Complete report patho


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Complete report patho

  1. 1. THE IMMUNE SYSTEM By: Dodge Churchill P. Toledo, RN Dorie Ann R. Daza, RN The Normal Immune Response INNATE IMMUNITY • (also called natural, or native, immunity) refers to defense mechanisms that are present even before infection and that have evolved to specifically recognize microbes and protect individuals against infections. • Innate immunity is the first line of defense, because it is always ready to prevent and eradicate infections. The two most important cellular reactions of innate immunity are: • inflammation, the process in which phagocytic leukocytes are recruited and activated to kill microbes • anti-viral defense, mediated by dendritic cells and NK cells. ADAPTIVE IMMUNITY • (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by (“adapt to”) microbes and are capable of recognizing microbial and nonmicrobial substances. • Adaptive immunity develops later, after exposure to microbes, and is even more powerful than innate immunity in combating infections. By convention, the term “immune response” refers to adaptive immunity. There are two types of adaptive immunity: • humoral immunity, which protects against extracellular microbes and their toxins. Humoral immunity is mediated by B (bone marrow–derived) lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig) • cell-mediated (or cellular) immunity, which is responsible for defense against intracellular microbes. Cellular immunity is mediated by T (thymus-derived) lymphocytes. Both classes of lymphocytes express highly specific receptors for a wide variety of substances, called antigens. Hypersensitivity • implying an excessive response to antigen There are several important general features of hypersensitivity disorders. • Both exogenous and endogenous antigens may elicit hypersensitivity reactions • The development of hypersensitivity diseases (both allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes.
  2. 2. • Hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses The main types of hypersensitivity reactions are the following: • Immediate hypersensitivity (type I hypersensitivity), the immune response is mediated by TH2 cells, IgE antibodies, and mast cells, and results in the release of mediators that act on vessels and smooth muscle and of pro-inflammatory cytokines that recruit inflammatory cells.These reactions are often called allergy. Immediate (type I) hypersensitivity is a complex disorder resulting from an IgE-mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition. These events are regulated mainly by the induction of TH2 helper T cells that stimulate production of IgE (which promotes mast cell activation), cause accumulation of inflammatory cells (particularly eosinophils), and trigger secretion of mucus. The clinical features result from release of mast cell mediators as well as the eosinophil-rich inflammation. • Antibody-mediated disorders (type II hypersensitivity), secreted IgG and IgM antibodies participate directly in injury to cells by promoting their phagocytosis or lysis and in injury to tissues by inducing inflammation. Antibodies may also interfere with cellular functions and cause disease without tissue injury. • Immune complex–mediated disorders (type III hypersensitivity), IgG and IgM antibodies bind antigens usually in the circulation, and the antigen-antibody complexes deposit in tissues and induce inflammation. The leukocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals. • Cell-mediated immune disorders (type IV hypersensitivity), sensitized T lymphocytes (TH1 and TH17 cells and CTLs) are the cause of the cellular and tissue injury. TH2 cells induce lesions that are part of immediate hypersensitivity reactions, and are not considered a form of type IV hypersensitivity Autoimmune diseases SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) • SLE is the prototype of a multisystem disease of autoimmune origin, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs). Etiology and Pathogenesis of SLE The cause of SLE remains unknown, but the existence in these patients of a seemingly limitless number of antibodies against self-constituents indicates that the fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance. As is true of most autoimmune diseases, both genetic and environmental factors play a role in the pathogenesis of SLE. To summarize, SLE is a complex disorder of multifactorial origin resulting from interactions among genetic, immunological, and environmental factors that act in concert to cause activation of helper T cells and B cells and result in the production of several species of pathogenic autoantibodies. Morphology. The morphologic changes in SLE are extremely variable, as are the clinical manifestations and course of disease. The constellation of clinical, serologic, and morphologic changes is essential for diagnosis. The most characteristic lesions result from immune complexes depositing in blood vessels, kidneys, connective tissue, and skin. An acute necrotizing vasculitis involving capillaries, small arteries and arterioles may be present in any tissue.The arteritis is characterized by fibrinoid deposits in the vessel walls. In chronic stages, vessels undergo fibrous thickening with luminal narrowing.
