickly removed by fixed macrophages of the RES system. IgM is the first antibody secreted after an initial immune challenge and provides resistance early in the course of infection. It has a half-life of about 5 days. IgE is a monomeric antibody that is slightly larger than IgG, but has a relatively short half-life of about 3 days. IgE avidly binds via its Fc region to cells such as mast cells and basophils, which are involved in allergic reactions (see Immune Diseases below). IgD is found in plasma and on the surface of some immature B cells. It has a half-life of 3 days. An exact function is not known. It is expressed early during B-cell differentiation and has been postulated to be involved in the induction of immune tolerance. IgD serum concentration does increase during chronic infection, but is not associated with any particular disease.
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INFLAMMATION Inflammation is the initial response of the body to infection or trauma. Although microbial infection is probably the most common cause for inflammation, many types of tissue injury can evoke inflammatory reactions. These include mechanical injury, radiation, burns, frostbites, chemical irritants, and tissue necrosis resulting from lack of oxygen or nutrients. The body instigates a non-specific cascade of physiological processes involving elements of the innate immune system, with the goal to repair cellular damage in vascularized tissues and to restore the tissue to its normal function. Inflammation is the response of a complex system that mobilizes immune, endocrine, and neurological mediators (see Neuroendoimmunology below). In a normal response, it is self-initiating, temporally self-propagating, and self-terminating. Inflammation is a necessary response to tissue injury, and human life without inflammation is unthinkable. On the other hand, inflammation often overshoots in its reactions, which leads to a vicious circle of repeated injury and persistent inflammation. In this respect, inflammation is closely connected with all kinds of illnesses so that anti-inflammatory therapy is at the heart of a wide variety of therapies.
Inflamed Tissue is Swollen, Red, Hot and Painful, Resembling an “Internal Fire” The clinical aspects of inflammation have been known for over two thousand years and gave inflammation its name as resembling an internal fire. These include four signs: first, rubor (redness), generated by increased blood flow due to dilation of small blood vessels, and second, calor (heat) generated by the metabolism of leukocytes and macrophages recruited to the site of damage. While the increased blood flow contributes to a small temperature increase in the skin, systemic fever occurs as a result of the chemical mediators of inflammation, especially IL-1 acting at hypothalamic neurons. The third and fourth signs are tumor (swelling) due to edema, and dolor (pain) caused by the production of prostaglandins, bradykinin, and serotonin. With increasing knowledge of the complexity of
  19. 19. Rhoades/Bell 3e Chapter 10, page 19 First draft Insert date of submission inflammation, many models have been put forward to expand on and to categorize the great variety of inflammatory responses. However, they are not yet commonly used in clinics beyond the addition of a fifth sign, functio laesa (the loss of function), which is a common, well-known consequence of inflammation. Laboratory investigation of inflammation usually reveals an increased number of neutrophils in peripheral blood, an increased erythrocyte sedimentation rate (see Chapter 9), and increased concentration of acute-phase blood proteins. The latter are produced by the liver in response to circulating pro-inflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor alpha (TNF-α). An important member of the blood protein profile is C-reactive protein, a pro-inflammatory marker which is used to monitor the severity and progression of some cardiovascular diseases. A high serum level of the amino acid homocysteine has been associated with increased risk of atherosclerosis and other conditions involving inflammation.
Acute Inflammation Involves Vasodilation, Vascular Leakage and Leukocyte Emigration The immediate response of acute inflammation includes local dilation of blood vessels, which increases blood flow to the injured area, sometimes up to ten-fold. The vessel walls become leaky, on the one hand due to the injury-related necrosis of endothelial cells, and on the other hand due to chemically directed retraction of endothelial cells. Next, water, salts and small proteins, such as fibrinogen, exit from the plasma into the damaged area in a process called exudation. The leaking fluid is called exudate, or pus in the case of an infected wound. Fibrinogen forms fibrin, which impedes the movement of microorganisms and makes them easier to phagocytose. Acute inflammation is initially mediated by histamine, followed by factors derived from local cells (e.g. bradykinin), and recruited neutrophils (Table 10.5).
  20. 20. Rhoades/Bell 3e Chapter 10, page 20 First draft Insert date of submission Recruited neutrophils adhere to the endothelial cells via selectins. Loose bridges are established between P-selectin and E-selectin on endothelial cells and L-selectins on neutrophils (margination). Thus slowed down, the neutrophils move along the endothelium like tumbleweed (rolling). A more firm connection is built between integrins on neutrophils, and Intracellular and Vascular Adhesion Molecules (ICAM, VCAM) on the endothelial side. This allows neutrophils to actively migrate through the blood vessel basement membranes into the tissue (transmigration or diapedesis) without damaging the endothelial cells. Eventually, monocytes are attracted and differentiate into macrophages when leaving the blood. Lymphocytes follow as well. The appearance of these non-granular cells marks the entry into chronic inflammation.
Inflammatory Mediators Are Small Secreted Substances Which Regulate Inflammation Inflammatory mediators are soluble molecules that act locally at the site of damage and coordinate the development of inflammatory responses. Exogenous mediators include endotoxin, bacterial toxin associated with the LPS complex of gram-negative bacteria. It is released when bacteria are lysed and binds to receptors on monocytes and macrophages thus activating them. Endogenous mediators are released from injured or activated cells at the inflammation site. There is a long list of substances that are known to regulate inflammation, many of them with seemingly redundant functions. Table 10.5 lists a few of them. An important class of mediators is cytokines, which are cell products synthesized de novo in response to immune stimuli. They generally act over short distances and short time spans. They include lymphokines (cytokines made by lymphocytes), monokines (made by monocytes), chemokines (chemoattractants made by various cells), and interleukins (made by one leukocyte and acting on other leukocytes). Many mediators can interact with multiple receptors, often exerting very diverse functions. For instance, histamine interacts with three receptors. The H1 receptors mediate acute pro-inflammatory
  21. 21. Rhoades/Bell 3e Chapter 10, page 21 First draft Insert date of submission vascular effects, while activation of H2 receptors results in anti-inflammatory actions. H3 receptors are involved in the control of histamine release. From a structural standpoint, inflammatory mediators belong to many different categories, such as proteins (e.g. complement, antibodies, acute phase reactants), lipids (e.g. prostaglandins, platelet- activating factor), amines (e.g. histamine), gases (e.g. NO, O2-), kinins (e.g. bradykinin) and neuropeptides (e.g. substance P). Many plasma-derived mediators are present as precursors and need enzymatic cleavage to become active. Cell-derived mediators can be preformed (e.g. histamine) or synthesized as needed (e.g. prostaglandin).
