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Primary therapy with a lipid formulation of amphotericin B diabetes mellitus type 2 news buy amaryl 1 mg with visa, voriconazole diabetes prevention home remedy buy amaryl 4mg mastercard, or posaconazole diabetes free cheap amaryl 1mg with visa, plus vigorous efforts at immune reconstitution definition diabetes mellitus uk buy amaryl 3mg without prescription, is recommended for treatment of fusariosis. In culture, colonies are woolly to cottony and are initially white, becoming smoky brown to green. Microscopically, conidia are one celled, elongate, and pale brown and are borne singly or in balls on either short or long conidiophores (Figure 65-21). Species of Sarocladium are commonly found in soil, decaying vegetation, and decaying food. The conidia may be single celled in chains or a conidial mass arising from short, unbranched, tapered phialides. A recent report of successful treatment of a pulmonary infection caused by Sarocladium (formerly Acremonium) strictum with posaconazole suggests that the new triazoles may be useful in treatment of Sarocladium/Acremonium infections. The portal of infection is often through breaks in the skin or intravascular catheters. Dissemination of the infection may be aided by adventitious conidiation that takes place within tissues. In a recent taxonomic shuffle, Paecilomyces lilacinus has been assigned to the genus Purpureocillium (Purpureocillium lilacinus). Voriconazole has been used successfully to treat both severe cutaneous infection and disseminated disease. Both local and disseminated infections have been described, with involvement of the nasal septum, skin and soft tissues, blood, lungs, and brain. Conidiophores are simple or branched; the conidiogenous cells are annellides that form singly or in clusters or may form a broomlike structure, or scopula, similar to that seen with Penicillium spp. The annelloconidia are smooth initially, become rough at maturity, are shaped like light bulbs, and form basipetal chains. Invasive infections may require surgical and medical treatment and are often fatal. Primary inoculation, resulting in localized subcutaneous infection, occurs commonly in underdeveloped countries and has been discussed in Chapter 63. The dematiaceous fungi that have been documented to cause human infection encompass a large number of different genera; however, the more common causes of human infection include Alternaria, Bipolaris, Cladosporium, Curvularia, and Exserohilum species. In addition, several of the dematiaceous fungi appear to be neurotropic: Cladophialophora bantiana, Bipolaris (Curvularia) spicifera, Exophiala spp. Most often, the pale brown to dark melanin-like pigment within the cell wall is apparent in H&E- or Papanicolaoustained tissue (Figure 65-22). Staining with the FontanaMasson technique (a melanin-specific stain) may help visualize the dematiaceous elements. Dematiaceous fungi differ considerably in the clinical spectrum of infection and response to therapy. Furthermore, the different genera are not readily distinguished on histopathologic examination. Thus an accurate microbiological diagnosis based on culture of the infected tissue is important for optimal clinical management of infections caused by these fungi. Other sites of infection include skin and soft tissue, cornea, lower respiratory tract, and peritoneum. Lactophenol cotton blue preparation showing darkly pigmented chains of muriform conidia. The conidiophores arise from the hyphae and are dematiaceous, tall, and branching. The conidia may be smooth or rough and single to several celled and form branching chains at the apex of the conidiophore. Sites of infection include endocarditis, local catheter, nasal septum and paranasal sinuses, lower respiratory tract, skin and subcutaneous tissues, bones, and cornea. Microscopically, the conidia are dematiaceous, solitary or in groups, septate, simple or branched, sympodial, and geniculate. Infections caused by the genera Bipolaris and Exserohilum present similarly to those of Aspergillus spp. These organisms cause sinusitis in "normal" (atopic or asthmatic) hosts and more invasive disease in immunocompromised hosts. In culture, both Bipolaris and Exserohilum form rapidly growing, woolly, gray to black colonies. The conidia are dematiaceous, oblong to cylindrical, and multicelled (Figure 65-24). The preponderant Bipolaris species in human infections are Bipolaris australiensis, B. The optimal treatment of deep-seated phaeohyphomycosis has not yet been established, although it most often includes early administration of amphotericin B and aggressive surgical excision. Despite these efforts, phaeohyphomycosis does not respond well to treatment and relapses are common. Posaconazole has been used successfully to treat disseminated infection caused by Exophiala spinifera. In those patients with brain abscesses, complete excision of the lesion has been associated with improved survival. Longterm triazole (posaconazole or voriconazole) therapy coupled with repeated surgical excision may prevent recurrences. Lactophenol cotton blue preparation showing pigmented conidia (black arrow) borne on geniculate conidiophores (red