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These vaccines elicit helper T cells to simulate germinal center reactions 300 medications for nclex buy discount solian 100 mg on line, which would not occur with simple polysaccharide vaccines symptoms 5 days post embryo transfer order solian 50 mg without prescription. Such vaccines work like hapten-carrier conjugates and are a practical application of the principle of T-B cell cooperation (see Chapter 12). Synthetic Antigen Vaccines A goal of vaccine research has been to identify the most immunogenic microbial antigens or epitopes, to synthesize these in the laboratory, and to use the synthetic antigens as vaccines. Heat-killed bacteria are powerful adjuvants that are commonly used in experimental animals. However, the severe local inflammation that such adjuvants trigger precludes their use in humans. Much effort is currently being devoted to development of safe and effective adjuvants for use in humans. Only two are approved for patients-aluminum hydroxide gel (which appears to promote mostly B cell responses) and a lipid formulation called Squalene that may activate phagocytes. An alternative to adjuvants is to administer natural substances that stimulate T cell responses together with antigens. Live Viral Vaccines Involving Recombinant Viruses Another approach for vaccine development is to introduce genes encoding microbial antigens into a noncytopathic virus and to infect individuals with this virus. This technique has been used most commonly with vaccinia virus vectors, and more recently with canarypox viral vectors, which are not pathogenic in humans. Inoculation of such recombinant viruses into many species of animals induces both humoral and cellmediated immunity against the antigen produced by the foreign gene (and, of course, against vaccinia virus antigens as well). These and other safety concerns have limited widespread use of viral vectors for vaccine delivery. Passive Immunization Protective immunity can also be conferred by passive immunization, for instance, by transfer of specific antibodies. In the clinical situation, passive immunization is most commonly used for rapid treatment of potentially fatal diseases caused by toxins, such as tetanus, and for protection from rabies and hepatitis. Antibodies against snake venom can be lifesaving when administered after poisonous snakebites. Passive immunity, using current approaches, is short-lived because the host does not respond to the immunization, and protection lasts only as long as the injected antibody persists. Moreover, passive immunization does not induce memory, so an immunized individual is not protected against subsequent exposure to the toxin or microbe. In this approach, adeno-associated viral vectors are used to introduce cloned human Ig heavy and light chain genes for a neutralizing antibody into human subjects. The goal is to have injected humans synthesize a specific protective broadly neutralizing antibody for an extended period of time. Different types of infectious agents stimulate distinct types of immune responses and have evolved unique mechanisms for evading immunity. In some infections, the immune response is the cause of tissue injury and disease. Innate immunity against extracellular bacteria is mediated by phagocytes and the complement system (the alternative and lectin pathways). The principal adaptive immune response against extracellular bacteria consists of specific antibodies that opsonize the bacteria for phagocytosis and activate the complement system. Some bacterial toxins are powerful inducers of cytokine production, and cytokines account for much of the systemic disease associated with severe, disseminated infections with these microbes. However, intracellular bacteria are capable of surviving and replicating within host cells, including phagocytes, because they have developed mechanisms for resisting degradation within phagocytes. The characteristic pathologic response to infection by intracellular bacteria is granulomatous inflammation. Protective responses to fungi consist of innate immunity, mediated by neutrophils and macrophages, and adaptive cell-mediated and humoral immunity. Fungi are usually readily eliminated by phagocytes and a competent immune system, because of which disseminated fungal infections are seen mostly in immunodeficient persons. Neutralizing antibodies protect against virus entry into cells early in the course of infection and later if the viruses are released from killed infected cells. Viruses evade immune responses by antigenic variation, inhibition of antigen presentation, and production of immunosuppressive molecules. Y Parasites such as protozoa and helminths give rise to chronic and persistent infections because innate immunity against them is weak and parasites have evolved multiple mechanisms for evading and resisting specific immunity.