  3. 3. Kidney. Lupus nephritis affects up to 50% of SLE patients. The principal mechanism of injury is immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or larger blood vessels. Other injuries may include thrombi in glomerular capillaries, arterioles, or arteries, often associated with antiphospholipid antibodies. All of the glomerular lesions described below are the result of deposition of immune complexes that are regularly present in the mesangium or along the entire basement membrane and sometimes throughout the glomerulus. The immune complexes consist of DNA and anti-DNA antibodies, but other antigens such as histones have also been implicated. Both in situ formation and deposition of preformed circulating immune complexes may contribute to the injury, but the reason for the wide spectrum of histopathologic lesions (and clinical manifestations) in lupus nephritis patients remains uncertain. A morphologic classification of lupus nephritis has proven to be clinically useful. Five patterns are recognized: minimal mesangial (class I); mesangial proliferative (class II); focal proliferative (class III); diffuse proliferative (class IV); and membranous (class V). None of these patterns is specific for lupus. Mesangial lupus glomerulonephritis is seen in 10% to 25% of patients and is characterized by mesangial cell proliferation and immune complex deposition without involvement of glomerular capillaries. There is no or slight (class I) to moderate (class II) increase in both mesangial matrix and number of mesangial cells. Granular mesangial deposits of immunoglobulin and complement are always present. Classes III to V nephritis, described below, are usually superimposed on some degree of mesangial changes. Focal proliferative glomerulonephritis (class III) is seen in 20% to 35% of patients, and is defined by fewer than 50% involvement of all glomeruli. The lesions may be segmental (affecting only a portion of the glomerulus) or global (involving the entire glomerulus). Affected glomeruli may exhibit crescent formation, fibrinoid necrosis, proliferation of endothelial and mesangial cells, infiltrating leukocytes, and eosinophilic deposits or intracapillary thrombi , which often correlate with hematuria and proteinuria. Some patients may progress to diffuse proliferative glomerulonephritis. The active (or proliferative) inflammatory lesions can heal completely or lead to chronic global or segmental glomerular scarring. Diffuse proliferative glomerulonephritis (class IV) is the most severe form of lupus nephritis, occurring in 35% to 60% of patients. Pathologic glomerular changes may be identical to focal (class III) lupus nephritis, including proliferation of endothelial, mesangial and, sometimes, epithelial cells, with the latter producing cellular crescents that fill Bowman's space. The entire glomerulus is frequently affected but segmental lesions also may occur. Both acutely injured and chronically scarred glomeruli in focal or diffuse lupus nephritis are qualitatively indistinguishable from one another; the distinction is based solely on the percentage of glomerular involvement (<50% for class III vs >50% for class IV). Patients with diffuse glomerulonephritis are usually symptomatic, showing hematuria as well as proteinuria. Hypertension and mild to severe renal insufficiency are also common. Membranous glomerulonephritis (class V) is characterized by diffuse thickening of the capillary walls, which is similar to idiopathic membranous glomerulonephritis. This lesion is seen in 10% to 15% of lupus nephritis patients, is usually accompanied by severe proteinuria or nephrotic syndrome, and may occur concurrently with focal or diffuse lupus nephritis. Granular deposits of antibody and complement can be detected by immunofluorescence. Electron microscopy demonstrates electron-dense deposits that represent immune complexes in mesangial, intramembranous, subepithelial, or subendothelial locations. All classes show variable amounts of mesangial deposits. In membranous lupus nephritis, the deposits are predominantly subepithelial (between the basement membrane and visceral epithelial cells). Subendothelial deposits (between the endothelium and the basement membrane) are seen in the proliferative types (classes III and IV) but may be encountered rarely in class I, II, and V lupus nephritis. When prominent, subendothelial deposits create a homogeneous thickening of the capillary wall, which are seen by light microscopy as a “wire-loop” lesion. Such wire loops are often found in both focal and diffuse proliferative (class III or IV) lupus nephritis, which reflects active disease.
  4. 4. Changes in the interstitium and tubules are frequently present in lupus nephritis patients. Rarely, tubulointerstitial lesions may be the dominant abnormality. Discrete immune complexes similar to those in glomeruli are present in the tubular or peritubular capillary basement membranes in many lupus nephritis patients. Skin. Characteristic erythema affects the facial butterfly (malar) area (bridge of the nose and cheeks) in approximately 50% of patients, but a similar rash may also be seen on the extremities and trunk. Urticaria, bullae, maculopapular lesions, and ulcerations also occur. Exposure to sunlight incites or accentuates the erythema. Histologically the involved areas show vacuolar degeneration of the basal layer of the epidermis. In the dermis, there is variable edema and perivascular inflammation. Vasculitis with fibrinoid necrosis may be prominent. Immunofluorescence microscopy shows deposition of immunoglobulin and complement along the dermoepidermal junction, which may also be present in uninvolved skin. This finding is not diagnostic of SLE and is sometimes seen in scleroderma or dermatomyositis. Joints. Joint involvement is typically a nonerosive synovitis with little deformity, which contrasts with rheumatoid arthritis. Central Nervous System. The pathologic basis of central nervous system symptoms is not entirely clear, but antibodies against a synaptic membrane protein have been implicated. Neuropsychiatric symptoms of SLE have often been ascribed to acute vasculitis, but in histologic studies of the nervous system in such patients significant vasculitis is rarely present. Instead, noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted, which may be due to endothelial damage by antiphospholipid antibodies. Pericarditis and Other Serosal Cavity Involvement. Inflammation of the serosal lining membranes may be acute, subacute, or chronic. During the acute phases, the mesothelial surfaces are sometimes covered with fibrinous exudate. Later they become thickened, opaque, and coated with a shaggy fibrous tissue that may lead to partial or total obliteration of the serosal cavity. Cardiovascular system involvement may manifest as damage to any layer of the heart. Symptomatic or asymptomatic pericardial involvement is present in up to 50% of patients. Myocarditis, or mononuclear cell infiltration, is less common and may cause resting tachycardia and electrocardiographic abnormalities. Valvular abnormalities primarily of the mitral and aortic valves manifest as diffuse leaflet thickening that may be associated with dysfunction (stenosis and/or regurgitation). Valvular (or so-called Libman-Sacks) endocarditis was more common prior to the widespread use of steroids. This nonbacterial verrucous endocarditis takes the form of single or multiple 1- to 3-mm warty deposits on any heart valve, distinctively on either surface of the leaflets. By comparison, the vegetations in infective endocarditis are considerably larger, and those in rheumatic heart disease are smaller and confined to the lines of closure of the valve leaflets. An increasing number of patients have clinical evidence of coronary artery disease (angina, myocardial infarction) owing to coronary atherosclerosis. This complication is noted particularly in young patients with long-standing disease and especially in those who have been treated with corticosteroids. The pathogenesis of accelerated coronary atherosclerosis is unclear but is probably multifactorial. The traditional risk factors, including hypertension, obesity, and hyperlipidemia, are more common in SLE patients than in control populations. In addition, immune complexes and antiphospholipid antibodies may cause endothelial damage and promote atherosclerosis. Spleen. Splenomegaly, capsular thickening, and follicular hyperplasia are common features. Central penicilliary arteries may show concentric intimal and smooth muscle cell hyperplasia, producing so- called onion-skin lesions. Lungs. Pleuritis and pleural effusions are the most common pulmonary manifestations, affecting almost 50% of patients. Alveolar injury with edema and hemorrhage is less common. In some cases, there is chronic interstitial fibrosis and secondary pulmonary hypertension. None of these changes is specific for SLE. Other Organs and Tissues. LE, or hematoxylin, bodies in the bone marrow or other organs are strongly indicative of SLE. Lymph nodes may be enlarged with hyperplastic follicles or even demonstrate necrotizing lymphadenitis.