arrow). Although it was previously considered to be a protozoan parasite, molecular and genetic evidence place it among the fungi (see Chapter 57). After rupture of the cyst, the cyst wall may be seen as an empty collapsed structure (Figure 65-26). Although airborne transmission has been documented experimentally among rodents, the rodent strains are genetically distinct from those of humans, making it unlikely that rodents serve as a zoonotic reservoir for human disease. Involvement of lymph nodes, spleen, bone marrow, liver, small bowel, genitourinary tract, eyes, ears, skin, bone, and thyroid have been reported. Recent evidence suggests that both reactivation of quiescent old infection and primary infection can occur. The radiographic appearance is typically one of diffuse interstitial infiltrates with a ground-glass appearance extending from the hilar region, but radiographs may appear normal or show nodules or cavitation. The mortality rate is high among untreated patients, and death is due to respiratory failure. Histologically, a foamy exudate is seen within the alveolar spaces, with an intense interstitial infiltrate composed predominantly of plasma cells. Other patterns, including diffuse alveolar damage, noncaseating granulomatous inflammation, and infarct-like coagulative necrosis may also be seen. The -d-glucan test has proven to be quite useful for rapid diagnosis of Pneumocystis pneumonia with a high degree of sensitivity and specificity. The cornerstone for both prophylaxis and treatment is trimethoprim-sulfamethoxazole. A chest radiogram shows a ball-like mass in a preexisting right upper lobe cavity. Although examination and culture of sputum may yield an organism, the most direct approach would be bronchoscopy and biopsy of the mass. Examination of the tissue will show branching septate hyphae consistent with a fungus ball. In the event of pulmonary hemorrhage, which may be severe and lifethreatening, surgical excision of the cavity and fungus ball may be indicated. In the process, a chest radiograph revealed a nodule in the left upper lobe of his lung. Because of his age and prior smoking history, Jim underwent a thoracotomy, and the nodule was excised. Pathologic examination revealed fibrosis and several large spherical structures but no evidence of cancer.
Antigen A introduced at time zero encounters little specific antibody in the serum diabetic ulcer causes buy generic amaryl 1mg online. After a lag phase diabetes diet plans free discount amaryl 2mg on line, antibody against antigen A (blue) appears; its concentration rises to a plateau diabetes mellitus y sus complicaciones pdf discount amaryl 4mg without prescription, and then declines diabetes dyslipidemia definition generic 2 mg amaryl. When the serum is tested for antibody against another antigen, B (yellow), there is none present, demonstrating the specificity of the antibody response. Note that the response to B resembles the initial or primary response to A, as this is the first encounter of the animal with antigen B. It is immunological memory that enables successful vaccination and prevents reinfection with pathogens that have been repelled successfully by an adaptive immune response. Immunological memory is the most important biological consequence of the development of adaptive immunity, although its cellular and molecular basis is still not fully understood, as we shall see in Chapter 10. Interaction with other cells as well as with antigen is necessary for lymphocyte activation. Peripheral lymphoid tissues are specialized not only to trap phagocytic cells that have ingested antigen (see Sections 1-3 and 1-6) but also to promote their interactions with lymphocytes that are needed to initiate an adaptive immune response. The spleen and lymph nodes in particular are highly organized for the latter function. All lymphocyte responses to antigen require not only the signal that results from antigen binding to their receptors, but also a second signal, which is delivered by another cell. Because of their ability to deliver activating signals, these three cell types are known as professional antigen-presenting cells, or often just antigen-presenting cells. Dendritic cells are the most important antigenpresenting cell of the three, with a central role in the initiation of adaptive immune responses (see Section 1-6). Macrophages can also mediate innate immune responses directly and make a crucial contribution to the effector phase of the adaptive immune response. B cells contribute to adaptive immunity by presenting peptides from antigens they have ingested and by secreting antibody. As well as receiving a signal through their antigen receptor, mature naive lymphocytes must also receive a second signal to become activated. For T cells (left panel) it is delivered by a professional antigen-presenting cell such as the dendritic cell shown here. For B cells (right panel), the second signal is usually delivered by an activated T cell. The three types of professional antigen-presenting cell are shown in the form in which they will be depicted throughout this book (top row), as they appear in the light microscope (second row; the relevant cell is indicated by an arrow), by