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L. Rathgar, M.B. B.CH., M.B.B.Ch., Ph.D.

Clinical Director, Kansas City University of Medicine and Biosciences College of Osteopathic Medicine

These cytokines stimulate the B cell to undergo recombination events within the immunoglobulin gene to switch from production of IgM and IgD to production of specific types and subtypes of IgG, IgE, or IgA. They also promote development of germinal centers, which are foci of specific memory cell, plasma cell, and antibody production. Antibody molecules also serve as the cell surface receptors that stimulate the appropriate B-cell antibody factories to grow and produce more antibody in response to antigenic challenge. Antibodies provide protection from rechallenge by an infectious agent, block spread of the agent in the blood, neutralize virulence factors, and facilitate elimination of the infectious agent. To accomplish these tasks, an incredibly large repertoire of antibody molecules must be available to recognize the tremendous number of infectious agents and molecules that challenge our bodies. In addition to interacting specifically with foreign structures, the antibody molecules must also interact with host systems and cells. They are subdivided into classes and subclasses based on the structure and antigenic distinction of their heavy chains. IgG, IgM, and IgA are the major antibody forms, whereas IgD and IgE make up less than 1% of the total immunoglobulins. The IgA and IgG classes of immunoglobulin are divided further into subclasses based on differences in the Fc portion. There are four subclasses of IgG, designated as IgG1 through IgG4, and two IgA subclasses (IgA1 and IgA2) (Figure 9-11). Antibody molecules are Y-shaped molecules with two major structural regions that mediate the two major functions of the molecule (Table 9-2; also see Figure 9-11). The variable-region/antigen-combining site must be able to identify and specifically interact with an epitope on an antigen. A large number of different antibody molecules, each with a different variable region, are produced in every individual to recognize the seemingly infinite number of different antigens in nature. The Fc portion (stem of the antibody Y) interacts with host systems and cells to promote clearance of antigen and activation of subsequent immune responses. For IgG and IgA, the Fc portion interacts with other proteins to promote transfer across the placenta and the mucosa, respectively (Table 9-3). Table 9-3 FcInteractionswithImmuneComponents ImmuneComponent Interaction Function Fc receptor Macrophages Polymorphonuclear neutrophils T cells Natural killer cells (antibody-dependent cellular cytotoxicity) Mast cells for immunoglobulin (Ig)E Neonatal IgG receptor Opsonization Opsonization Activation Killing Allergic reactions, antiparasitic Transport across capillary membranes Opsonization, killing (especially bacteria), activation of inflammation Complement Complement system with a membrane-spanning portion to make it a cell surface antigen receptor. IgG and IgA have a flexible hinge region rich in proline and susceptible to cleavage by proteolytic enzymes. Digestion of IgG molecules with papain yields two Fab fragments and one Fc fragment (Figure 9-12). Pepsin cleaves the molecule, producing an F(ab)2 fragment with two antigen-binding sites and a pFc fragment. The different types and parts of immunoglobulin can also be distinguished using antibodies directed against different portions of the molecule. Isotypes (IgM, IgD, IgG, IgA, IgE) are determined by antibodies directed against the Fc portion of the molecule (iso meaning the same for all people. The heavy and light chains of immunoglobulin are fastened together by interchain disulfide bonds. Two types of light chains- and -are present in all five immunoglobulin classes, although only one type is present in an individual molecule. Approximately 60% of human immunoglobulin molecules have light chains, and 40% have light chains. There are five types of heavy chains, one for each isotype of antibody (IgM, µ; IgG,; IgD,; IgA,; and IgE,). The heavy chains have a variable and three (IgG, IgA) or four (IgM, IgE) constant domains. The variable domains on the heavy and light chains interact to form the antigen-binding site. The heavy chain of the different antibody molecules can also be synthesized with a membranespanning region to make the antibody an antigen-specific cell surface receptor for the B cell. Immunoglobulin D IgD, which has a molecular mass of 185 kDa, accounts for less than 1% of serum immunoglobulins. IgD exists primarily as membrane IgD, which serves with IgM as an antigen receptor on early B-cell membranes to help initiate antibody responses by activating B-cell growth.