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Not included are natural killer cells and other innate lymphoid cells medicine and science in sports and exercise discount solian uk, which are discussed in Chapter 4 symptoms mono safe solian 50 mg. Cells of the Immune System 23 of T cells expressing receptors; their function is to inhibit immune responses. The functions of these classes of B and T cells will be discussed in later chapters. Development of Lymphocytes After birth, lymphocytes, like all blood cells, arise from stem cells in the bone marrow. The origin of lymphocytes from bone marrow progenitors was first demonstrated by experiments with radiation-induced bone marrow chimeras. Lymphocytes and their precursors are radiosensitive and are killed by high doses of -irradiation. Such approaches have proved useful for examining the maturation of lymphocytes and other blood cells. The anatomic sites where the major steps in lymphocyte development occur are called the generative (or primary, or central) lymphoid organs. These include the bone marrow, where precursors of all lymphocytes arise and B cells mature, and the thymus, where T cells mature. We will discuss the processes of B and T lymphocyte maturation in much more detail in Chapter 8. The mature lymphocytes that emerge from the bone marrow or thymus are called naive lymphocytes. Naive lymphocytes are functionally quiescent, but after activation by antigen, they proliferate and go through dramatic changes in phenotype and functional activity. The activation of naive lymphocytes follows a series of sequential steps beginning with the synthesis of new proteins, such as cytokine receptors and cytokines, which are required for many of the subsequent changes. The cells then undergo proliferation, resulting in increased size of the antigen-specific clones, a process called clonal expansion. In some infections the number of microbespecific T cells may increase more than 50,000-fold within a week, and the number of specific B cells may increase up to 5,000-fold. Fully mature T cells leave the thymus, but immature B cells leave the bone marrow and complete their maturation in secondary lymphoid organs. Naive lymphocytes may respond to foreign antigens in these secondary lymphoid tissues or return by lymphatic drainage to the blood and recirculate through other secondary lymphoid organs. Naive T cells emerging from the thymus and immature B cells emerging from the bone marrow migrate into secondary lymphoid organs, including lymph nodes and spleen. In these locations, B cells complete their maturation; naive B and T cells activated by antigens differentiate into effector and memory lymphocytes. Some effector and memory lymphocytes migrate into peripheral tissue sites of infection. Antibodies secreted by effector B cells in lymph node, spleen, and bone marrow (not shown) enter the blood and are delivered to sites of infection. Concurrently with proliferation, antigen-stimulated lymphocytes differentiate into effector cells whose function is to eliminate the antigen. Other progeny of antigen-stimulated B and T lymphocytes differentiate into long-lived memory cells, whose function is to mediate rapid and enhanced. Naive, effector, and memory lymphocytes can be distinguished by several functional and phenotypic criteria (see Table 2. The details of lymphocyte activation and differentiation, as well as the functions of each of these populations, will be addressed later in this book. Naive Lymphocytes Naive lymphocytes are mature T or B cells that have never encountered foreign antigen. Naive and memory lymphocytes are both called resting lymphocytes because they are not actively dividing, nor are they performing effector functions. Naive (and memory) B and T lymphocytes cannot be readily distinguished morphologically, and both are often called small lymphocytes when observed in blood smears. Before antigenic stimulation, naive lymphocytes are in a state of rest, or in the G0 stage of the cell cycle.

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Calcium symptoms rectal cancer order solian 100mg without a prescription, Magnesium treatment zygomycetes purchase solian 100mg without prescription, and Phosphate Ions the precise mechanisms by which calcium, magnesium, and phosphate concentrations are regulated by the kidneys are not well understood. It is known, however, that elevated levels of any one of these ions in the extracellular fluid cause the tubules to decrease reabsorption and to pass the substances into the urine. In contrast, when any one of these substances is low in concentration, the tubules rapidly reabsorb the substance until its concentration in the extracellular fluids returns to normal. The rate of secretion is directly proportional to the hydrogen ion concentration in the blood. Thus, when the extracellular fluids become too acidic, the kidneys excrete hydrogen ions into the urine. In contrast, when the extracellular fluids become too alkaline, the kidneys excrete basic substances (primarily sodium bicarbonate) into the urine. In both of these examples, the excretion of either acidic or alkaline substances moves the pH toward normal. Blood Volume In the adult, the normal blood volume is about 5 L, and it rarely increases or decreases more than a few hundred milliliters from that value. The capillary fluid shifts and the renal system are the two major mechanisms responsible for this constancy of the blood volume. Capillary Fluid Shift System Under normal circumstances, the pressure in the systemic capillaries is about 17 mm Hg. When the pressure rises above this value, fluid begins to leak into the tissue spaces, causing the blood volume to decrease toward normal. In contrast, when the blood volume falls, the capillary pressure decreases, and fluid is then absorbed from the interstitial spaces, causing the blood volume to move back toward normal. This mechanism, however, has its limitations because the tissue spaces cannot expand indefinitely when the blood volume becomes too