Acute Inflammation Is Considered to Be a Stereotypic but Highly Complex Process That Self Terminates Modern molecular biology superimposes many additional layers of complexity onto the presented model of inflammation, and our current understanding of acute inflammation as a stereotypic response might soon need to be revised. For instance, it has been shown that aspects of both inflammation and repair can be triggered and modulated by factors independent of the vasculature. Vibration and hypoxia can lead to degranulation of mast cells and release of histamine, hence initiating inflammatory events. Similarly, increased mechanical load on tendon fibroblasts can modulate their inflammatory response. In addition, pro-inflammatory molecules can be upregulated without any stimulation by inflammatory cell invasions. Under normal circumstances acute inflammation terminates itself. Chemical mediators disappear due to a short half-life or are enzymatically inactivated (e.g. kininases inactivate kinins). Substrates are consumed, and the lymph flow carries the mediators away faster than they can be produced. Repair of damaged tissue is induced by anti-inflammatory cytokines such as IL-4, IL-10, and transforming growth factor beta (TGF-β). Pools of lymph fluid (blisters) may form in response to burns, infections, or
  22. 22. Rhoades/Bell 3e Chapter 10, page 22 First draft Insert date of submission irritating agents. If an infected area is further liquefied and shielded from surrounding tissue as a response of the body, it is called an abscess. Some abscesses are acutely cleared (e.g. pimples), but other lesions might become chronic and then require natural or surgical drainage for healing. Following inflammation, tissue that is capable of regeneration will be almost completely restored, while, otherwise, scar formation occurs.
Chronic Inflammation Is the Failure to Resolve Inflammation and Usually Causes Serious Body Harm Chronic inflammation develops when neither agent nor host is strong enough to overwhelm the other (e.g in the case of osteomyelitis, the staphylococcus infection of bone), when there is prolonged exposure to the toxic agent (e.g. silicosis from inhalation of crystalline silica dust), or as part of autoimmune diseases (e.g. rheumatoid arthritis). It can also develop without being preceded by acute inflammation (e.g. in tuberculosis). Chronic inflammation may last weeks, months, or years and leads to chronic wounds. They are composed of loosely arranged connective tissue (granulation tissue), infiltrated fibroblast, and inflammatory cells. The vastly dominant inflammatory cell type, and the only cell type present in the case of chronic inflammation due to a non-antigenic agent (e.g. suture thread), is monocytes/ macrophages. In the case that the injurious agents are also antigenic, other cell types appear such as lymphocytes, plasma cells, and eosinophils. Chronic inflammation leads to ongoing tissue damage and clinical symptoms found in typical inflammatory diseases such as rheumatoid arthritis, atherosclerosis, or psoriasis. Inflammatory cells secrete products such as reactive oxygen species and proteases that cause additional cell damage. Other products, such as arachidonic acid and pro-inflammatory cytokines, amplify, as well as propagate, the responses. This is a vicious cycle that weakens the body and makes it more susceptible to infection. Overwhelming inflammation combined with immune suppression can lead to Systemic Inflammatory
  23. 23. Rhoades/Bell 3e Chapter 10, page 23 First draft Insert date of submission Response Syndrome (SIRS), which is called sepsis when the inflammation is due to infection. This can lead in the worst case to organ failure and death. Inflammation can happen everywhere in the body. Inflammatory conditions are usually indicated by adding the suffix “itis”. Myocarditis is the inflammation of the heart, nephritis is the inflammation of the kidney. Some inflammatory conditions don’t follow the conventional terminology. The most common one is Asthma (see Clinical Focus Box 1). Another example is pneumonia, which is more commonly used than pneumonitis to name chronic infection of the lung, characterized by inflamed and fluid-filled alveoli.
Novel Solutions to Resolve Chronic Inflammation Are a Core Topic of 21st Century Medical Research In recent years, the role of inflammation in diseases that were traditionally not recognized as inflammatory diseases is viewed with considerable interest. In fact, inflammation is now recognized to be a critical pathologic component underlying a wide variety of diseases ranging from Alzheimer’s and Parkinson’s disease to diabetes and certain types of cancer (e.g. colon cancer). While the association between inflammation and disease has been recognized for a long time, inflammation was mainly considered as being a result of the illness, instead of being a cause of it. Recent studies clearly show that the destructive self-promoting cycle between oxidative stress and resulting inflammation that causes more oxidative stress, contributes to the development of chronic illnesses. These chain of events may initially occur at a low, unnoticeable level, which leads to the speculation that subacute chronic inflammation is part of, and may be even the source of, all illnesses. This is a provocative, but interesting thought that is worth pursuing in light of the increasing occurrence of chronic diseases in our aging population.
  24. 24. Rhoades/Bell 3e Chapter 10, page 24 First draft Insert date of submission Glucocorticoid steroid hormones are the most powerful anti-inflammatory drugs currently available. Corticosteroids inhibit the accumulation of neutrophils at sites of inflammation, (see Neuroendoimmunology below) but also have widespread effects on other inflammatory cells and processes. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (Cox) involved in prostaglandin production. There are at least two isoforms of the enzyme. Cox-1 is found in platelets, and catalyzes the production of thromboxane A2. Cox-1 inhibition leads to diminished blood clotting, thus drugs that block Cox-1 can be used as blood thinners. Cox-2 is expressed in blood vessels and macrophages in response to inflammation, and leads to production of prostaglandin I2. Drugs that specifically block Cox-2 can decrease inflammatory pain. However, both Cox-1 and Cox-2 are present at many more sites, a reason for the abundant pharmacological side effects of the drugs. Alternative medical therapies include nutrients (e.g. vitamin E), herbs (e.g. chamomile) and supplements (e.g. glucosamines) with anti-oxidative and anti-inflammatory abilities. Since the side effects of many available anti-inflammatory drugs outweigh their benefits, a main focus of 21st century medical research is to develop novel anti-inflammatory strategies. New drugs generally aim to target specific pathways instead of general inflammatory processes. For instance, leukotriene modifiers are a relatively new class of anti-inflammatory medications for asthma patients (see Clinical Focus Box 1) that specifically block the products of arachidonic acid metabolism to prevent an asthma episode before it even starts. Another example is the use of molecularly engineered antibodies that are directed against specific inflammatory cytokines or cytokine receptors by using gene recombinant techniques. Novel non-pharmacological anti-inflammatory therapies may be developed from research that shows that vibration or low energy radiation suppresses inflammation.
ORGAN TRANSPLANTATION