  5. 5. Clinical Features: • butterfly rash over the face • fever • pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, --fingers, wrists, elbows, shoulders) • pleuritic chest pain • photosensitivity The following sections describe two syndromes in which the cutaneous involvement is the exclusive or most prominent feature. Chronic Discoid Lupus Erythematosus Chronic discoid lupus erythematosus is a disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare. It is characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border. The face and scalp are usually affected, but widely disseminated lesions occasionally occur. The disease is usually confined to the skin, but 5% to 10% of patients with discoid lupus erythematosus develop multisystem manifestations after many years. Conversely, some patients with SLE may have prominent discoid lesions in the skin. Approximately 35% of patients show a positive ANA test, but antibodies to double-stranded DNA are rarely present. Immunofluorescence studies of skin biopsy specimens show deposition of immunoglobulin and C3 at the dermoepidermal junction similar to that in SLE. Subacute Cutaneous Lupus Erythematosus This condition also presents with predominant skin involvement and can be distinguished from chronic discoid lupus erythematosus by several criteria. The skin rash in this disease tends to be widespread, superficial, and nonscarring, although scarring lesions may occur in some patients. Most patients have mild systemic symptoms consistent with SLE. Furthermore, there is a strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype. Thus, the term subacute cutaneous lupus erythematosus seems to define a group intermediate between SLE and lupus erythematosus localized only to skin. Drug-Induced Lupus Erythematosus A lupus erythematosus–like syndrome may develop in patients receiving a variety of drugs, including hydralazine, procainamide, isoniazid, and D-penicillamine, to name only a few. Many of these drugs are associated with the development of ANAs, but most patients do not have symptoms of lupus erythematosus. For example, 80% of patients receiving procainamide test positive for ANAs, but only one third of these manifest clinical symptoms, such as arthralgias, fever, and serositis. Although multiple organs are affected, renal and central nervous system involvement is distinctly uncommon. There are serologic and genetic differences from classical SLE, as well. Antibodies specific for double-stranded DNA are rare, but there is an extremely high frequency of antibodies specific for histone. Persons with the HLA-DR4 allele are at a greater risk of developing lupus erythematosus after administration of hydralazine. The disease remits after withdrawal of the offending drug. RHEUMATOID ARTHRITIS Rheumatoid arthritis is a chronic inflammatory disease that affects primarily the joints but may involve extra-articular tissues such as the skin, blood vessels, lungs, and heart. Abundant evidence supports the autoimmune nature of the disease. Because the principal manifestations of the disease are in the joints .
  6. 6. SJÖGREN SYNDROME Sjögren syndrome is a chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary glands. It occurs as an isolated disorder (primary form), also known as the sicca syndrome, or more often in association with another autoimmune disease (secondary form). Among the associated disorders, rheumatoid arthritis is the most common, but some patients have SLE, polymyositis, scleroderma, vasculitis, mixed connective tissue disease, or thyroiditis. Morphology. As mentioned earlier, lacrimal and salivary glands are the major targets of the disease, although other exocrine glands, including those lining the respiratory and gastrointestinal tracts and the vagina, may also be involved. The earliest histologic finding in both the major and the minor salivary glands is periductal and perivascular lymphocytic infiltration. Eventually the lymphocytic infiltrate becomes extensive ( Fig. 6-35 ), and in the larger salivary glands lymphoid follicles with germinal centers may be seen. The ductal lining epithelial cells may show hyperplasia, thus obstructing the ducts. Later there is atrophy of the acini, fibrosis, and hyalinization; still later in the course atrophy and replacement of parenchyma with fat are seen. In some cases the lymphoid infiltrate may be so intense as to give the appearance of a lymphoma. Indeed, these patients are at high risk for development of B-cell lymphomas, and molecular assessments of clonality may be necessary to distinguish intense reactive chronic inflammation from early involvement by lymphoma. The lack of tears leads to drying of the corneal epithelium, which becomes inflamed, eroded, and ulcerated; the oral mucosa may atrophy, with inflammatory fissuring and ulceration; and dryness and crusting of the nose may lead to ulcerations and even perforation of the nasal septum. Clinical Features: -Sjögren syndrome occurs most commonly in women between the ages of 50 and 60 -Keratoconjunctivitis: produces blurring of vision, burning, and itching, and thick secretions accumulate in the conjunctival sac -Xerostomia: results in difficulty in swallowing solid foods, a decrease in the ability to taste, cracks and fissures in the mouth, and dryness of the buccal mucosa -Parotid gland enlargement -dryness of the nasal mucosa -epistaxis -recurrent bronchitis, and pneumonitis SYSTEMIC SCLEROSIS (SCLERODERMA) Systemic