high, nor can the tissue spaces supply an inexhaustible amount of fluid when the blood volume is too low. Renal System When the blood volume increases, the glomerular pressure in the kidney rises, causing the amount of the glomerular filtrate and the volume of the urine to increase. In addition, the pressure in the peritubular capillaries decreases fluid reabsorption from the tubules, which further increases the volume of urine. Increased blood volume increases the glomerular pressure (normally 60 mm Hg) by means of two mechanisms: (1) the increased blood volume increases the blood flow through the afferent arterioles that lead into the kidneys and thus increases the intrarenal pressure, and (2) the increased blood volume stretches the atria of the heart, which contain stretch receptors called volume receptors. When the volume receptors in the atria are stretched, a neural reflex is initiated, which causes the renal afferent arterioles to dilate. This causes the blood flow into the kidneys to increase and thus increases the amount of urine formed. Clinical Connection 16-1 Case Study-Adverse Effects of Poor Blood Circulation on Kidney and Lung Function In the Clinical Application Case 1 (page 514), the respiratory therapist is called to help care for a 73-year-old woman who was admitted to the hospital for severe renal failure and left ventricular heart failure. The more common causes of renal failure are (1) congenital disorders, (2) infections, (3) obstructive disorders, (4) inflammation and immune responses, and (5) neoplasms. Common Causes of Renal Disorders Congenital Disorders Approximately 10 percent of infants are born with a potentially life-threatening malformation of the renal system. Such abnormalities include unilateral renal agenesis, renal dysplasia, and polycystic disease of the kidney. Infections Urinary tract infections are the second most common type of bacterial infections (after respiratory tract infections). Approximately 20 percent of all women will develop at least one urinary tract infection during their lifetime. These infections range from bacteriuria to severe kidney infections that cause irreversible damage to the kidneys. Obstructive Disorders Urinary obstruction can affect all age groups and can occur in any part of the urinary tract. Persons who have a urinary obstruction are prone to infections, a heightened susceptibility to calculus formation, and permanent kidney damage. Inflammation and Immune Responses Kidney inflammation is caused by altered immune responses, drugs and related chemicals, and radiation. Inflammation can cause significant alterations in the glomeruli, tubules, and interstitium. The various forms of glomerulonephritis are believed to be caused by natural immune responses.

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Not only does this practice lead to errors in establishing an accurate dose treatments yeast infections pregnant buy 100mg solian otc, but also symptoms xxy solian 100 mg low price, depending on the nature of the study, other erroneous conclusions may be drawn. For example, the presence of related compounds in the dosage form of a tricyclic antidepressant led to erroneous conclusions about the metabolic products of the drug when it was administered together with the unidentified contaminants (Saady et al. An even greater error may result when a small amount of a contaminant may be supertoxic. A well-publicized Separation of the classes specified above is generally achieved by adjusting the acidity of the aqueous matrix and extracting with a water-immiscible solvent or a solid-phase sorbent material. Finally, a miscellaneous category must also be included to cover the large number of compounds that cannot be detected by the routine application of the methods described above. Venoms and other toxic mixtures of proteins, or uncharacterized constituents, fall into this class. Frequently, if antibodies can be produced against the active constituent, an immunoassay may be the most practical means of detecting and measuring these highly potent and difficult-to-isolate substances. Some of the adverse effects of Agent Orange are considered to be due to the low concentration of dioxin in those mixtures. Other researchers have reported that the toxicity of mixtures of polybrominated biphenyls may be due to the high toxicity of specific components, whereas other brominated biphenyls are relatively nontoxic (Mills et al. A related application of analytical toxicology is the monitoring of dosage forms or solutions for stability throughout the course of an experimental study. Chemicals may degrade when in contact with air, by exposure to ultraviolet or other radiation, by interaction with constituents of the vehicle or dosing solution, and by other means. Developing an analytical procedure by which these changes can be recognized and corrected is essential in achieving consistent and reliable results over the course of a study (Blanke, 1987; Peters et al. Finally, analytical methods are necessary to determine the bioavailability of a compound that is under study. Some substances with low water solubility are difficult to introduce into an animal, and a variety of vehicles may be investigated. However, a comparison of the blood concentrations for the compound under study provides a simple means of comparing the effectiveness of vehicles. Introducing a compound into the stomach in an oil vehicle may not be the most effective means of enhancing the absorption of that compound (Granger et al. The complete investigation of the cause or causes of sudden death is an important civic and legal responsibility. The responsibility of establishing the cause of death rests with the medical examiner or coroner, but success in arriving at the correct conclusion often depends on the combined efforts of the pathologist and the toxicologist. The cause of death in cases of poisoning cannot be proved beyond contention without toxicological analysis that confirms the presence of the toxicant in either body fluids or tissues