  25. 25. Rhoades/Bell 3e Chapter 10, page 25 First draft Insert date of submission Organ transplantation is indicated when irreversible damage has occurred and alternative treatments are not applicable. The first human kidney was transplanted in the early 1950’s to the donor’s identical twin brother. Such a transplant is called an isograft since donor and recipient are genetically identical. Today, over 10,000 kidneys and many other organs are transplanted in the US per year, most often as allografts between genetically different, but immunogenically matched people. Kidneys, lungs and livers come from living donors since a person can live with one kidney and one lung and since liver tissue regenerates. Transplants of heart, whole lung, pancreas, or cornea come from deceased donors. So-called non-vital transplants of body parts such as hands, knees, uterus, trachea and the larynx have also been achieved. Tissue that is transplanted in the same individual from one place to another place is called an autograft. Skin and blood vessels are common tissue for such transplantation. While transplantation is nowadays a viable therapeutic option, it is mainly limited by the immensely larger demand for transplantation organs compared to their availability (see Clinical Box 2). An attempt to overcome the donor organ shortage is xenograft transplantation, where animal tissue is used to replace human organs. Two other avenues for replacement of necrotic tissue are the development of artificial organs and the transplantation of stem cells that may be able to regenerate full functioning organs. The latter is the holy grail of organ replacement since the new tissue would not be recognized as foreign, if the stem cells come from the recipient. However, as of today, these alternatives don’t work nearly as well as allografted organs. Additionally, there are major ethical problems involved. Xenotransplantation may introduce new diseases to humans and disrespectfully treat animals. The use of animal and artificial organs may raise problems of self esteem, and stem cell therapy may require the destruction of human embryos.
Histocompatibility is the Most Important Criterion for Match in Organ Donation
  26. 26. Rhoades/Bell 3e Chapter 10, page 26 First draft Insert date of submission The major reason for the donor organ shortage is that the blood and tissue of the donor and recipient need to have similar immunogenic markers to avoid rejection. For instance, virtually all kidneys with unmatched ABO blood group between donor and recipient will be rejected within minutes. It is critical that the recipient does not have, or develop, antibodies against the donor’s human leukocyte antigen (HLA). HLA are the human antigens of the MHC complex (see T Cell Mediated Immunity above). These antigens are present on the surface of most body cells, but were first discovered on leukocytes. For minimum requirements, transplant doctors look at only six of the many HLA antigens (two A, two B, and two DRB1 antigens) for matching donors to patients. However, research has shown that a match in more HLA antigens and additional factors such as race, age and sex, improves the patient’s chances for success. Although tissue typing decreases the risk of transplant rejection, the match between donor and recipient is never perfect (except for identical twins). The reality of clinical practice results in organ transfer from less well-matched donors. So, clinical symptoms resulting from immune attacks on the transplant are fairly common. Table 10.6 summarizes the different types of rejections. Immunosuppressive drugs greatly decrease the risk of rejection. There are a wide variety of drugs available that inhibit different immune processes. Many of them aim to downregulate the unwanted T cell responses. Total destruction of T cells and other leukocytes by whole body irradiation is used before bone marrow transplanation (see Clinical Focus Box 2).
IMMUNE SYSTEM DISORDERS Many things can go wrong in the complex world of the immune system. First, the immune system may overreact. It is important for proper functioning that the immune system be very sensitive to pathogens and use enough power to definitely defeat the pathogen since even small numbers of residual microorganisms may soon endanger the body again. But this principle comes at the risk of overdoing it.
  27. 27. Rhoades/Bell 3e Chapter 10, page 27 First draft Insert date of submission Asthma, familial Mediterranean fever (recurrent episodes of peritonitis, pleuritis and arthritis) and Crohn's disease (inflammatory bowel disease) are examples of an over-reacting immune system. The most common overreactions of the immune system are known as allergies, or anaphylaxis in the case of severe forms. Allergies are categorized into four classes (see Table 10.7). Dependent on the sensitivity of the affected person, they can cause localized or systemic symptoms. Localized reactions are usually biphasic, with an immediate response mainly due to histamine (erythema, wheal and flare) and a delayed response that may last several hours. Systemic reactions might be life-threatening due to the sudden loss of blood pressure as a result of general vasodilation and due to airway obstruction as a result of smooth muscle contraction. Second, the immune system may not respond. Immunodeficiencies occur when a part of the immune system is not present or not working properly. A large variety of disorders falls into this category, although the number of patients with congenital immunodeficiency diseases is low. The study of these diseases reveal important insights into cellular and molecular immunology. For instance, Severe Combined Immuno Deficiency (SCID), commonly known as “bubble boy disease”, represents a group of congenital disorders characterized by little or no immune response. Research showed that in the x- linked form of SCID, T cells are disfunctioning due to a mutation of the IL-2 receptor gamma chain. The immunological consequences are severe and may lead to the patient’s death within the first year of life. Third, the immune system may respond inappropriately. Autoimmune disorders are the attack on the body’s own cells, with minimal to devastating consequences. What triggers autoimmune reactions is still poorly understood and involves genetic, hormonal, and environmental factors. An example is Systemic lupus erythematosus (SLE), a chronic autoimmune disease with largely unknown etiology that affects multiple organs, possibly as a result of unregulated apoptosis. Autoimmune phenomena may also occur secondarily to another disease.
  28. 28. Rhoades/Bell 3e Chapter 10, page 28 First draft Insert date of submission The examples presented in Table 10.7 are not intended to be comprehensive, but to provide a framework, which can be expanded in pathology courses. Many diseases involve mechanisms that fit into several of the categories. Rheumatoid arthritis (RA) is a good example. It is thought to be initiated by an unknown antigen that stimulates antibody formation, characteristic of type III hypersensitivity. This leads to joint damage, and as a result, auto-antigens are released, which perpetuate the disease in the typical fashion of an autoimmune disease. T cells are recruited and activate macrophages which leads to chronic inflammation. The disease is maintained by immune responses dominated by T helper 1 cells, characteristic of type IV hypersensitivity reactions.