transmission electron microscopy (third row) and by scanning electron microscopy (bottom row). Mature dendritic cells are found in lymphoid tissues and are derived from immature tissue dendritic cells that interact with many distinct types of pathogen. Macrophages are specialized to internalize extracellular pathogens, especially after they have been coated with antibody, and to present their antigens. B cells have antigen-specific receptors that enable them to internalize large amounts of specific antigen, process it, and present it. Thus, the final postulate of adaptive immunity is that it occurs on a cell that also presents the antigen. This appears to be an absolute rule in vivo, although exceptions have been observed in in vitro systems. Nevertheless, what we are attempting to define is what does happen, not what can happen. The early innate systems of defense, which depend on invariant receptors recognizing common features of pathogens, are crucially important, but they are evaded or overcome by many pathogens and do not lead to immunological memory. The abilities to recognize all pathogens specifically and to provide enhanced protection against reinfection are the unique features of adaptive immunity, which is based on clonal selection of lymphocytes bearing antigenspecific receptors. The clonal selection of lymphocytes provides a theoretical framework for understanding all the key features of adaptive immunity. Each lymphocyte carries cell-surface receptors of a single specificity, generated by the random recombination of variable receptor gene segments and the pairing of different variable chains. This produces lymphocytes, each bearing a distinct receptor, so that the total repertoire of receptors can recognize virtually any antigen. If the receptor on a lymphocyte is specific for a ubiquitous self antigen, the cell is eliminated by encountering the antigen early in its development, while survival signals received through the antigen receptor select and maintain a functional lymphocyte repertoire. Adaptive immunity is initiated when an innate immune response fails to eliminate a new infection, and antigen and activated antigen-presenting cells are delivered to the draining lymphoid tissues. When a recirculating lymphocyte encounters its specific foreign antigen in peripheral lymphoid tissues, it is induced to proliferate and its progeny then differentiate into effector cells that can eliminate the infectious agent. A subset of these proliferating lymphocytes differentiate into memory cells, ready to respond rapidly to the same pathogen if it is encountered again. The details of these processes of recognition, development, and differentiation form the main material of the middle three parts of this book. Clonal selection describes the basic operating principle of the adaptive immune response but not how it defends the body against infection. In the last part of this chapter, we outline the mechanisms by which pathogens are detected by lymphocytes and are eventually destroyed in a successful adaptive immune response. The distinct lifestyles of different pathogens require different response mechanisms, not only to ensure their destruction but also for their detection and recognition. We have already seen that there are two different kinds of antigen receptor: the surface immunoglobulin of B cells, and the smaller antigen receptor of T cells. These surface receptors are adapted to recognize antigen in two different ways: B cells recognize antigen that is present outside the cells of the body, where, for example, most bacteria are found; T cells, by contrast, can detect antigens generated inside infected cells, for example those due to viruses. The major pathogen types confronting the immune system and some of the diseases that they cause. The effector mechanisms that operate to eliminate pathogens in an adaptive immune response are essentially identical to those of innate immunity. Indeed, it seems likely that specific recognition by clonally distributed receptors evolved as a late addition to existing innate effector mechanisms to produce the present-day adaptive immune response. We begin by outlining the effector actions of antibodies, which depend almost entirely on recruiting cells and molecules of the innate immune system. Antibodies, which were the first specific product of the adaptive immune response to be identified, are found in the fluid component of blood, or plasma, and in extracellular fluids. Because body fluids were once known as humors, immunity mediated by antibodies is known as humoral immunity. These are highly variable from one molecule to another, providing the diversity required for specific antigen recognition. The stem of the Y, which defines the class of the antibody and determines its functional properties, takes one of only five major forms, or isotypes. Each of the five antibody classes engages a distinct set of effector mechanisms for disposing of antigen once it is recognized. The stem can take one of only a limited number of forms and is known as the constant region. It is the region that engages the effector mechanisms that antibodies activate to eliminate pathogens. The simplest and most direct way in which