Finally, many Salmonella strains have no host specificity and cause disease in both human and nonhuman hosts. Most infections result from ingestion of contaminated food products and, in children, from direct fecal-oral spread. The incidence of disease is greatest in children younger than 5 years and adults older than 60 years, who are infected during the summer and autumn months when contaminated foods are consumed at outdoor social gatherings. The most common sources of human infections are poultry, eggs, dairy products, and foods prepared on contaminated work surfaces. Approximately 50,000 cases of nontyphoidal Salmonella infections are reported annually in the United States, although it has been estimated that 1. Salmonella Typhi infections occur when food or water contaminated by infected food handlers is ingested. An average of 400 to 500 Salmonella Typhi infections are reported annually in the United States, most of which are acquired during foreign travel. In contrast, it is estimated that 27 million Salmonella Typhi and Salmonella Paratyphi infections and more than 200,000 deaths occur each year worldwide. The risk of disease is highest in children living in poverty in a developing country. The infectious dose for Salmonella Typhi infections is low, so person-to-person spread is common. The organisms can multiply to this high density if contaminated food products are improperly stored. The infectious dose is lower for people at high risk for disease because of age, immunosuppression or underlying disease (leukemia, lymphoma, sickle cell disease), or reduced gastric acidity. Clinical Diseases the following four forms of Salmonella infection exist: gastroenteritis, septicemia, enteric fever, and asymptomatic colonization. Gastroenteritis Gastroenteritis is the most common form of salmonellosis in the United States. Symptoms generally appear 6 to 48 hours after the consumption of contaminated food or water, with the initial presentation consisting of nausea, vomiting, and nonbloody diarrhea. Epidemiology Salmonella can colonize virtually all animals, including poultry, reptiles, livestock, rodents, domestic animals, birds, and humans. Animal-to-animal spread and the use of Salmonella-contaminated animal feeds maintain an animal reservoir. Serotypes such as Salmonella Typhi and Salmonella Paratyphi are highly adapted to humans and do not cause disease in nonhuman hosts. She was a resident of the Philippines who had been traveling in the United States for the previous 11 days. On physical examination, she was febrile and had an enlarged liver, abdominal pain, and an abnormal urinalysis. Blood cultures were collected upon admission to the hospital and were positive the next day with Salmonella Typhi. Because the organism was susceptible to fluoroquinolones, this therapy was selected. Within 4 days, she had defervesced and was discharged to return home to the Philippines. Although typhoid fever can be a very serious lifethreatening illness, it can initially present with nonspecific symptoms, as was seen in this woman. Pathogenesis and Immunity Shigellae cause disease by invading and replicating in cells lining the colon. Structural gene proteins mediate the adherence of the organisms to the cells, as well as their invasion, intracellular replication, and cell-to-cell spread. These genes are carried on a large virulence plasmid but are regulated by chromosomal genes. Shigella species appear unable to attach to differentiated mucosal cells; rather, they first attach to and invade the M cells located in Peyer patches. These proteins induce membrane ruffling on the target cell, leading to engulfment of the bacteria. Shigellae lyse the phagocytic vacuole and replicate in the host cell cytoplasm (unlike Salmonella, which replicate in the vacuole). With the rearrangement of actin filaments in the host cells, the bacteria are propelled through the cytoplasm to adjacent cells, where cell-to-cell passage occurs. This, in turn, destabilizes the integrity of the intestinal wall and allows the bacteria to reach the deeper epithelial cells.

Newman: my wife, Susan; my children Andrea and Natalie; my parents Paul, Rose, John, and Inez. Barrie Kenney for his support in providing me the opportunity to manage this large, complex, and time-consuming project. My gratitude to my co-editors and contributors whose expertise and willingness to participate in this work have made this book an excellent educational standard. Takei: My wife, June; my children Scott and Akemi; their spouses, Kozue and David; my grandchildren, Hana, Markus, Carter, and Arden. Special gratitude to Laura Miyabe for her professional support and Rose Kitayama for her technical support. Klokkevold: my wife, Angie; my daughters Ashley and Brianna; my parents Carl and Loretta Klokkevold; my mentors Henry H. I thank all of the residents with whom I have had the pleasure to work over the years, for the passion and inspiration they bring to me as an educator and clinician. Carranza: my wife, Rita; my children Fermin, Patricia, and Laura; and my grandchildren. Carranza Gingival and periodontal diseases, in their various forms, have afflicted humans since the dawn of history. Studies in paleopathology have indicated that destructive periodontal disease, as evidenced by bone loss, affected early humans in such diverse cultures as ancient Egypt and early pre-Columbian America. The earliest historical records dealing with medical topics reveal an awareness of periodontal disease and the need for treatment. Almost all the early writings that have been preserved have sections or chapters dealing with oral diseases, and periodontal problems comprise a significant amount of space in these writings. The relationship between calculus and periodontal disease often was considered, and underlying systemic disease was frequently postulated as a cause of periodontal disorders. However, methodic, carefully reasoned, therapeutic discussions did not exist until the Arabic surgical treatises of the Middle Ages, and modern treatment, with illustrated text and sophisticated instrumentation, did not develop until the time of Pierre Fauchard in the eighteenth century. The Babylonians and Assyrians, like the earlier Sumerians, apparently suffered from periodontal problems, and a clay tablet of the period tells of treatment by gingival massage combined with various herbal medications. Gingival inflammations, periodontal abscesses, and gingival ulcerations are described. The Chinese used the "chewstick" as a toothpick and toothbrush to clean the teeth and massage the gingival tissues. Many pathologic conditions of the teeth and surrounding structures are described in the Talmudic writings. He believed that inflammation of the gums could be caused by accumulations of "pituita" or calculus, with gingival hemorrhage occurring in cases of persistent splenic maladies. He wrote that tartar incrustations must be removed with either scrapers or a small file and that the teeth should be carefully cleaned after the last meal of the day. The Arabic treatises derived their information from Greek medical treatises but added many refinements and novel approaches, particularly in surgical specialties. He also wrote on the extraction of teeth, the splinting of loose teeth with gold wire, and the filing of gross occlusal abnormalities. Born in Persia, Avicenna (980­1037) was possibly the greatest of the Arabic physicians. His Canon, a comprehensive treatise on medicine, was in continuous use for almost 600 years. Avicenna used an extensive "materia medica" for oral and periodontal diseases and rarely resorted to surgery. Paracelsus (1493­1541) developed an interesting and unusual theory of disease: the doctrine of calculus. He understood that pathologic calcification occurred in a variety of organs and considered it the result of metabolic disturbances whereby the body takes nourishment from food and discards the refuse as "tartarus," a material that cannot be broken down and is the ultimate matter, or materia ultima. Paracelsus recognized the extensive formation of tartar on the teeth and related this to toothache. Toothache was thus comparable to the pain produced by calculus in other organs, such as the kidneys. Andreas Vesalius (1514­1564), born in Brussels, taught at the University of Padua in the Venetian Republic, where he performed human dissections and wrote a magnificent book on anatomy with excellent illustrations throughout, which were drawn by Calcar, a student of Titian.