The Adaptive Immune System Can Cause Malignant Tumors, But Also Recognize Tumors From Other Tissues Like any cell, cells of the immune system can grow out of control. Leukemia, the abnormal growth of leukocytes, is the most common childhood cancer. Lymphomas encompass a diverse group of cancers which present as solid masses specific to the lymphatic system. At least two viral infections have been associated with immune system malignancies. The human T cell leukemia virus type 1 (HTLV-1) can cause acute T cell leukemia and lymphoma (ATLL), and the Epstein-Barr virus of the herpes family is linked to Burkitt’s lymphoma and possibly Hodgkin’s lymphoma. In both cases, most people remain healthy when infected. However, people who are immuno-compromised due to previous infections, other diseases, or age, may develop cancer. For instance, Burkitt’s lymphoma is the most common childhood cancer in central Africa, where malaria and malnutrition lead to immune weakness. Some leukemias and lymphomas are easy to differentiate histologically from healthy tissue, others are not. For instance, lymphoblasts in acute lymphoblastic leukemia (ALL) look very different from normal lymphocytes. However, the cells in chronic lymphocytic leukemia (CLL) are hard to distinguish from normal cells and the disease might resemble a physiological high lymphocyte count. In this case,
  29. 29. Rhoades/Bell 3e Chapter 10, page 29 First draft Insert date of submission identification of specific cell markers, which are not present in healthy cells, will aid the diagnosis. If these tumor markers are antigenic, the immune system might recognize them as well. The resulting combat of the immune system against cancer that has already developed is not well understood. It has led, however, to the rapidly advancing field of cancer immunotherapy, which aims to enhance the body’s natural defense against malignant tumors.
NEURO-ENDO-IMMUNOLOGY: The actions of the immune system are interconnected with the actions of the endocrine and the neuronal systems (Fig. 10.6). For instance, it is well known that the physiological stress response downregulates the immune system. As a consequence, individuals, stressed from losing a relative, or stressed by examinations, become sick more easily. From the fast growing knowledge of the mechanisms that underlie such phenomena the picture emerges that there is far more information exchange among the three systems through hormones, neurotransmitters and cytokines than previously thought. Immune, endocrine, and neuronal systems share a number of the same receptors and synthesize and secrete some of the same molecules. Accordingly, the strength of a person’s immune response depends not only on the type of antigen or the person’s age and genetic makeup, but also on the individual’s lifestyle choices, emotional character, and ability to cope with stress.
Neuronal Components of the Central and Autonomic Nervous System Modulate Immune Functions During an immune response cytokines such as IL-1 stimulate the activity of paraventricular hypothalamic neurons to release corticotropin-releasing factor (CRF). This starts the physiological stress response aimed at bringing an individual back to physiological homeostasis. In the pituitary gland CRF stimulates the expression of POMC, which is converted to beta-endorphin and ACTH. ACTH
  30. 30. Rhoades/Bell 3e Chapter 10, page 30 First draft Insert date of submission stimulates the release of corticosteroids from the adrenal gland. All these molecules can bind directly to receptors on immune cells. The resulting actions are generally inhibitory to the immune system, but can also be immunosupportive, especially during acute stress. Activating the stress response via CRF also leads to activation of the sympathetic nervous system and the release of its neurotransmitter norepinephrine. This autonomic path of the stress response can also be activated by cytokines that are released by immune cells, or by cells of the central nervous system (CNS) such as microglia and astrocytes. A network of autonomic nerve fibers send information from the CNS to the spleen and lymph nodes, where the fibers end in close proximity to T lymphocytes and macrophages. These immune cells, as well as B cells, express beta-adrenergic receptors of the beta 2 subtype and their activation generally leads to inhibition of cell function. For instance, adrenergic activation of T cells decreases their expression of integrins, so that they cannot migrate out of the blood vessel into the tissue, which explains the high T cell counts seen soon after a stressful event. Sympathetic nerve endings and the adrenal medulla also release endorphins and enkephalins. These opioid peptides oppose the body’s stress response and help maintain homeostasis during times of physical and psychological stress. The immune responses to opioids vary, dependent on the subtype and concentration of the neuropeptide. Melatonin, a hormone of the pineal gland, seems to regulate the opioid network and consequently the immune system. Melatonin therapy is under consideration to support the immune system of aged people to avoid immunosenescence.
Immune Cells and Their Secretions Affect the Central Nervous System, Modulated by Hormones The information flow from the peripheral immune system to the CNS is carried by lymphokines and and thymokines (produced by the thymus). For instance, IL-1 is a potent mitogen for astroglial cells. In addition, it acts at hypothalamic cells causing fever. IL-2 promotes the division and maturation of
  31. 31. Rhoades/Bell 3e Chapter 10, page 31 First draft Insert date of submission oligodendrocytes, and IL-3 supports the survival of cholinergic neurons. Additionally, CD4+ T cells and macrophages manufacture neuropeptides such as Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) which was previously thought to be products solely of non-immunological cells. Until recently, it was also believed that the brain is devoid of peripheral immune cells. It is now known that immune cells can pass the blood brain barrier and enter the central nervous system, where they may trigger autoimmune disorders. For instance, autoimmune T cells that recognize myelin basic protein of myelin sheaths might be associated with the development of the demyelinating disease multiple sclerosis. However, it seems that neuronal autoimmune cells are present in the CNS in the first place to regulate physiological neuronal events. For instance, it is discussed that they contribute to maintaining the brain’s ability for cognitive functions. A large number of hormones have been linked to immune functions. For instance, thyroid stimulating hormone (TSH), best known as a regulator of metabolic functions, is also produced and used by cells of the immune system. Growth hormone, prolactin, female and male sex hormones, and leptin are additional examples of hormones that unequivocally modulate the immune system. In the typical fashion of hormones, they exert multiple actions in a variety of target cells, dependent on the hormone concentration, the target tissue, and the environment. This makes hormones optimal regulators of the body’s homeostasis, but usually causes unwanted side effects when used clinically. Currently available immune therapies using hormones or neuropeptides are still limited. The adrenal hormone epinephrine is given to reverse some effects of allergy, and immunocompromised people are counseled to find ways for dealing with stress. However, many new applications are being developed and it is safe to say that in the near future distinct enhancement or suppression of immune cell functions will play a more important role in our approaches to help the body to maintain homeostasis.