of the deceased. Many drugs or poisons do not produce characteristic pathological lesions; their presence in the body can be demonstrated only by chemical methods of isolation and identification. If toxicological analyses are limited, deaths resulting from poisoning may be erroneously ascribed to an entirely different cause or poisoning may be designated as the cause of death without empirical proof. Additionally, a toxicologist can furnish valuable evidence concerning the circumstances surrounding a death. Such cases commonly involve demonstrating the presence of intoxicating concentrations of ethanol in victims of automotive or industrial accidents, or measurements of concentrations of carbon monoxide in fire victims. The degree of carbon monoxide saturation of the blood may indicate whether the deceased died as a result of the fire or was dead before the fire started. Also, licit or illicit psychoactive drugs often play a significant role in the circumstances associated with sudden or violent death. The behavioral toxicity of many illicit drugs may explain the bizarre or "risk-taking" behavior of the deceased that led to his or her demise. At times, a negative toxicological finding is of particular importance in assessing the cause of death.

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The relative amounts of a particular molecule on different cell populations can be compared by staining each population with the same probe and determining the amount of fluorescence emitted medicine 5e solian 100mg discount. In preparation for flow cytometric analysis medications adhd purchase 100 mg solian mastercard, cell suspensions are stained with the fluorescent probes of choice. Most often, these probes are fluorochrome-labeled antibodies specific for a cell surface molecule. Alternatively, cytoplasmic molecules can be stained by temporarily permeabilizing cells and permitting the labeled antibodies to enter through the plasma membrane. In addition to antibodies, various fluorescent indicators of cytoplasmic ion concentrations and reduction-oxidation potential can be detected by flow cytometry. Apoptotic cells can be identified with fluorescent probes, such as annexin V, that bind to abnormally exposed phospholipids on the surface of the dying cells. Modern flow cytometers can routinely detect three or more different-colored fluorescent signals, each attached to a different antibody or other probe. This technique permits simultaneous analysis of the expression of many different combinations of molecules by a cell. In addition to detecting fluorescent signals, flow cytometers also measure the forward and side light-scattering properties of cells, which reflect cell size and internal complexity, respectively. For example, compared with lymphocytes, neutrophils cause greater side scatter because of their cytoplasmic granules, and monocytes cause greater forward scatter because of their size. A newly developed antibody-based technology called mass cytometry combines the single-cell flow technology of flow cytometers with mass spectrometry. Antibodies specific for molecules of interest are labeled with any one of a large number of heavy metals, using a different metal for each antibody specificity. Unlike fluorescence labels, many different heavy metal labels can be resolved by mass spectrometry without overlap, allowing for the detection of as many as 100 different molecules on a single cell. These beads are mixed with the test solution that contains multiple cytokines, such as serum or supernatants of lymphocyte cultures. Each cytokine will bind only to beads of one particular size and fluorescence intensity. The beads are simultaneously analyzed by a two-laser flow-based detection instrument. Standard solutions with known concentrations of the cytokines are used to calibrate the results. The cells may be labeled with fluorescently tagged antibodies ex vivo, or, in the case of experimental animal studies, labeling may be accomplished in vivo by expression of transgenes that encode fluorescent proteins, such as green fluorescent protein. These "immunomagnetic reagents" will bind to certain cells, depending on the specificity of the antibody used, and the bound cells can then be pulled out of suspension by a strong magnet. Immunofluorescence and Immunohistochemistry Antibodies can be used to identify the anatomic distribution of an antigen within a tissue or within compartments of a cell. To do so, the tissue or cell is incubated with an antibody that is labeled with a fluorochrome or enzyme, and the position of the label, determined with a suitable microscope, is used to infer the position of the antigen. In the earliest version of this method, called immunofluorescence, the antibody was labeled with a fluorescent dye and allowed to bind to a monolayer of cells or to a frozen section of a tissue. The stained cells or tissues were examined with a fluorescence microscope to locate the antibody. Although sensitive, the fluorescence microscope is not an ideal tool to identify the detailed structures of the cell or tissue because of a low signal-to-noise ratio. This problem has been overcome by new technologies including confocal microscopy, which uses optical sectioning technology to filter out unfocused fluorescent light, and two-photon microscopy, which prevents outof-focus light from forming. Alternatively, antibodies may be coupled to enzymes that convert colorless substrates to colored insoluble substances that precipitate at Cytokine Bead Assays In these assays, the concentration of many different cytokines in a single solution can be determined simultaneously. A conventional light microscope may then be used to localize the antibody in a stained cell or tissue. The most common variant of this method uses the enzyme horseradish peroxidase, and the method is commonly referred to as the immunoperoxidase technique. Different antibodies coupled to different enzymes may be used in conjunction to produce simultaneous two-color localizations of different antigens.

