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Although the amino acid sequences of the constant regions of the H chains show homologies among the Ig classes and subclasses, there are also very significant differences. The structural features appear to be important in giving the molecule its particular biologic function that distinguishes one class from another. More than one domain in the Fc region of the IgG H chain is required to react with the binding sites on rheumatoid factors (see Chapter 286). For example, papain cleaves IgG into an Fc fragment and two Fab fragments, whereas pepsin degrades the Fc fragment and yields the two Fab fragments still joined by a disulfide bridge (Fab)2 (see. Different enzymes cleave the various classes in different ways, and this approach has been important in defining structural corollaries to biologic properties. It has 10 H and 10 L chains and, therefore, 10 antibody-binding sites per molecule. However, because of steric factors, when IgM reacts with large protein antigens, it tends to bind with a valence of five. This can best be seen in the case of IgM rheumatoid factor binding to IgG, which yields a 22 s complex with a formula (mu2 L2)5-(IgG)5. Several sequences of events must take place for immunoglobulin genes to be expressed. As shown in Figure 270-5, each C region is coded by a single gene, but many gene segments Figure 270-3 the molecular events involved in antigen presentation to the T cell. For any given H-chain gene, the total V region is formed from a single V region, a single D, and a single J. The C region genes are located in tandem, so a switching process must occur in order to allow a given assembled V-D-J region to attach to any constant region. The gene rearrangements that take place at various stages of the differentiation pathway are indicated. Combinatorial diversity, which results from the combination of various gene segments as described above Junctional diversity, which results at the joining site because of some imprecision in codon formation Junctional insertion, by which diversity may arise because of insertion of extra nucleotides Somatic mutational events Exchange rearrangement of the H segments the combination of associated H and L chains this process allows an essentially random extrapolation of combinations into the millions of possibilities. Both of these chains contain amino-terminal variable regions and carboxy-terminal constant regions, just as occur in immunoglobulins. These chains contain carbohydrate and are bound within the surface of the T cell with membrane-spanning regions. A subset of T cells possesses similar receptors made up of gamma and delta chains that seem to be highly specialized and located in certain regions of the body, such as the gastrointestinal tract. It is of special note that variable regions of the T-cell receptor genes are assembled from V-D-J segment joining just as the immunoglobulin V region genes are assembled. Much less if any somatic hypermutation occurs in the T-cell receptor V region genes. Thus, rearrangement occurs during the process of differentiation, and once it has occurred it produces a stable clone with a fixed specificity. Note that intervening gene sequences at each step of joining are deleted, giving rise to the final finished product of an entire V region with the constant region at some distance. Figure 270-7 Diagrammatic representation of the idiotypic network showing the development of anti-idiotypes and anti-anti-idiotypes in sequential processes. This complementary fit mechanism provides the structural basis for the feedback network. Activating complement allows important events such as removing infectious agents and expressing the inflammatory response to take place. These involve active fragments of the pathway that enhance chemotaxis of macrophages, alter blood vessel permeability, change blood vessel diameters, cause lysis to cells, alter blood clotting, and cause numerous other subtle points of modification. Therefore, an idiotope of immunoglobulin is functionally equivalent to the clonotypic antigenic determinant of a clonal line of T cells. Conceptually, this interrelated system provides mechanisms for regulation based on recognition of receptors without need for exogenous antigen. This method of regulation may allow certain idiotopes to become dominantly expressed and may be operative with unique clonal markers, such as those that are observed due to clonal expansion in malignant lymphoid diseases. Cytokines can regulate levels of response or induce differentiation and proliferation of cells. Table 270-2 summarizes the properties of some of these molecules that may be encountered in immune regulation (see also Chapters 158 and 312). Therefore, any qualitative or quantitative change in this system can produce profound effects.