sclerosis is a chronic disease characterized by: (1) chronic inflammation thought to be the result of autoimmunity, (2) widespread damage to small blood vessels, and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs. Morphology. Virtually all organs can be involved in systemic sclerosis. Prominent changes occur in the skin, alimentary tract, musculoskeletal system, and kidney, but lesions also are often present in the blood vessels, heart, lungs, and peripheral nerves. Skin. A great majority of patients have diffuse, sclerotic atrophy of the skin, which usually begins in the fingers and distal regions of the upper extremities and extends proximally to involve the upper arms, shoulders, neck, and face. Histologically, there are edema and perivascular infiltrates containing CD4+ T cells, together with swelling and degeneration of collagen fibers, which become eosinophilic. Capillaries and small arteries (150 to 500 μm in diameter) may show thickening of the basal lamina, endothelial cell damage, and partial occlusion. With progression of the disease, there is increasing fibrosis of the dermis, which becomes tightly bound to the subcutaneous structures. There is marked increase of compact collagen in the dermis, usually with thinning of the epidermis, loss of rete pegs, atrophy of the dermal appendages, and hyaline thickening of the walls of dermal arterioles and capillaries. Focal and sometimes diffuse subcutaneous calcifications may develop, especially in patients with the CREST syndrome. In advanced stages the fingers take on a tapered, clawlike appearance with limitation of motion in the joints, and the face becomes a drawn mask. Loss of blood supply may lead to cutaneous ulcerations and to atrophic changes in the terminal phalanges. Sometimes the tips of the fingers undergo autoamputation.
  7. 7. Alimentary Tract. The alimentary tract is affected in approximately 90% of patients. Progressive atrophy and collagenous fibrous replacement of the muscularis may develop at any level of the gut but are most severe in the esophagus. The lower two thirds of the esophagus often develops a rubber-hose inflexibility. The associated dysfunction of the lower esophageal sphincter gives rise to gastroesophageal reflux and its complications, including Barrett metaplasia and strictures. The mucosa is thinned and may be ulcerated, and there is excessive collagenization of the lamina propria and submucosa. Loss of villi and microvilli in the small bowel is the anatomic basis for the malabsorption syndrome sometimes encountered. Musculoskeletal System. Inflammation of the synovium, associated with hypertrophy and hyperplasia of the synovial soft tissues, is common in the early stages; fibrosis later ensues. These changes are reminiscent of rheumatoid arthritis, but joint destruction is not common in systemic sclerosis. In a small subset of patients (approximately 10%), inflammatory myositis indistinguishable from polymyositis may develop. Kidneys. Renal abnormalities occur in two thirds of patients with systemic sclerosis. The most prominent are the vascular lesions. Interlobular arteries show intimal thickening as a result of deposition of mucinous or finely collagenous material, which stains histochemically for glycoprotein and acid mucopolysaccharides. There is also concentric proliferation of intimal cells. These changes may resemble those seen in malignant hypertension, but in scleroderma the alterations are restricted to vessels 150 to 500 μm in diameter and are not always associated with hypertension. Hypertension, however, does occur in 30% of patients with scleroderma, and in 20% it takes an ominously rapid, downhill course (malignant hypertension). In hypertensive patients, vascular alterations are more pronounced and are often associated with fibrinoid necrosis involving the arterioles together with thrombosis and infarction. Such patients often die of renal failure, which accounts for about 50% of deaths in persons with this disease. There are no specific glomerular changes. Lungs. The lungs are involved in more than 50% of individuals with systemic sclerosis. This involvement may manifest as pulmonary hypertension and interstitial fibrosis. Pulmonary vasospasm, secondary to pulmonary vascular endothelial dysfunction, is considered important in the pathogenesis of pulmonary hypertension. Pulmonary fibrosis, when present, is indistinguishable from that seen in idiopathic pulmonary fibrosis. Heart. Pericarditis with effusion and myocardial fibrosis, along with thickening of intramyocardial arterioles, occurs in one third of the patients. Clinical myocardial involvement, however, is less common. Clinical Features: • Systemic sclerosis has a female-to-male ratio of 3 : 1 • peak incidence in the 50- to 60-year age group • skin thickening • Raynaud's phenomenon Rejection of Tissue Transplants Transplant rejection is discussed here because it involves several of the immunological reactions that underlie immune-mediated inflammatory diseases. A major barrier to transplantation is the process of rejection, in which the recipient's immune system recognizes the graft as being foreign and attacks it. Mechanisms of Recognition and Rejection of Allografts Rejection is a complex process in which both cell-mediated immunity and circulating antibodies play a role]; moreover, the contributions of these two mechanisms are often reflected in the histologic features of the rejected organs.