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Of this volume treatment zone guiseley cheap solian 100 mg mastercard, about 75 percent is in the systemic circulation medications gabapentin buy discount solian 50 mg on-line, 15 percent in the heart, and 10 percent in the pulmonary circulation. Overall, about 60 percent of the total blood volume is in the veins, and about 10 percent is in the arteries. Normally, the pulmonary capillary bed contains about 75 mL of blood, although it has the capacity of about 200 mL. This linear distribution of blood is a function of (1) gravity, (2) cardiac output, and (3) pulmonary vascular resistance. Apex Base Gravity Because blood is a relatively heavy substance, it is gravity dependent; that is, it naturally moves to the portion of the body, or portion of the organ, that is closest to the ground. In the average lung, there is a distance of about 30 cm between the base and the apex. The blood that fills the lung from the bottom to the top is analogous to a column of water 30 cm long and, therefore, exerts a pressure of about 30 cm H2O (22 mm Hg) between the base and apex. Because the pulmonary artery enters each lung about midway between the top and bottom of the lung, the pulmonary artery pressure must be greater than 15 cm H2O (11 mm Hg) to overcome the gravitational force and, thereby, supply blood to the lung apex. For this reason, most of the blood flows through (or falls into) the lower half of the lung-the gravity-dependent portion of the lung. As a result of the gravitational effect on blood flow, the intraluminal pressures of the vessels in the gravity-dependent area (lower lung region) are greater than the intraluminal pressures in the least gravity-dependent area (upper lung region). The high intraluminal pressure of the vessels in the gravitydependent area causes the vessels to distend. As the vessels widen, the vascular resistance decreases and, thus, permits blood flow to increase. The position of the body can significantly change the gravity-dependent portion of the lungs. In Zone 1 (the least gravity-dependent area), the alveolar pressure is sometimes greater than both the arterial and the venous intraluminal pressures. As a result, the pulmonary capillaries can be compressed, and blood is prevented from flowing through this region. Thus, body position affects the distribution of the pulmonary blood flow as illustrated in the (a) erect, (B) supine, (c) lateral, and (D) upside-down positions. There are, however, a variety of conditions-such as severe hemorrhage, dehydration, and positive pressure ventilation-that can result in the alveolar pressure being higher than the arterial and venous pressures. In Zone 2, the arterial pressure is greater than the alveolar pressure, and therefore, the pulmonary capillaries are perfused. Because the alveolar pressure is greater than the venous pressure, the effective driving pressure for blood flow is determined by the pulmonary arterial pressure minus the alveolar pressure-not the normal arterial-venous pressure difference. Thus, because the alveolar pressure is essentially the same throughout all the lung regions, and because the arterial pressure progressively increases toward the gravity-dependent areas of the lung, the effective driving pressure (arterial pressure minus alveolar pressure) steadily increases down the vertical axis of Zone 2. As a result, from the beginning of the upper portion of Zone 2 (the point at which the arterial pressure equals the alveolar pressure) to the lower portion of Zone 2 (the point at which the venous pressure equals the alveolar pressure) the flow of blood progressively increases. In Zone 3 (gravity-dependent area), both the arterial and the venous pressures are greater than the alveolar pressure and, therefore, blood flow through this region is constant. Because the arterial pressure and venous pressure both increase equally downward in Zone 3, the arterial-venous pressure difference and, therefore, blood flow is essentially the same throughout all of Zone 3. The stroke volume is determined by (1) ventricular preload, (2) ventricular afterload, and (3) myocardial contractility. Within limits, the more the myocardial fiber is stretched during diastole (preload), the more strongly it will contract during systole and, therefore, the greater the myocardial contractility will be. This mechanism enables the heart to convert an increased venous return into an increased stroke volume. Beyond a certain point, however, the cardiac output does not increase as the preload increases. The Frank-Starling curve shows that the more the myocardial fiber is stretched as a result of the blood pressure that develops as blood returns to the chambers of the heart during diastole, the more the heart muscle will contract during systole. Clinically, it would be best to determine the preload of the left ventricle by measuring the end-diastolic pressure of the left ventricle or left atrium.