If oral intake is poorly tolerated or is contraindicated by distention and ileus, intravenous administration of glucose (at least 300 g daily) is usually indicated. A central venous line facilitates more complete parenteral nutrition support and avoids excess fluid volumes. Parenteral nutrition support may be indicated in some patients who require heme therapy. Numerous other therapies have been tried in this disease but have not been consistently useful. Recurrent attacks of porphyria occur in some patients and can be disabling, but they do not occur throughout adult life. Occasionally, chronic pain and other symptoms develop, but they may improve in the long term. Chronic symptoms and depression increase the risk of suicide and thus require careful management. Diet regimens for obesity should provide for gradual weight loss during periods of clinical remission of porphyria. Most patients have unrelated parents and have inherited a different mutation from each parent. The severity of the disease is variable and relates to the degree of enzyme deficiency caused by the particular mutations. There is considerable accumulation of hydroxymethylbilane (the substrate of the deficient enzyme), which is converted non-enzymatically to uroporphyrinogen I. Uroporphyrin I and other porphyrins accumulate in bone marrow erythroid cells that are actively synthesizing hemoglobin and lead to intramedullary and intravascular hemolysis. Even in the most severe cases some residual cosynthase activity is noted, and heme production is actually increased in response to hemolysis. Sunlight, other sources of ultraviolet light, and minor trauma to friable skin are other determinants of clinical expression. In most cases, reddish urine and severe cutaneous photosensitivity are noted in early infancy. Lesions on sun-exposed skin include bullae and vesicles, which are prone to rupture and become infected, hypopigmented or hyperpigmented areas, and hypertrichosis. Porphyrins are deposited in the teeth (producing a reddish brown color termed "erythrodontia") and in bone. No neurologic manifestations are known, but hemolysis and splenomegaly are almost always present. Porphyrins in urine are primarily uroporphyrin and coproporphyrin, and in feces porphyrins mostly consist of coproporphyrin. Protection of the skin from sunlight and minor trauma and prompt treatment of secondary bacterial infections help prevent scarring and mutilation. Blood transfusions sufficient to suppress erythropoiesis and bone marrow transplantation may be the most effective current therapies but entail significant risks. It is most common in men but has become more frequent in women in association with alcohol and estrogen use. The majority of cases are type I, in which uroporphyrinogen decarboxylase mutations are not found and the enzyme is deficient in the liver but not in erythrocytes and other tissues. The amount of hepatic uroporphyrinogen decarboxylase protein, as measured immunochemically, is normal, thus suggesting that an acquired process has inactivated the enzyme. With treatment and remission of the disease, enzyme activity gradually increases to normal. This deficiency is an autosomal dominant trait and can result from a number of different mutations of the uroporphyrinogen decarboxylase gene. Most notably, an extensive outbreak of porphyria occurred in eastern Turkey in 1955-1958 after seed wheat containing the fungicide hexachlorobenzene was used for food. This accumulation precedes the appearance of excess porphyrins in plasma and urine. The enzyme-catalyzed decarboxylation of uroporphyrinogen occurs in four sequential steps. In addition, pentacarboxyl porphyrinogen can be metabolized by coproporphyrinogen oxidase to a series of tetracarboxyl porphyrins termed isocoproporphyrins. These substances are excreted primarily in bile and feces and are diagnostic of uroporphyrinogen decarboxylase deficiency.

This material is then infused to produce hematologic rescue following doses of chemotherapy/radiotherapy that would otherwise be lethal from marrow ablation. Because autologous transplants are not alloreactive, the procedure has a lower treatment-related morbidity and mortality than seen with allografting. However, the lack of an alloreactive "graft-versus-tumor" effect may explain why autografting generally has a higher risk of tumor relapse than allografting does. Relapse may also be associated with contamination of the graft with tumorigenic cells if these cells survive the conventional levels of chemotherapy that were given before stem cell harvest. Efforts to remove these cells by treating marrow with physical, pharmaceutical, or immunologic techniques are of uncertain benefit and may retard engraftment. Autografting is currently in wide clinical practice as treatment of a variety of hematologic and solid malignancies, including lymphoma and breast cancer. Unfortunately, there has been a disappointing lack of randomized studies to confirm that the approach genuinely increases patient survival in comparison to conventional chemotherapy/radiotherapy. Hence the usefulness of autologous transplantation in many malignant diseases remains uncertain. More recently, autologous transplantation has been used as a means of introducing genetically modified cells to treat inherited or 988 acquired disorders of hematopoietic cells. This approach is of great promise but is limited by the inefficiency of current gene transfer technologies. The value of autologous transplantation as treatment of severe autoimmune disorders is also under investigation. This approach is based on animal models in which it has been shown that "resetting" the immune system in this way may produce a long-term cure. For most non-malignant indications, allogeneic stem cell transplantation is the only current option. Under general anesthetic, marrow is removed though needle punctures made in the iliac crest. Serious complications of this procedure are rare, although bruising and pain at aspiration sites are common. Infrequent but serious sequelae include the complications of anesthesia, as well as infection or cardiorespiratory instability. No general anesthetic or hospital stay is required, and the procedure can be performed by technical rather than medical staff. These characteristics not only reduce both the costs of the procedure and the accompanying morbidity but may also increase overall patient survival after autologous transplantation. However, some patients-especially those who have received extensive prior chemotherapy-may fail to mobilize and may then require marrow harvest in addition. However, locating and counseling prospective donors, performing phenotypic and molecular tissue typing, and harvesting the marrow require an average of 120 days, a delay that may doom a seriously ill patient. Moreover, patients from many minority groups simply may not have a suitable donor. Interest has therefore increased in transplanting the stem cells present in placental blood. Hence placental blood transplantation is available as soon as typing is confirmed. At present, the results of placental blood transplantation appear relatively comparable to results using more conventional sources of stem cells in children and small adults. Because volumes of placental blood are small, however, they may be insufficient for engraftment in large adults, and outcomes in some diseases such as aplastic anemia and chronic myelocytic anemia appear to be less good. The intensity of this treatment regimen depends on the type of donor and on the underlying condition, but for hematologic malignancy it typically consists of a combination of high doses of one or more cytotoxic drugs such as cyclophosphamide (200 mg/m2) with total-body irradiation (1400 cGy) given in several fractions. Patients may also receive immunosuppressive antibodies such as antithymocyte globulin.