antibodies can protect from pathogens or their toxic products is by binding to them and thereby blocking their access to cells that they might infect or destroy. This is known as neutralization and is important for protection against bacterial toxins and against pathogens such as viruses, which can thus be prevented from entering cells and replicating. Binding by antibodies, however, is not sufficient on its own to arrest the replication of bacteria that multiply outside cells. In this case, one role of antibody is to enable a phagocytic cell to ingest and destroy the bacterium. This is important for the many bacteria that mare resistant to direct recognition by phagocytes; instead, the phagocytes recognize the constant region of the antibodies coating the bacterium. The coating of pathogens and foreign particles in this way is known as opsonization. Unbound toxin can react with receptors on the host cell, whereas the toxin:antibody complex cannot. The right panels show activation of the complement system by antibodies coating a bacterial cell. The third function of antibodies is to activate a system of plasma proteins known as complement. The complement system, which we shall discuss in detail in Chapter 2, can also be activated without the help of antibodies on many microbial surfaces, and therefore contributes to innate as well as adaptive immunity. The pores formed by activated complement components directly destroy bacteria, and this is important in a few bacterial infections.
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Before being used by the polymerase diabetes symptoms and prevention generic amaryl 4 mg amex, the nucleoside analogs must be phosphorylated to the triphosphate form by viral enzymes diabetes likelihood test discount 3mg amaryl otc. Nucleoside analogs selectively inhibit viral polymerases blood glucose ios proven 3 mg amaryl, because these enzymes are less accurate than host cell enzymes blood glucose for newborn purchase amaryl 1 mg fast delivery. The viral enzyme binds nucleoside analogs with modifications of the base, sugar, or both several hundred times better than the host cell enzyme. These drugs either prevent chain elongation, as a result of the absence of a 3-hydroxyl on the sugar, or alter recognition and base pairing, as a result of a base modification, and induce inactivating mutations (see Figure 40-1). Hypermutation of a viral genome by an antiviral drug (like ribavirin) is the equivalent of replacing every fourth letter in an essay with a random letter. The chemical distinctions between the natural deoxynucleoside and the antiviral drug analogs are highlighted. Both of these drugs are metabolized to the active drug in the liver or intestinal wall. A variety of other nucleoside analogs are also being developed as antiviral drugs. Nevirapine, delavirdine, and other nonnucleoside reverse transcriptase inhibitors bind, as noncompetitive inhibitors of the enzyme, to sites on the enzyme other than the substrate site. Protein Synthesis Although bacterial protein synthesis is the target for several antibacterial compounds, viral protein synthesis is a poor target for antiviral drugs. The virus uses host cell ribosomes and synthetic mechanisms for replication, so selective inhibition is not possible. Inhibition of the posttranslational modification of proteins, such as the proteolysis of a viral polyprotein (protease inhibitors) or glycoprotein processing (castanospermine, deoxynojirimycin), can also inhibit virus replication. The enzyme structures were defined by x-ray crystallography and molecular biology studies. The neuraminidase of influenza is essential to prevent aggregation of viral glycoproteins and allow their incorporation into the envelope. Zanamivir (Relenza) and oseltamivir (Tamiflu) act as enzyme inhibitors and, unlike amantadine and rimantadine, can inhibit influenza A and B. Innate responses of dendritic cells, macrophages, and other cells can be stimulated by imiquimod, resiquimod, and CpG oligodeoxynucleotides, which bind to Toll-like receptors to stimulate release of protective cytokines, activation of natural killer cells, and subsequent cell-mediated immune responses. Antibodies, acquired naturally or by passive immunization (see Chapters 10 and 11), prevent both acquisition and spread of the virus. The viral thymidine kinase is required to activate the drug by phosphorylation, and host cell enzymes complete the progression to the diphosphate form and finally to the triphosphate form. The fact that it is not toxic to uninfected cells allows use of it and its analogs as a prophylactic treatment to prevent recurrent outbreaks, especially in immunosuppressed people. A recurrent episode may be prevented if it is treated before or soon after the triggering event. Famciclovir is a prodrug derivative of penciclovir that is well absorbed orally and then is converted to penciclovir in the liver or intestinal lining. Of interest, this potential toxicity has been used as the basis for the development of an antitumor therapy. Cidofovir and Adefovir Cidofovir and adefovir are both nucleotide analogs and contain a phosphate attached to the sugar analog. Ribavirin is administered in an aerosol to children