  8. 8. T Cell–Mediated Reactions The critical role of T cells in transplant rejection has been documented both in humans and in experimental animals. T cell–mediated graft rejection is called cellular rejection, and it involves destruction of graft cells by CD8+ CTLs and delayed hypersensitivity reactions triggered by activated CD4+ helper cells. The major antigenic differences between a donor and recipient that result in rejection of transplants are differences in highly polymorphic HLA alleles. The recipient's T cells recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways, called direct and indirect. Direct Pathways T cells of the transplant recipient recognize allogeneic (donor) MHC molecules on the surface of APCs in the graft. It is believed that dendritic cells carried in the donor organs are the most important APCs for initiating the antigraft response, because they not only express high levels of class I and II MHC molecules but also are endowed with costimulatory molecules (e.g., B7-1 and B7-2). The T cells of the host encounter the donor dendritic cells either within the grafted organ or after the dendritic cells migrate to the draining lymph nodes. CD8+ T cells recognize class I MHC mdecules and differentiate into active CTLs, which can kill the graft cells by mechanisms already discussed. CD4+ helper T cells recognize allogeneic class II molecules and proliferate and differentiate into TH1 (and possibly TH17) effector cells. Cytokines secreted by the activated CD4+ T cells trigger a delayed hypersensitivity reaction in the graft, resulting in increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages), and graft injury caused by the activated macrophages. The direct recognition of allogeneic MHC molecules seems paradoxical to the rules of self-MHC restriction: If T cells normally are restricted to recognizing foreign peptides displayed by self-MHC molecules, why should these T cells recognize foreign MHC? The probable explanation is that allogeneic MHC molecules, with their bound peptides, resemble, or mimic, the self-MHC–foreign peptide complexes that are recognized by self-MHC–restricted T cells. Thus, recognition of allogeneic MHC molecules is a cross-reaction of T cells selected to recognize self-MHC plus foreign peptides. Indirect pathways Recipient T lymphocytes recognize MHC antigens of the graft donor after they are presented by the recipient's own APCs. This process involves the uptake and processing of MHC and other foreign molecules from the grafted organ by host APCs. The peptides derived from the donor tissue are presented by the host's own MHC molecules, like any other foreign peptide. Thus, the indirect pathway is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens. The indirect pathway generates CD4+ T cells that enter the graft and recognize graft antigens being displayed by host APCs that have also entered the graft, and the result is a delayed hypersensitivity type of reaction. However, CD8+ CTLs that may be generated by the indirect pathway cannot directly recognize or kill graft cells, because these CTLs recognize graft antigens presented by the host's APCs. Therefore, when T cells react to a graft by the indirect pathway, the principal mechanism of cellular rejection may be T-cell cytokine production and delayed hypersensitivity. It is postulated that the direct pathway is the major pathway in acute cellular rejection, whereas the indirect pathway is more important in chronic rejection. However, this separation is by no means absolute. Antibody-Mediated Reactions Although T cells are pivotal in the rejection of organ transplants, antibodies produced against alloantigens in the graft are also important mediators of rejection. This process is called humoral rejection, and it can take two forms. Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of the recipient. Such antibodies may be present in a recipient who has previously rejected a kidney transplant. Multiparous women who develop anti-HLA antibodies against paternal antigens shed from the fetus may have preformed antibodies to grafts taken from their husbands or children, or even from unrelated individuals who share HLA alleles with the husbands. Prior blood transfusions can also lead to presensitization, because platelets and white blood cells are rich in HLA antigens and donors and recipients are usually not HLA-identical. With the
  9. 9. current practice of cross-matching, that is, testing recipient's serum for antibodies against donor's cells, hyperacute rejection is no longer a significant clinical problem. Rejection of Kidney Grafts Morphology. On the basis of the morphology and the underlying mechanism, rejection reactions are classified as hyperacute, acute, and chronic. The morphologic changes in these patterns are described below as they relate to renal transplants. Similar changes may occur in any other vascularized organ transplant and are discussed in relevant chapters. Hyperacute Rejection. This form of rejection occurs within minutes or hours after transplantation. A hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid, and may excrete a mere few drops of bloody urine. Immunoglobulin and complement are deposited in the vessel wall, causing endothelial injury and fibrin-platelet thrombi. Neutrophils rapidly accumulate within arterioles, glomeruli, and peritubular capillaries. As these changes become diffuse and intense, the glomeruli undergo thrombotic occlusion of the capillaries, and fibrinoid necrosis occurs in arterial walls. The kidney cortex then undergoes outright necrosis (infarction), and such nonfunctioning kidneys have to be removed. Acute Rejection. This may occur within days of transplantation in the untreated recipient or may appear suddenly months or even years later, after immunosuppression has been used and terminated. In any one patient, cellular or humoral immune mechanisms may predominate. Histologically, humoral rejection is associated with