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The molecules that are recog nized as foreign in allografts are called alloantigens treatment stye order solian with amex, and those in xenografts are called xenoantigens medicine vs nursing generic 50 mg solian free shipping. The lymphocytes and antibodies that react with alloantigens or xenoantigens are described as being alloreactive or xenoreactive, respectively. In addition to the adaptive immune responses specific for allogeneic differences between donor and host, innate immunity plays a role in the outcome of transplantation. The interruption of blood supply to tissue and organs during the time between removal from a donor and placement in a host usually cause some ischemic damage. Most of this chapter focuses on allogeneic transplanta tion because it is far more commonly practiced than xenogeneic transplantation, which is discussed briefly at the end of the chapter. We will consider both the basic immunology and some aspects of the clinical prac tice of transplantation. The molecular and cellular mechanisms of allorecognition are best understood by considering the graft antigens that stimulate allogeneic responses and the properties of the responding lymphocytes. The Nature of Alloantigens Most of the antigens that stimulate adaptive immune responses against allografts are proteins encoded by polymorphic genes that differ among individuals. As we discussed in Chapter 6, all of the animals of an inbred strain are genetically identical, and they are homozygous for all genes (except genes on the sex chro mosomes in males). In contrast, inbred animals of differ ent strains, and individuals in an outbred species (except identical twins), differ in many of the genes they inherit. Cells or organs transplanted between genetically non identical people or members of two different inbred strains of a species are almost always rejected. The offspring of a mating between two different inbred strains of animal will not reject grafts from either parent. Results of the experiments shown indicate that graft rejection displays the features of adaptive immune responses, namely, memory and mediation by lymphocytes. An inbred strain B mouse will reject a graft from an inbred strain A mouse with first-set kinetics (left panel). An inbred strain B mouse sensitized by a previous graft from an inbred strain A mouse will reject a second graft from an inbred strain A mouse with second-set kinetics (middle panel), demonstrating memory. An inbred strain B mouse injected with lymphocytes from another strain B mouse that has rejected a graft from a strain A mouse will reject a graft from a strain A mouse with second-set kinetics (right panel), demonstrating the role of lymphocytes in mediating rejection and memory. An inbred strain B mouse sensitized by a previous graft from a strain A mouse will reject a graft from a third unrelated strain with first-set kinetics, thus demonstrating another feature of adaptive immunity, specificity (not shown). Such results suggested that the molecules in the grafts that are responsible for eliciting rejection must be poly morphic and their expression is codominant. Polymorphic refers to the fact that these graft antigens differ among the individuals of a species (other than identical twins) or between different inbred strains of animals. Codomi nant expression means that every individual inherits genes encoding these molecules from both parents, and both parental alleles are expressed. George Snell and colleagues produced pairs of congenic strains of inbred mice that were bred to be genetically identical to each other except for genes needed for graft rejection. The relevance of minor histocompatibility antigens in clinical solid organ transplantation is uncertain, mainly because there has been little success in identifying the relevant antigens. Although in humans there is a slightly higher risk of rejection of heart transplants from male donor to female recipient, compared with Adaptive Immune Responses to Allografts 377 gendermatched transplants, given the scarcity of donor hearts, gender matching is not practical. This process is called indirect presentation (or indirect recognition), and it is essentially the same as the recognition of any foreign. Because these complexes are not normally expressed in the thymus or peripheral tissues, they have not participated in negative selection of T cells potentially dangerous to allogeneic grafts. It is likely that these memory cells were gener ated during previous exposure to other foreign. These memory cells not only are expanded populations of antigenspecific cells but also are more rapid and powerful responders than are naive lymphocytes, and thus contribute to the greater strength of the initial alloreactive T cell response to a new graft.