  32. 32. Rhoades/Bell 3e Chapter 10, page 32 First draft Insert date of submission CHAPTER SUMMARY • The immune system encompasses key immunological organs such as thymus, spleen, bone marrow, lymph system. It additionally includes cells and non-cellular elements that are part of every tissue throughout the body. • Leukocytes traffick between lymphoid organs, lymphatics and blood vessels. • A substance that elicits an immune response is called immunogen. Haptens and antigens are substances that bind to T cells or antibodies, but only antigens elicit an immune response. • The overall goal of the immune system is to distinguish between self and foreign molecules inside our body tolerating normal body substances and eliminating any invasion by foreign substances. • To battle foreign invaders, the immune system has two systems: the innate system as the immediate response to common immunogens, and the adaptive system, which changes throughout life and which has memory to respond to an encounter more strongly the second time compared to the first time. • Innate immunity includes physical, chemical, and mechanical barriers to entry of pathogens. It also includes phagocytes, killer cells, eosinophils and mast cells. • Phagocytes encompass neutrophils, macrophages, and dendritic cells. They have receptors for pathogens and for complement-coated and antibody-coated antigens. They can engulf and destroy pathogens, influence immune responses via immune mediators. Macrophages and dendritic cells can act as antigen-presenting cells to T cells. • Acute inflammation is the body’s initial response to infectious microorganisms and injuries. It is characterized by the dilation and leaking of blood vessels and subsequent attraction of circulating leukocytes to the inflammatory site, where innate immune responses occur. • Adaptive immunity is a delayed, but highly effective, immune response against specific antigens. The adaptive immune system is divided into cell-mediated immunity, which targets infected cells
  33. 33. Rhoades/Bell 3e Chapter 10, page 33 First draft Insert date of submission and is managed by T cells, and humoral immunity, which deals with infectious agents in blood and tissues, and is mediated by B cells and their antibodies. • B and T cells have antigen-specific receptors, which bind pure antigen in the case of B cells, or antigen presented on MHC in the case of T cells. • Stimulation by antigen plus other signals causes T lymphocytes to proliferate into clones of effector cells and memory cells. • Cytotoxic CD8+ T cells recognize and kill cells that are infected with endogenous pathogen presented on class I MHC. CD4+ T helper 1 cells activate macrophages that present antigen on class II MHC. CD4+ T helper 2 cells activate B cells that present exogenous antigen on Class II MHC. • Activated B cells become antibody-producing plasma cells and memory cells. • Antibodies are antigen-specific binding proteins that neutralize and opsonize antigen and activate complement to promote various immune reactions. Antibodies occur in five isotpyes with special functions. • Graft rejection is the major complication of organ transplantation and mainly depends on the allogeneic differences in the human leukocyte antigens (HLAs) between organ donor and recipient. • Every acute illness evokes an immunological response, and nearly every prolonged serious illness interferes with the immune system. • Chronic inflammation leads to tissue damage and clinical symptoms. It is associated with the predisposition to a multitude of diseases. • Immune system diseases are caused by abnormal or absent immunologic mechanisms, whether humoral, cell-mediated, or both. • The actions of the immune system are closely interrelated with the actions of the endocrine and the neuronal systems to keep body homeostasis.
  34. 34. Rhoades/Bell 3e Chapter 10, page 34 First draft Insert date of submission REVIEW QUESTIONS 1. After the nurse covers a patient’s wound with an adhesive bandage, he rapidly develops a red rash with small blisters. The called clinician diagnoses acute dermatitis. He explains to the nurse that the patient’s T lymphocytes are overreacting, while in most other acute inflammatory conditions another cell type dominates. To which other cells is the doctor referring? A. B cells B. Dendritic cells C. Eosinophils D. Mast cells E. Neutrophils 2. Penicillin is a small antibiotic molecule with a molecular weight of 300 Dalton. It binds to an enzyme in the wall of many bacteria, which leads to the weakening of the cell wall. As an unwanted side effect, penicillin can also bind to serum or tissue proteins, and the resulting complexes can cause allergic reactions mediated through IgE antibodies. Which of the following describes the parent penicillin molecule? A. Antigen B. Hapten C. Immunogen D. Opsonin E. Pathogen 3. A 40-year old woman is determined to run a marathon once in her life. For the last 4 months, she trained almost every day, ate high protein meals, and lost 10 kg, while still keeping up with her job and
  35. 35. Rhoades/Bell 3e Chapter 10, page 35 First draft Insert date of submission motherly duties. Her husband recognizes that she more frequently blows her nose, rubs her eyes and clears her throat in the evening. Which of the following best characterizes her condition? A. Acquired immunodeficiency B. Anaphylaxis C. Atopic disease D. Food allergy E. Non-allergic asthma 4. A scientific article announces a breakthrough for organ transplantation in an article entitled “Specific suppression of CD4+ T cell alloreactivity by allo-MHC class I- restricted CD8+ T cells.” Which of the following bests describes the finding? A. Cytotoxic T cells were suppressed by MHC antigen-presenting cells B. Cytotoxic T cells were suppressed by T helper cells C. MHC antigen-presenting cells were suppressed by T helper cells D. T helper cells were suppressed by cytotoxic T cells E. T helper cells were suppressed by MHC antigen-presenting cells 5. Herpes simplex viruses tend to infect cells of skin or mucous membranes. As part of the immune response against the infection, the virus is presented by a host cell (1), with antigen-presenting molecules (2), to target cells (3). Which of the following are correct for 1, 2 and 3? A. 1: Any cell 2: MHC class I 3: Cytotoxic T cell B. 1: Any cell 2: MHC class II 3: T helper cell C. 1: Any cell 2: MHC class I 3: T helper 1 cell D. 1: B cell 2: MHC class II 3: Cytotoxic T cell E. 1: Dendritic cell 3: MHC class II 3: Cytotoxic T cell
  36. 36. Rhoades/Bell 3e Chapter 10, page 36 First draft Insert date of submission ANSWERS AND RATIONALES 1. The answer is E. Neutrophils are the main cells to mediate the effects of acute inflammation. They remove the irritating agents by phagocytosis and destroy microorganisms by lysosomal enzymes and reactive oxygen radicals. The presence of lymphocytes and monocytes/macrophages is usually an indication that the inflammation has reached the chronic state. However, in most inflammatory disorders of the skin, such as dermatitis, lymphocytes are the common reacting cells. This is even the case, with rare exceptions, for immune-mediated skin reactions. 2. The answer is B. Penicillin is a chemical hapten that needs to bind to a macromolecule, usually a protein, to become immunogenic. 3. The answer is E. Non-allergic asthma can be triggered by strenuous exercise or stress. It leads to the same symptoms as allergic asthma, also called atopic asthma. Anaphylaxis, or severe allergy, is not the best answer since her husband is the one that recognizes the symptoms. Food allergy is a possibility due to the altered diet, but there is no mentioning of any relation between the symptoms and meals. Acquired immunodeficiencies may develop after a disease or due to malnutrition. 4. The answer is D. CD4+ cells are T helper cells. CD8+ cells are cytotoxic T cells. Cytotoxic T cells were raised that could recognize MHC class I antigens on target antigen-presenting cells and consequently suppress the response of T helper cells to MHC class II antigen of the same antigen presenting cell. This would support the goal to suppress the host’s immune response to donor MHC antigens for organ transplantation. 5. The answer is A. Endogenous antigens such as viruses replicating within a host cell are digested by enzymes of the host cell and presented, coupled to MHC class I molecules, to CD8+ cytotoxic T cells, which destroy the infected cell. Class I MHC is expressed by almost all host cells.