However, different forms of anomic aphasia are seen with lesions in various parts of the cerebral cortex and are frequent early signs in degenerative dementia. Apraxias in which subjects pantomime poorly or are unable to perform gestures on command occur with lesions of the left inferior parietal lobule, left pre-motor cortex, and corpus callosum. Lesions of the right parietal lobe are frequently characterized by hemispatial neglect. In this condition the subject does not attend to stimuli in the neglected sphere contralateral to the lesion. They may ignore the left half of the visual field, the left half of their bodies, auditory stimuli from the left hemispace, or anything in the left hemiuniverse. A milder form of neglect called extinction has been described; in extinction, subjects are capable of attending to contralateral stimuli but, when presented with stimuli simultaneously on both sides, respond only to the ipsilateral side. Neglect has been reported with damage to the right dorsolateral frontal lobe, cingulate gyrus, putamen, and thalamus, but most consistently with lesions of the right inferior parietal lobule. Neglect associated with frontal lobe damage may result in a decreased tendency to react with the contralateral limb. When acute, as when caused by a stroke, neglect may be severe but then tends to recover. Neglect may also occur transiently with left parietal lobe lesions but usually resolves. Subjects may deny their left hemiparesis, hemianesthesia, or hemianopia and as a result attempt to perform activities of which they are incapable. If they are aware of their deficit, they may exhibit anosodiaphoria, or relative lack of concern regarding their impairment. Many studies have implicated a role for the parietal lobes, especially in the right hemisphere, in visuospatial functions. Specific tasks on which subjects with right parietal lesions have been shown to be more impaired include localization of points in space, estimation of line orientation, tests of topographic orientation, some tests of depth perception, and tests of facial discrimination. A common sequela of non-dominant parietal damage is difficulty dressing, which may be due to a combined hemibody neglect and spatial disorientation. A convergence of information from electrophysiologic and ablation studies in animals is suggesting that visual information initially processed in the striate cortex (Brodmann area 17 in the occipital lobe) undergoes further processing in two separate pathways. A ventral pathway passing forward into the temporal lobes is concerned primarily with identifying visual stimuli, the so-called what pathway. The dorsal pathway that involves occipitoparietal connections plays a role in determining the location of visual stimuli, the so-called where pathway. These animal data conform to human neuropsychological studies implicating a role for the parietal lobes in visuospatial functions. Disorders of visual perception may occur with lesions at the occipitoparietal or occipitotemporal borders. The isotypic primary visual receiving area (Brodmann area 17) forms the lips of the calcarine sulcus on the medial aspect of the occipital lobes. The superior lip receives afferents representing the contralateral inferior visual field, and the inferior lip receives afferents from the contralateral superior visual field. The unimodal visual association areas 18 and 19 form concentric rings around area 17. Lesions of the occipital lobes are therefore manifested as changes in visual perception, and a homonymous visual field cut is frequently seen. In part because of the small size of the occipital lobes, isolated occipital lobe syndromes are relatively rare. In complete cortical blindness, or blindness caused by bilateral destruction of the occipital lobes or their afferents, retention of pupillary responses reflects intact visual input to the brain stem. Hallucinations can occur as a result of occipital lobe injury by one of two mechanisms. When visual loss is cortical in origin, these 2037 hallucinations appear in the abnormal field and may be complex and continuous. Ictal hallucinations are rare and are a manifestation of seizures originating in the occipital lobes. Such hallucinations arising from area 17 generally consist of contralateral lights (or darkness) moving from the periphery to the center of the visual fields. Focal seizures arising from areas 18 or 19 may be motionless and pulsatile and may occur in both the ipsilateral and contralateral hemifields.