vasculitis, whereas cellular rejection is marked by an interstitial mononuclear cell infiltrate. Acute cellular rejection is most commonly seen within the initial months after transplantation and is heralded by clinical and biochemical signs of renal failure. Histologically, there may be extensive interstitial mononuclear cell infiltration and edema as well as mild interstitial hemorrhage. As might be expected, immunohistochemical staining reveals both CD4+ and CD8+ T lymphocytes, which express markers of activated T cells, such as the α chain of the IL-2 receptor. Glomerular and peritubular capillaries contain large numbers of mononuclear cells that may also invade the tubules, causing focal tubular necrosis. In addition to causing tubular damage, CD8+ T cells may injure vascular endothelial cells, causing a so-called endothelitis. The affected vessels have swollen endothelial cells, and at places the lymphocytes can be seen between the endothelium and the vessel wall. The recognition of cellular rejection is important because, in the absence of an accompanying humoral rejection, patients respond well to immunosuppressive therapy. Cyclosporine, a widely used immunosuppressive drug, is also nephrotoxic, and hence the histologic changes resulting from cyclosporine may be superimposed. Acute humoral rejection (rejection vasculitis) is mediated by antidonor antibodies, and hence it is manifested mainly by damage to the blood vessels. This may take the form of necrotizing vasculitis with endothelial cell necrosis, neutrophilic infiltration, deposition of immunoglobulins, complement, and fibrin, and thrombosis. Such lesions are associated with extensive necrosis of the renal parenchyma. In many cases, the vasculitis is less acute and is characterized by marked thickening of the intima with proliferating fibroblasts, myocytes, and foamy macrophages. The resultant narrowing of the arterioles may cause infarction or renal cortical atrophy. The proliferative vascular lesions mimic arteriosclerotic thickening and are believed to be caused by cytokines that cause proliferation of vascular smooth muscle cells. Deposition of the complement breakdown product C4d in allografts is a strong indicator of humoral rejection, because C4d is produced during activation of the complement system by the antibody-dependent classical pathway. The importance of making this diagnosis is that it provides a rationale for treating affected patients with B cell–depleting agents. Chronic Rejection. In recent years acute rejection has been significantly controlled by immunosuppressive therapy, and chronic rejection has emerged as an important cause of graft failure. Patients with chronic rejection present clinically with a progressive renal failure manifested by a rise in serum creatinine over a period of 4 to 6 months. Chronic rejection is dominated by vascular changes, interstitial fibrosis, and tubular atrophy with loss of renal parenchyma. The vascular changes consist of dense, obliterative intimal fibrosis, principally in the cortical arteries. These vascular lesions result in renal ischemia, manifested by glomerular loss, interstitial fibrosis and tubular atrophy, and shrinkage of the renal parenchyma. The glomeruli may show scarring, with duplication of
  10. 10. basement membranes; this appearance is sometimes called chronic transplant glomerulopathy. Chronically rejecting kidneys usually have interstitial mononuclear cell infiltrates of plasma cells and numerous eosinophils. Immunodeficiency Syndromes -Primary Immunodeficiency Disorders -Secondary Immunodeficiency State PRIMARY IMMUNODEFICIENCIES - are genetically determined and affect the humoral and/or cellular arms of adaptive immunity (mediated by B and T lymphocytes, respectively) or the defense mechanisms of innate immunity (NK cells, phagocytes, or complement). Defects in adaptive immunity are often subclassified on the basis of the primary component involved (i.e., B cells or T cells or both). -Most primary immunodeficiencies manifest themselves in infancy, between 6 months and 2 years of life, and they are detected because the affected infants are susceptible to recurrent infections Examples of Infections in Immunodeficiencies Pathogen Granulocyte Complement Type T-Cell Defect B-Cell Defect Defect Defect Bacteria Bacterial sepsis Streptococci, Staphylococci, Neisserial staphylococci, Pseudomonas infections, other Haemophilus pyogenic Viruses Cytomegalovirus, Enteroviral infections Epstein-Barr virus, encephalitis severe varicella, chronic infections with respiratory and intestinal viruses Fungi and Candida, Severe intestinal Candida, parasites Pneumocystis jiroveci giardiasis Nocardia, Aspergillus Special Aggressive disease Recurrent features with opportunistic sinopulmonary pathogens, failure to infections, sepsis, clear infections chronic meningitis X-Linked Agammaglobulinemia (Bruton's Agammaglobulinemia) • one of the more common forms of primary immunodeficiency • It is characterized by the failure of B-cell precursors to develop into mature B cells. • caused by mutations in a cytoplasmic tyrosine kinase, called Bruton tyrosine kinase (Btk) *Btk is a protein tyrosine kinase that is associated with the Ig receptor complex of pre-B and mature B cells and is needed to transduce signals from the receptor. • seen almost entirely in males, but sporadic cases have been described in females • The disease usually does not become apparent until about 6 months of age, as maternal immunoglobulins are depleted