  37. 37. Rhoades/Bell 3e Chapter 10, page 37 First draft Insert date of submission CLINICAL FOCUS BOXES <box>10.1 Allergies and Asthma Epidemiological data confirm what many parents suspected. Allergies amongst children are more common compared to the incidence rate during their childhood. In the past 30 years, the prevalence of allergies has been greatly increasing in the US and in the world, proportionally more so in wealthy countries compared to poorer countries and more so in urban areas compared to rural areas. One hypothesis to explain this phenomenon proposes that the children that are not exposed to enough antigens or innocuous microorganisms from soil or water early in their childhood don’t adequately develop their T helper 1 cell response. This leads to an imbalance towards T helper 2 cell responses which are present since birth. Even though this hypothesis is disputed as being desperately oversimplified, it is undisputed that the various manifestations of allergic inflammation are the result of wrongly activated T helper 2 cells. Asthma is one common allergic disorder, which affects about 5% of the US population. It belongs to the category of type I hypersensitivity reaction, and is characterized by airways that narrow excessively in response to a wide variety of provoking stimuli. Typical allergens causing atopic (also called extrinsic or allergic) asthma are animal dander, dust mites, grass pollen and cockroach antigen. Non-atopic asthma might be triggered by strenuous exercise or worry. The symptoms of both asthma types are similar and include wheezing, breathlessness, chest tightness, and coughing. They are caused by chronic inflammation of the airways which leads to their swelling. The restriction of the airflow to and from the lungs is further exacerbated by bronchoconstriction, excess production of mucus, and increased collagen deposition. The development of asthmatic symptoms ultimately depends on the presence of T helper 2 cells, which secrete a characteristic cytokine repertoire. Interleukin-4 activates B cells to produce IgE antibodies, which bind to mast cells, eosinophils and other airway cells via receptors that are specific for the Fc
  38. 38. Rhoades/Bell 3e Chapter 10, page 38 First draft Insert date of submission portions of IgE antibodies. Upon subsequent encounter with the antigen, IgE-crosslinking on mast cells and eosinophils occurs and leads to the cells’ activation and their release of histamine and leukotrienes. These and other inflammatory factors recruit inflammatory cells including additional T helper 2 cells to the lung resulting in a damaging immunological positive feedback cycle. IL-4, together with IL-9, is also necessary for mast cell maturation, and along with IL-5, for eosinophil recruitment. Several treatments are available that interfere with the different allergic processes. Antihistamine drugs for treatment of atopic asthma are targeting H1 receptors or prevent the release of histamine from mast cells. Epinephrine and beta-2 selective agonists for treatment of systemic anaphylaxis modulate the sympathetic nervous system (see Neuroendoimmunology). Corticosteroids and leukotriene receptor antagonists aim at suppression of inflammation. Immunotherapy (also called hypo- or desensitization) involves subcutaneous injections that contain gradually increasing doses of an allergen extract. The immune system responds with gradually increasing levels of IgG antibodies, which seems to avoid dramatic reactions when the allergen is then encountered naturally. <box>10.2 Bone Marrow Transplantation When a patient has a terminal bone marrow disease, such as leukemia or aplastic anemia, often the only possibility for a cure is a bone marrow transplant. In this procedure, healthy bone marrow cells are used to replace the patient’s diseased hematopoietic system. To identify a suitable donor, blood leukocytes of prospective donors, usually a close relative, are screened to determine whether their antigenic pattern matches that of the patient. The antigenic composition of leukocytes in bone marrow and peripheral blood are identical, so analysis of blood leukocytes usually provides enough information to determine whether the transplanted cells will engraft successfully. If significantly different from the recipient’s tissue type, transplanted leukocytes may be recognized as foreign by the patient’s immune system and, therefore, be rejected, a phenomenon called host-versus-graft response.
  39. 39. Rhoades/Bell 3e Chapter 10, page 39 First draft Insert date of submission More commonly, sufficient differences between the engrafted cells and the host’s own tissue lead to debilitating consequences as a result of graft-versus-host disease (GVHD). In GVHD, functional T cells in the proliferating graft recognize host tissue as foreign and mount an immune response. The disease often begins with a skin rash, as transplanted lymphocytes invade the dermis, and ends in death as lymphocytes destroy every organ system in the marrow recipient. Recent advances have decreased the morbidity of marrow transplants and have substantially increased the potential pool of bone marrow donors for a given patient. Immunosuppressive agents, including steroids, cyclosporine, and anti-T cell antiserum, effectively decrease the immune function of the transplanted lymphocytes. Another useful approach involves “purging”—the physical removal of T cells from bone marrow prior to transplantation. T cell-depleted bone marrow is much less capable of causing acute GVHD than untreated marrow. These techniques have enabled the successful transplantation of bone marrow obtained from unrelated donors. Many problems remain, however. One of the most serious is donor identification. An unrelated transplant is successful only if the donor’s human leukocyte antigens (HLA) closely match those of the recipient. Since there are several antigenic determinants and each can be occupied by any one of several genes, there are thousands of possible combinations of leukocyte antigens. The chance that any individual’s cells will randomly match those of another is less than one in a million. Finding a suitable donor is a formidable problem that often generates intense frustration. In conjunction with continued development of methods to reduce or eliminate GVHD, the expanding bone marrow transplant registries may someday allow identification of a donor for anyone who needs a bone marrow transplant. <box>10.3 Vaccination and DNA vaccines against AIDS (From Bench to Bedside) According to a 2006 estimate, about 1.2 million people in the US and over 60 million worldwide are infected with HIV, the human immunodeficiency virus causing acquired immunodeficiency syndrome