Some macrophages are mobile, whereas others are fixed, providing effective defence at key body locations. Collections of fixed macrophages include: synovial cells in joints Langerhans cells in the skin microglia in the brain hepatic macrophages (Kupffer cells) in the liver alveolar macrophages in the lungs sinus-lining macrophages (reticular cells) in the spleen, lymph nodes and thymus gland mesangial cells in the glomerulus of nephrons in the kidney osteoclasts in bone. They are actively phagocytic and are much more powerful and longer-lived than the smaller neutophils. They synthesise and release an array of biologically active chemicals, called cytokines, including interleukin 1 mentioned earlier. They also have a central role linking the non-specific and specific (immune) systems of body defence (Ch. In the lungs, for example, resistant bacteria such as tuberculosis bacilli and inhaled inorganic dusts can be sealed off in such capsules. They circulate in the blood and are present in great numbers in lymphatic tissue such as lymph nodes and the spleen. Lymphocytes develop from pluripotent stem cells in red bone marrow and from precursors in lymphoid tissue, then travel in the blood to lymphoid tissue elsewhere in the body where they are activated, i. Although all lymphocytes originate from one type of stem cell, when they are activated in lymphatic tissue, two distinct types of lymphocyte are produced ­ T-lymphocytes and B-lymphocytes. Platelets (thrombocytes) these are very small non-nucleated discs, 2 to 4 m in diameter, derived from the cytoplasm of megakaryocytes in red bone marrow (Fig. They contain a variety of substances that promote blood clotting, which causes haemostasis (cessation of bleeding). The normal blood platelet count is between 200 Ч 109/l and 350 Ч 109/l (200 000 to 350 000/mm3). The control of platelet production is not yet entirely clear but one stimulus is a fall in platelet count. The kidneys release a substance called thrombopoietin, which stimulates platelet synthesis. The life span of platelets is between 8 and 11 days and those not used in haemostasis are destroyed by macrophages, mainly in the spleen. About a third of platelets are stored within the spleen rather than in the circulation; this is an emergency store that can be released as required to control excessive bleeding. Haemostasis When a blood vessel is damaged, loss of blood is stopped and healing occurs in a series of overlapping processes, in which platelets play a vital part. The more badly damaged the vessel wall is, the faster coagulation begins, sometimes as quickly as 15 seconds after injury. They then release serotonin (5-hydroxytryptamine), which constricts (narrows) the vessel, reducing blood flow through it. Passing platelets stick to those already at the damaged vessel and they too release their chemicals. This is a positive feedback system by which many platelets rapidly arrive at the site of vascular damage and quickly form a temporary seal ­ the platelet plug. Their numbers represent the order in which they were discovered and not the order of participation in the clotting process. These clotting factors activate each other in a specific order, eventually resulting in the formation of prothrombin activator, which is the first step in the final common pathway. Prothrombin activates the enzyme thrombin, which converts inactive fibrinogen to insoluble threads of fibrin (Fig. As clotting proceeds, the platelet plug is progressively stabilised by increasing amounts of fibrin laid down in a three-dimensional meshwork within it. The maturing blood clot traps blood cells and is much stronger than the rapidly formed platelet plug. The final common pathway can be initiated by two processes which often occur together: the extrinsic and intrinsic pathways (Fig. The extrinsic pathway is activated rapidly (within seconds) following tissue damage. Damaged tissue releases a complex of chemicals called thromboplastin or tissue factor, which initiates coagulation. The intrinsic pathway is slower (3­6 minutes) and is triggered when blood comes into contact with damaged blood vessel lining (endothelium).