  11. 11. • Prophylactic intravenous Ig therapy allows most individuals to reach adulthood. Bacterial Infections of the Respiratory Tract • Acute and Chronic Pharyngitis • Sinusitis • Otitis media • Bronchitis • Pneumonia Causative Organism • Haemophilus influenzae • Streptococcus pneumoniae • Staphylococcus aureus Viral Infections: • Echovirus • Poliovirus • Coxsackievirus • Giardia lamblia - an intestinal protozoan that is normally resisted by secreted IgA, causes persistent infections in persons with this disorder. The classic form of this disease has the following characteristics: B cells are absent or markedly decreased in the circulation, and the serum levels of all classes of immunoglobulins are depressed. Pre-B cells, which express the B-lineage marker CD19 but not membrane Ig, are found in normal numbers in the bone marrow. • Germinal centers of lymph nodes, Peyer's patches, the appendix, and tonsils are underdeveloped. • Plasma cells are absent throughout the body. • T cell–mediated reactions are normal. Common Variable Immunodeficiency • relatively common but poorly defined entity represents a heterogeneous group of disorders • Hypogammaglobulinemia - generally affecting all the antibody classes but sometimes only IgG. • It is based on exclusion of other well-defined causes of decreased antibody production. • most individuals have normal or near-normal numbers of B cells in the blood and lymphoid tissues. • affects both sexes equally – onset of symptoms is later in childhood or adolescence
  12. 12. Clinical Manifestations of Common Variable Immunodeficiency • recurrent sinopulmonary pyogenic infections • recurrent herpesvirus infections • meningoencephalitis • persistent diarrhea Isolated IgA Deficiency • is a common immunodeficiency • European descent, it is far less common in blacks and Asians • Affected individuals have extremely low levels of both serum and secretory IgA • It may be familial, or acquired in association with toxoplasmosis, measles, or some other viral infection • Most individuals with this disease are asymptomatic. • IgA is the major Ig in external secretions, mucosal defenses are weakened, and infections occur in the respiratory, gastrointestinal, and urogenital tracts • Some individuals with IgA deficiency are also deficient in the IgG2 and IgG4 subclasses of IgG. • IgA-deficient patients have a high frequency of respiratory tract allergy and a variety of autoimmune diseases, particularly SLE and rheumatoid arthritis. • When transfused with blood containing normal IgA, some of these patients develop severe, even fatal, anaphylactic reactions, because the IgA behaves like a foreign antigen (since the patients do not produce it and are not tolerant to it). • Impaired differentiation of naive B lymphocytes to IgA-producing cells. Hyper-IgM Syndrome • affected patients make IgM antibodies but are deficient in their ability to produce IgG, IgA, and IgE antibodies. • It is inherited in an autosomal recessive pattern • The number of B and T cells is normal. • Many of the IgM antibodies react with elements of blood, giving rise to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. In older patients there may be uncontrolled proliferation of IgM-producing plasma cells with infiltrations of the gastrointestinal tract. Although the proliferating B cells are polyclonal, extensive infiltration may lead to death. • individuals with the hyper-IgM syndrome present with recurrent pyogenic infections, because the level of opsonizing IgG antibodies is low. In addition, those with CD40L mutations are also susceptible to pneumonia caused by the intracellular organism Pneumocystis jiroveci, because of the defect in cell-mediated immunity. DiGeorge Syndrome (Thymic Hypoplasia)
  13. 13. • is a T-cell deficiency that results from failure of development of the third and fourth pharyngeal pouches • individuals with this syndrome have a variable loss of T cell–mediated immunity, tetany and congenital defects of the heart and great vessels. • Not a familial disorder Severe Combined Immunodeficiency • represents a constellation of genetically distinct syndromes, all having in common defects in both humoral and cell-mediated immune responses. • Affected infants present with prominent thrush, extensive diaper rash, and failure to thrive. • Some patients develop a morbilliform rash shortly after birth because maternal T cells are transferred across the placenta and attack the fetus, causing GVH disease. • 50%- 60% of cases is a X-linked • extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, P. jiroveci, Pseudomonas, cytomegalovirus, varicella, and a whole host of bacteria • The remaining cases of SCID are inherited as autosomal recessive. The most common cause of autosomal recessive SCID is a deficiency of the enzyme adenosine deaminase (ADA). Although the mechanisms by which ADA deficiency causes SCID are not entirely clear, it has been proposed that deficiency of ADA leads to accumulation of deoxyadenosine and its derivatives (e.g., deoxy-ATP), which are toxic to rapidly dividing immature lymphocytes, especially those of the T-cell lineage • Bone marrow transplantation – is the mainstay treatment • Gene therapy – x-linked SCID, is the first human disease that has been successful Several other less common causes of autosomal recessive SCID have been discovered • Mutations in recombinase-activating genes prevent the somatic gene rearrangements essential for the assembly of T-cell receptor and Ig genes. This blocks the development of T and B cells. • An intracellular kinase called Jak3 is essential for signal transduction through the common cytokine receptor γ chain (which is mutated in X-linked SCID, as discussed above). Mutations of Jak3 therefore have the same effects as mutations in the γc chain. • Several mutations have been described in signaling molecules, including kinases associated with the T-cell antigen receptor and components of calcium channels that are required for entry of calcium and activation of many signaling pathways. • Mutations that impair the expression of class II MHC molecules prevent the development of CD4+ T cells. CD4+ T cells are involved in cellular immunity and provide help to B cells, and hence class II MHC deficiency results in combined immunodeficiency. This disease, called the bare lymphocyte syndrome, is usually caused by mutations in transcription factors that are required for class II MHC gene expression.