  40. 40. Rhoades/Bell 3e Chapter 10, page 40 First draft Insert date of submission (AIDS). Since its first diagnosis in 1981, more than 20 million people have died of AIDS. One preventative measure against the spreading of pandemic infectious diseases such as AIDS is vaccination. For instance, vaccination has eradicated the polio virus from the Western hemisphere. Great effort is currently being undertaken to develop an AIDS vaccine. The principle of vaccination, also called immunization, is to stimulate the acquired immune system of the body to fight diseases. Passive immunization refers to the administration of antibodies and lymphocytes. These last only a few days and hence provide only transient protection. Nevertheless, it might be a life saving measure in emergencies as in the case of a person bitten by an animal with the rabies virus. Active immunization is necessary to provide long-term protection, because it generates immunological memory. To immunize against viral diseases, the vaccine generally contains an attenuated (weakened) or killed virus. The vaccine for immunization against bacterial diseases often contains only a portion of the bacteria. These vaccines might be generated by recombinant technology, where the gene coding for the pathogenic epitope of the bacteria is isolated and expressed in an appropriate host cell. In the fight against AIDS, several clinical trials are underway using another type of vaccine, DNA plasmid vaccine. In this case, genes that encode proteins of pathogens are injected into a person, rather than the pathogens themselves. The gene of interest is grown in bacteria and hence called plasmid DNA. When injected in humans, it is taken up by mainly antigen-presenting cells, which then produce the encoded protein. This antigenic protein elicits an immune response just like a conventional vaccine. DNA vaccines are attractive for protection against HIV, where inoculation with a dead or attenuated virus is very risky. It has been proven, at least in animal models, that DNA vaccines activate both cellular and humoral immune responses. This is advantageous since live viral vaccines only induce the cellular response, while vaccines containing killed microorganisms, or subunits of them, only induce the humoral response. Another advantage is the stability of DNA vaccines at ambient temperatures, which
  41. 41. Rhoades/Bell 3e Chapter 10, page 41 First draft Insert date of submission makes them useable in areas where constant refrigeration of the vaccine is not possible. Finally, DNA vaccines are cheaper and easier to produce than conventional vaccines and can be manipulated by the tools of recombinant technology. The potential that the vaccine plasmid DNA might become integrated into human chromosomal DNA raises concern. This could induce cancer due to the disruption of a cell division gene or the activation of an oncogene. Another problem of DNA vaccines includes the question of how to terminate their actions. Continuous antigenic stimulation may lead to immune tolerance or autoimmunity. Another safety consideration involves the potential induction of antibodies against the plasmid DNA, which again might lead to autoimmune diseases. These concerns are currently being addressed, for instance, by improving the delivery of the plasmid DNA only to antigen-presenting cells, and at the correct time for immune cells to respond. While the ultimate clinical effectiveness of DNA vaccines is unclear, they have shown promising results in preclinical trials against diseases such as AIDS.
  42. 42. Rhoades/Bell 3e Chapter 10, page 42 First draft Insert date of submission Table 10.1 Characteristics of the Innate and Adaptive Immune Systems Innate Adaptive System Old, present in all Evolved in early vertebrates animals Present at birth Transferable to other individuals Highly reliable Frequently malfunctioning Stimulation Not required Required Specificity Minimal Highly specific Self vs non-self discrimination Receptor mediated Response Within minutes Develops over days No change in quality and Improved by previous infection quantity over time Memory No Yes Soluble factors Lysozyme, complement, Antibodies acute phase proteins, interferon, cytokines Cells Phagocytic leukocytes, T cells, B cells NK Cells
  43. 43. Rhoades/Bell 3e Chapter 10, page 43 First draft Insert date of submission Table 10.2 Cellular Elements of the Innate Immune System Effector Cells Main function Phagocytosis Neutrophils Kill microorganisms + intracellularly Macrophages Kill microorganisms intra- + and extracellularly Dendritic cells Destroy microorganisms + NK and LAK Destroy virus infected and - cells tumor cells Eosinophils Secrete factors that kill - certain parasites and worms Mast Cells Release factors which - increase blood flow and vascular permeability
  44. 44. Rhoades/Bell 3e Chapter 10, page 44 First draft Insert date of submission Table 10.3 T cell mediated immunity response Source of antigen : Viruses, some bacteria Bacteria, phagocytosed or Extracellular proteins living in phagosomes (vaccines, toxins) Location of antigen : Cytosol Phagosomes Endosomes Antigen Presenting Cell (APC) : Any cell Macrophages, dendritic B cells cells Location of APC : Anywhere Lymphoid and Lymphoid tissues, Blood Connective tissue, Body cavities, Epithelium Molecules of display : MHC class I MHC class II MHC class II + + Antigen recognition cells : CD8 CTL cells CD4 TH1 cells CD4+ TH2 cells Response : Release of cytotoxic Release of macrophage- B cell activation effector molecules activating effector molecules Effect : Death of infected cell Killing of bacteria and Secretion of antibody to parasites eliminate bacteria and toxins
  45. 45. Rhoades/Bell 3e Chapter 10, page 45 First draft Insert date of submission Table 10.4 Characteristics of Different Antibody Classes IgG IgA IgM IgD IgE Molecular weight (x 10-3 Daltons) 150 150, 400 900 180 190 Y units/molecule 1 1–2 5 1 1 Serum concentration (mg/dL) 600–1500 85–300 50–400 <15 0.01–0.03 Serum concentration (% of Ig) ~76 ~15 8 1 0.002 Crosses placenta + - - - - Enters secretions + ++ - - - Agglutinates particles + + +++ - - Allergic reactions + - - - ++++ Complement fixation + - ++ - - Fc receptor binding to monocytes and ++ - + - - neutrophils Dominant in secondary immune response + Main antibody in external secretions + Dominant in primary immune responses + Responsible for hypersensitivity +
  46. 46. Rhoades/Bell 3e Chapter 10, page 46 First draft Insert date of submission Table 10.5 Endogenous Inflammatory Mediators Released By Some Actions Chemical Histamine Mast cells, basophils, Vasodilation mediators eosinophils, leukocytes, Vascular permeability platelets Lysosomal compounds Neutrophils, Vascular permeability macrophages Complement activation Eicosanoids Prostaglandins Many cells Vasoactive properties, platelet Thromboxanes Neutrophils aggregation, prolong edema Leukotrienes Platelet activating factor Neutrophils, Vascular permeability monocytes, mast cells, Neutrophil migration eosinophils Bronchoconstriction Serotonin Mast cells, platelets Vasoconstriction Cytokines Lymphocytes, Vasoactive and chemotactic monocytes properties Chemokines Tissues cells, Chemotaxis of inflammatory effector endothelial cells, cells leukocytes Gases Nitric oxide Endothelial cells, Vascular smooth muscle relaxation macrophages and vasodilation, kills microbes, counteracts platelet actions Neuropeptide Tachykinins Mainly sensory neurons Vasodilation, vascular permeability, s Kinins smooth muscle contraction, mucus secretion, pain Activated By Plasma Complement Enzymes from dying Chemotaxis, phagocyte, mast cell and factors (most important C5a, cells; antigen-antibody platelet degranulation, cytolytic C3a, but others also complexes (classical activity, opsonization of bacteria involved) pathway); endotoxins (facilitates phagocytosis) (alternate pathway); products of kinin, coagulation and fibrinolytic system Kinins Coagulation factor XII Vascular permeability Mediators of pain Non-vascular smooth muscle contraction Coagulation Factors Coagulation factor XII Conversion of fibrinogen to fibrin Fibrinolytic system Plasmin lyses fibrin
  47. 47. Rhoades/Bell 3e Chapter 10, page 47 First draft Insert date of submission Table 10.6 Types of Graft Rejection Type Time Reasons Hyper- Minutes - hours Pre-formed anti-donor antibodies trigger acute type II hypersensitivity reactions Acute Days – weeks HLA incompatibility or inappropriate connection to blood supply trigger T cell activation and type IV hypersensitivity reactions. Complicated by antibody- mediated rejection. Chronic Months - years Unclear. Cellular and humoral mechanisms involved. Reoccurance of disease possible.