with severe respiratory syncytial virus bronchopneumonia and potentially to adults with severe influenza or measles. The drug may be effective for the treatment of influenza B, as well as Lassa, Rift Valley, Crimean-Congo, Korean, and Argentine hemorrhagic fevers, for which it is administered orally or intravenously. Other Nucleoside Analogs Idoxuridine, trifluorothymidine (see Figure 40-1), and fluorouracil are analogs of thymidine. These actions inhibit further synthesis of the virus or cause extensive misreading of the genome, leading to mutation and inactivation of the virus. Fluorouracil is an antineoplastic drug that kills rapidly growing cells but has also been used for topical treatment of warts caused by human papillomaviruses. Ara-A is an adenosine nucleoside analog with an arabinose substituted for deoxyribose as the sugar moiety (see Figure 40-1). Dideoxyinosine (didanosine) is a nucleoside analog that is converted to dideoxyadenosine triphosphate (see Figure 40-1). Ribavirin depletes the cellular stores of guanine by inhibiting inosine monophosphate dehydrogenase, an enzyme important in the synthetic pathway of guanosine. Nevirapine, delavirdine, efavirenz, and other nonnucleoside reverse transcriptase inhibitors bind to sites on the enzyme different from the substrate. Without the neuraminidase to cleave sialic acid, the hemagglutinin of the virus binds to these sugars on other glycoproteins, forming clumps and preventing assembly and virus release. These drugs can be taken prophylactically as an alternative to vaccination or, if taken within the first 48 hours of infection, to reduce the length of illness. Interferons work by binding to cell surface receptors and initiating a cellular antiviral response. In addition, interferons stimulate the immune response and promote the immune clearance of viral infection. It has been approved for the treatment of condyloma acuminatum (genital warts, a presentation of papillomavirus) and hepatitis C (in combination therapy). Natural interferon causes the influenza-like symptoms observed during many viremic and respiratory tract infections, and the synthetic agent has similar side effects during treatment. Imiquimod, a Toll-like receptor ligand, stimulates innate responses to attack the virus infection. This therapeutic approach can activate local protective responses against papillomas, which generally escape immune control. Saquinavir, indinavir, ritonavir, nelfinavir, and other agents work by slipping into the hydrophobic active site of the enzyme to inhibit its action. Protease inhibitors (boceprevir, telaprevir, simeprevir) are also improving the outlook for treating patients with chronic hepatitis C. Educating all personnel regarding points 1, 2, and 3 and in the ways to decrease high-risk behaviors Methods for disinfection differ for each virus and depend on its structure. Most viruses are inactivated by 70% ethanol, 15% chlorine bleach, 2% glutaraldehyde, 4% formaldehyde, or autoclaving (as described in Guidelines for Prevention of Transmission of Human Immunodeficiency Virus and Hepatitis B Virus to Health-Care and Public-Safety Workers, issued in 1989 by the U. Most enveloped viruses do not require such rigorous treatment and are inactivated by soap and detergents. Both compounds are acidotrophic and concentrate in and buffer the contents of the endosomal vesicles involved in the uptake of the influenza virus. This effect can inhibit the acidmediated change in conformation in the hemagglutinin protein that promotes fusion of the viral envelope with cell membranes. However, the specificity for influenza A is a result of its ability to bind to and block the proton channel formed by the M2 membrane protein of the influenza A virus. Amantadine and rimantadine may be useful in ameliorating an influenza A infection if either agent is taken within 48 hours of exposure. The principal toxic effect is on the central nervous system, with patients experiencing nervousness, irritability, and insomnia. Control of an outbreak usually requires identification of the source or reservoir of the virus, followed by cleanup, quarantine, immunization, or a combination of these measures. The first step in controlling an outbreak of gastroenteritis or hepatitis A is identification of the food, water, or possibly the day-care center that is the source of the outbreak. Education programs can promote compliance with immunization programs and help people change lifestyles associated with viral transmission. Such programs have had a significant impact in reducing the prevalence of vaccinepreventable diseases such as smallpox, polio, measles, mumps, and rubella. Bibliography Carter J, Saunders V: Virology: principles and applications, Chichester, England, 2007, Wiley. Websites New Medical Information and Health Information: Antiviral drugs: Antiviral agents, antiviral medications.