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Unlike other mucosa 8h9 treatment discount solian 50mg with visa, in which IgA is the dominant antibody isotype medications and grapefruit purchase solian 50 mg without a prescription, most of the antibody in genital secretions is IgG, about half of which is produced by plasma cells in genital tract mucosa and the rest is from the circulation. The skin of an adult is about 2 m2 in area and is the second-largest barrier of the body against environmental microbes and other foreign materials. Nonetheless, given its outermost location, the skin is normally colonized by many microbes and is frequently breached by trauma and burns. Therefore, the skin is a common portal of entry for a wide variety of microbes and other foreign substances and is the site of many immune responses. Innate and Adaptive Immune Responses in the Skin the epidermis provides a physical barrier to microbial invasion. The epidermis consists of multiple layers of stratified squamous epithelium, made up almost entirely of specialized epithelial cells called keratinocytes. The basal layer of keratinocytes, anchored onto the basement membrane, continuously proliferate, and their maturing progeny cells are displaced upward and differentiate to form several different layers. In the top layer, called the stratum corneum, the cells undergo programmed death, thereby forming a keratin- and lipid-rich permeability barrier that is important for protection against microbes as well as harmful physical and chemical agents. In addition to forming a physical barrier, keratinocytes actively respond to pathogens and injury by producing antimicrobial peptides, which kill microbes, and various cytokines, which promote and regulate immune responses. The antimicrobial peptides that keratinocytes produce include defensins, S100, and cathelicidins (see Chapter 4). The major components of the cutaneous immune system shown in this schematic diagram include keratinocytes, Langerhans cells, and intraepithelial lymphocytes, all located in the epidermis, and T lymphocytes, dendritic cells, and macrophages, located in the dermis. Innate immune responses to pathogens that breach the epidermal barrier are initiated by macrophages, mast cells, and innate lymphoid cells in the dermis. Several dendritic cell populations are normally present in the skin and contribute to innate immune responses and to initiation of T cell responses to microbial and environmental antigens that enter the body through the skin. The dendrites of Langerhans cells form a dense meshwork between the keratinocytes of the epidermis. About 98% of these T cells are present in the dermis, and 2% are intraepidermal lymphocytes. Most of these dermal T cells are memory cells generated within lymph nodes during prior skin infections, which then home to and remain in the skin for long periods of time without recirculating; they are called resident memory T cells. Th1 and Th17 cells are important for microbial defense against intracellular and extracellular microbes, respectively, as in other tissues. The skin-homing properties of T cells are imprinted during activation in skin-draining lymph nodes, by a process analogous to imprinting of gut-homing properties of T cells in mesenteric lymph nodes, discussed earlier in the chapter. Interestingly, sunlight and vitamin D appear to play an important role in T cell migration to the skin, analogous to the role of vitamin A and its metabolite retinoic acid in lymphocyte migration to the gut. Thus, naive T cells activated in skin-draining lymph nodes will differentiate into effector T cells that preferentially home back into the skin. Diseases Related to Immune Responses in the Skin There are many different inflammatory diseases that are caused by dysregulated or inappropriately targeted immune responses in the skin. In addition to these inflammatory diseases, there are several malignant lymphomas that primarily affect the skin. The skin-homing properties of effector lymphocytes are imprinted in skin-draining lymph nodes where they have undergone differentiation from naive precursors. These T cells circulate to the dermis and further promote an inflammatory cascade and persistent keratinocyte proliferation. The identity of the antigens recognized by the T cells in psoriasis is an area of active investigation. Atopic dermatitis develops early in life in genetically susceptible individuals when there are underlying defects in filaggrin or other structural component of the epidermis that lead to impaired barrier function. Secondarily, the type 2 responses stimulate B cell production of IgE specific for environmental antigens, and IgE-dependent mast cell activation in response to those antigens (see Chapter 20) contributes to the clinical manifestations of the disease. Skin colonization by Staphylococcus aureus is commonly associated with flares in atopic dermatitis and therapies to reduce bacterial burden can be helpful, suggesting that immune responses to skin bacteria may contribute to inflammation in this disease. These tissues, which have evolved to be protected, to a variable degree, from immune responses, are called immune-privileged sites.