Quebec is making a few minor changes to its looming and controversial welfare reforms.

Labour Minister Agnes Maltais has been under fire for implementing cuts affecting families with young children, some people over 55, and people accessing drug and alcohol treatment.

Under current rules, welfare recipients who are older than 55-years-old and couples with children under the age of five are entitled to an additional $129 each month.

The Quebec government had announced that, starting June 1, those funds will be dramatically reformed.

The age of eligibility will be pushed to 58 from 55 and qualifying families and would need to register with Emploi Quebec for job-finding activities to receive any additional money.

In addition to those changes, anyone receiving social assistance and undergoing treatment in an addiction rehabilitation centre will be evaluated after 183 days to determine if they're able to return to the job market.

The changes aren't retroactive and will only affect new applicants.

Delayed until September

Maltais now says the new rules for families won't be implemented until September and additional measures will be brought in to help get anyone over 55 back to work.

At a news conference Tuesday, Maltais indicated there would be a significant and progressive bonus to provide further assistance to 85,000 of the poorest Quebecers. She did not provide further details.

She said more information on that bonus would be available in "a few short weeks."

The changes have been met with criticism from the opposition in the national assembly and anti-poverty groups, who have staged demonstrations to oppose the changes.

"The minister is trying to save face with this release today announcing a few changes to the cuts," Québec solidaire MNA and party co-spokesperson Françoise David said yesterday.

"But essentially, she's confirming that's she staying on the same track. She continues to ignore the opinions that are popping up everywhere that these cuts will have a negative impact on people."

'I think it's just crumbs'

Margaret van Nooten, a social rights worker with the group Project Genesis, said she already sees people struggling and failing to pay their bills on the $600 dollars a month they're afforded on social assistance.

Van Nooten said simply delaying a cut and adding other minor amendments is a slap in the face.

"After the groundswell of outrage that's happened, I just think it is crumbs," she said.

"Increasing the rates would be something that would actually help remove people from the terrible, terrible situation they're in...[This] is just worsening their situation. It's like a slap in the face to the people that are the most vulnerable."

Van Nooten says Maltais didn't do any consultation with anti-poverty groups before drafting the reforms and is now trying to smooth it over with minor changes.

Maltais has already acknowledged she made a mistake when she failed to publicly announce proposed changes to the welfare system.

In an interview with the Canadian Press in March, Maltais admitted she dropped the ball by neglecting to take the time to explain the changes to social assistance before leaving to meet with her federal counterpart Diane Finley in Ottawa.

The changes were not publicly announced by the Parti Québécois government; rather, they were quietly mentioned in the Gazette Officielle, a provincial government publication.

Maltais explained Tuesday that she "didn't have time," to speak with affected groups before the changes were drafted.

"The important thing is where we land," she said.