Were it not for substantial negative selection diabetes mellitus latin definition buy 4 mg amaryl amex, B cells dividing three to four times per day in a single germinal center would quickly create enough progeny to overwhelm the entire organism; more than a billion cells could be created in 10 days in a single germinal center diabetes oral medications and insulin therapies order 4 mg amaryl overnight delivery. The mark of positive selection diabetes type 1 patch buy amaryl 2mg on line, on the other hand diabetic diet 2200 calories purchase amaryl 4 mg on line, is an accumulation of numerous amino acid replacements in the complementarity-determining regions. The consequence of these cycles of proliferation, mutation, and selection, which all happen within the germinal center, is that the average affinity of the population of responding B cells for its antigen increases over time, largely explaining the observed phenomenon of affinity maturation of the antibody response. The selection process can be quite stringent: although 50 to 100 B cells may seed the germinal center, most of these leave no progeny, and by the time the germinal center reaches maximum size, it is typically composed of the descendants of only one or a few B cells. In some circumstances it is possible to follow the process of somatic hypermutation by sequencing immunoglobulin variable regions at different time points after immunization. Those B cells whose variable regions have acquired mutations that result in improved antigen binding are able to compete effectively for binding to the antigen, and receive signals that drive their proliferation and expansion, along with continued mutation (fourth panel). Germinal center B cells are inherently prone to die and, in order to survive, they must receive specific signals. Additional signals are also required for survival, which are delivered by direct contact with T cells. The source of antigen in the germinal center has been the matter of some controversy. Antigen can be trapped and stored for long periods of time in the form of immune complexes on follicular dendritic cells (Figs 9. While this may be true under certain circumstances, there is now evidence that antigen on follicular dendritic cells is not required to sustain a normal germinal center response. Indeed, the role of the antigen depot on these cells is unknown, although it could be to maintain long-lived plasma cells. Under normal circumstances, it is most likely that live pathogens carried to the lymphoid tissues and multiplying there will continue to provide antigens until they are eliminated by the immune response, after which the germinal center decays. Immunizations with protein antigens are usually given in a form that slowly releases the antigen over time, which mimics the situation with live pathogens. Indeed, it is difficult to stimulate germinal center formation by immunization without either a live replicating pathogen or a sustained release of antigen in adjuvant (see Appendix I, Section A-4). How the various signals that maintain the germinal center exert their effects on B cells is not completely understood. There are doubtless many other signals yet to be discovered that promote B-cell differentiation. Radiolabeled antigen localizes to , and persists in, lymphoid follicles of draining lymph nodes (see light micrograph and the schematic representation below, showing a germinal center in a lymph node). Radiolabeled antigen has been injected 3 days previously and its localization in the germinal center is shown by the intense dark staining. The antigen is in the form of antigen:antibody:complement complexes bound to Fc and complement receptors on the surface of the follicular dendritic cell. Surviving germinal center B cells differentiate into either plasma cells or memory cells. The purpose of the germinal center reaction is to enhance the later part of the primary immune response. Some germinal center cells differentiate first into plasmablasts and then into plasma cells. Plasmablasts continue to divide rapidly but have begun to specialize to secrete antibody at a high rate; they are destined to become nondividing, terminally differentiated plasma cells and thus represent an intermediate stage of differentiation. These plasma cells will migrate to the bone marrow, where a subset of them will live for a long period of time. Plasma cells obtain signals from bone marrow stromal cells that are essential for their survival. Memory B cells are long-lived descendents of cells that were once stimulated by antigen and had proliferated in the germinal center. These cells divide very slowly if at all; they express surface immunoglobulin, but do not secrete antibody at a high rate. Since the precursors of memory B cells once participated in a germinal center reaction, memory B cells inherit the genetic changes that occurred in germinal center cells, including somatic mutations and the gene rearrangements that result in isotype switch (see Sections 4-9 and 4-16). The signals that control which differentiation path a B cell takes, and even whether at any given point the B cell continues to divide instead of differentiating, are unclear. Another possibility is that affinity for antigen controls B-cell differentiation, with high-affinity cells perhaps being preferentially stimulated to become memory cells while the lower-affinity cells are allowed to undergo further cycles of proliferation, mutation, and selection. This is just one of the mysteries of the germinal center that immunologists have yet to solve. B-cell responses to bacterial antigens with intrinsic ability to activate B cells do not require T-cell help. Although antibody responses to most protein antigens are dependent on helper T cells, humans and mice with T-cell deficiencies nevertheless make antibodies to many bacterial antigens. This is because the special properties of some bacterial polysaccharides, polymeric proteins, and lipopolysaccharides enable them to stimulate naive B cells in the absence of peptide-specific T-cell help. These nonprotein bacterial products cannot elicit classical T-cell responses, yet they induce antibody responses in normal individuals. Thymus-independent antigens fall into two classes that activate B cells by two different mechanisms. At high concentration, these molecules cause the proliferation and differentiation of most B cells regardless of their antigen specificity; this is known as polyclonal activation. Such responses have an important role in defense against several extracellular pathogens, as they arise earlier than thymus-dependent responses since they do not require prior priming and clonal expansion of helper T cells. B-cell responses to bacterial polysaccharides do not require peptide-specific T-cell help. The second class of thymus-independent antigens consist of molecules such as bacterial capsular polysaccharides that have highly repetitive structures. This might be why infants do not make antibodies to polysaccharide antigens efficiently; most of their B cells are immature. Although B-1 cells arise early in development, young children do not make a fully effective response to carbohydrate antigens until about 5 years of age. Excessive receptor cross-linking, however, renders mature B cells unresponsive or anergic, just as it does immature B cells. Many common extracellular bacterial pathogens are surrounded by a polysaccharide capsule that enables them to resist ingestion by phagocytes. The bacteria not only escape direct destruction by phagocytes but also avoid stimulating Tcell responses through the presentation of bacterial peptides by macrophages. Antibody that is produced rapidly in response to this polysaccharide capsule without the help of peptide-specific T cells can coat these bacteria, promoting their ingestion and destruction by phagocytes by mechanisms we will describe later in this chapter. The common encapsulated extracellular bacteria are often known as pyogenic bacteria, as they typically cause the formation of abundant pus, which consists chiefly of dead and dying neutrophils that have been recruited to the site of infection. These patients can respond, although poorly, to protein antigens but fail to make antibody against polysaccharide antigens and are highly susceptible to infection with encapsulated bacteria. It is not clear how T cells are activated in this case, because polysaccharide antigens cannot produce peptide fragments that might be recognized by T cells on the B-cell surface. One possibility is that a component of the antigen binds to a cell-surface molecule common to all helper T cells, as shown in the figure. B-cell activation by many antigens, especially monomeric proteins, requires both binding of the antigen by the B-cell surface immunoglobulin the B-cell receptor and interaction of the B cell with antigen-specific helper T cells. The initial interaction occurs in the T-cell area of secondary lymphoid tissue, where both antigen-specific and helper T cells and antigen-specific B cells are trapped as a consequence of binding antigen; further interactions between T cells and B cells occur after migration into the B-cell zone or follicle, and formation of a germinal center. Helper T cells induce a phase of vigorous B-cell proliferation, and direct the differentiation of the clonally expanded progeny of the naive B cells into either antibody-secreting plasma cells or memory B cells. During the differentiation of activated B cells, the antibody isotype can change in response to cytokines released by helper T cells, and the antigen-binding properties of the antibody can change by somatic hypermutation of V-region genes. Somatic hypermutation and selection for high-affinity binding occur in the germinal centers. Helper T cells control these processes by selectively activating cells that have retained their specificity for the antigen and by inducing proliferation and differentiation into plasma cells and memory B cells. Some nonprotein antigens stimulate B cells in the absence of linked recognition by peptide-specific helper T cells. These thymus-independent antigens induce only limited isotype switching and do not induce memory B cells. However, responses to these antigens have a critical role in host defense against pathogens whose surface antigens cannot elicit peptide-specific T-cell responses. Extracellular pathogens can find their way to most sites in the body and antibodies must be equally widely distributed to combat them. Most classes of antibody are distributed by diffusion from their site of synthesis, but specialized transport mechanisms are required to deliver antibodies to lumenal epithelial surfaces, such as those of the lung and intestine.
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