  14. 14. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome) • is an X-linked recessive disease characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection, ending in early death • is caused by mutations in the gene encoding Wiskott-Aldrich syndrome protein (WASP) This protein belongs to a family of proteins that are believed to link membrane receptors, such as antigen receptors, to cytoskeletal elements. The WASP protein may be involved in cytoskeleton-dependent responses, including cell migration and signal transduction, but the essential functions of this protein in lymphocytes and platelets are unclear • Bone marrow transplantation Genetic Deficiencies of the Complement System • The complement system plays critical roles in host defense and inflammation • A deficiency of C2 is the most common of all. With a deficiency of C2 or the other early components of the classical pathway there is little or no increase in susceptibility to infections, but the dominant manifestation is an increased incidence of an SLE-like autoimmune disease • There is also increased incidence of immune complex–mediated glomerulonephritis; in the absence of complement, immune complex–mediated inflammation is presumably caused by Fc receptor–dependent leukocyte activation. • A deficiency of C1 inhibitor gives rise to hereditary angioedema. • This autosomal dominant disorder is more common than complement deficiency states. SECONDARY IMMUNODEFICIENCIES • may be encountered in individuals with cancer, diabetes and other metabolic diseases, malnutrition, chronic infection, and renal disease • They also occur in persons receiving chemotherapy or radiation therapy for cancer, or immunosuppressive drugs to prevent graft rejection or to treat autoimmune diseases. • can be caused by defective lymphocyte maturation (when the bone marrow is damaged by radiation or chemotherapy or involved by tumors, such as leukemias and metastatic cancers), loss of immunoglobulins (as in proteinuric renal diseases), inadequate Ig synthesis (as in malnutrition), or lymphocyte depletion (from drugs or severe infections). As a group, the secondary immune deficiencies are more common than the disorders of primary genetic origin. ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) - is a disease caused by the retrovirus human immunodeficiency virus (HIV) and characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations Epidemiology • Homosexual or bisexual men constitute the largest group, accounting for over 50% of the reported cases. • Intravenous drug abusers with no previous history of homosexuality are the next largest group, representing about 20% of infected individuals.
  15. 15. • Hemophiliacs, especially those who received large amounts of factor VIII or factor IX concentrates before 1985, make up about 0.5% of all cases. • Recipients of blood and blood components who are not hemophiliacs but who received transfusions of HIV-infected whole blood or components account for about 1% of patients. • Heterosexual contacts of members of other high-risk groups constitute about 10% of the patient population. • In approximately 5% of cases the risk factors cannot be determined. Routes of Transmission • Sexual Contact • Parental Inoculation • Passage of the virus from infected mothers to their newborns Sexual Contact Sexual Transmission is clearly the predominant mode of infection worldwide, accounting for over 75% of all cases of HIV transmission Viral Transmission • (1) direct inoculation into the blood vessels breached by trauma • (2) infection of dendritic cells or CD4+ cells within the mucosa Heterosexual Transmission -is globally the most common mode by which HIV is spread Sexually Transmitted Disease • Syphillis • Chancroid • Herpes • Gonorrhea • Chlamydia Parenteral transmission three groups of individuals: • intravenous drug abusers • hemophiliacs who received factor VIII and factor IX concentrates • random recipients of blood transfusion Mother-to-infant transmission - is the major cause of pediatric AIDS.
  16. 16. three routes: (1) in utero by transplacental spread (2) during delivery through an infected birth canal (3) after birth by ingestion of breast milk. Etiology: The Properties of HIV AIDS is caused by HIV, a nontransforming human retrovirus belonging to the lentivirus family. Included in this group are feline immunodeficiency virus, simian immunodeficiency virus, visna virus of sheep, bovine immunodeficiency virus, and the equine infectious anemia virus. Pathogenesis of HIV Infection and AIDS • Profound immune deficiency, primarily affecting cell-mediated immunity, is the hallmark of AIDS. This results chiefly from infection of and a severe loss of CD4+ T cells as well as impairment in the function of surviving helper T cells two major targets of HIV infection: • the immune system • the central nervous system Pathogenesis of Central Nervous System Involvement • nervous system is a major target of HIV infection • Macrophages and microglia, cells in the central nervous system that belong to the macrophage lineage, are the predominant cell types in the brain that are infected with HIV Natural History of HIV Infection HIV disease begins with acute infection, which is only partly controlled by the adaptive immune response, and advances to chronic progressive infection of peripheral lymphoid tissues phases: (1) an acute retroviral syndrome; (2) a middle, chronic phase, in which most individuals are asymptomatic; and (3) clinical AIDS Primary Infection, Virus Dissemination, and the Acute Retroviral Syndrome Acute (early) infection is characterized by infection of memory CD4+ T cells in mu-cosal lymphoid tissues, and death of many infected cells. Because the mucosal tissues are the largest reservoir of T cells in the body, and a major site of residence of memory T cells, this local loss results in considerable depletion of lymphocytes. Few infected cells are detectable in the blood and other tissues. Mucosal infection is followed by dissemination of the virus and the development of host immune responses.
  17. 17. Acute retroviral syndrome • is the clinical presentation of the initial spread of the virus and the host response. . *chronic phase of the disease, lymph nodes and the spleen are sites of continuous HIV replication and cell destruction Clinical latency period • few or no clinical manifestations of the HIV infection are present AIDS • breakdown of host defense, a dramatic increase in plasma virus, and severe, life-threatening clinical disease • with long-lasting fever (>1 month), fatigue, weight loss, and diarrhea. After a variable period, serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (grouped under the rubric AIDS indicator diseases, discussed below) emerge rapid progressors the middle, chronic phase is telescoped to 2 to 3 years after primary infection. long-term nonprogressors defined as untreated HIV-1–infected individuals who remain asymptomatic for 10 years or more Clinical Features of AIDS • Fever • weight loss • diarrhea • generalized lymphadenopathy • multiple opportunistic infections • neurologic disease • secondary neoplasms Amyloidosis • is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings • should not be considered a single disease; rather it is a group of diseases having in common the deposition of similar-appearing proteins • a variety of histochemical techniques are used. *Congo red stain, which under ordinary light imparts a pink or red color to tissue deposits, but far more striking and specific is the green birefringence of the stained amyloid when observed by polarizing microscopy
  18. 18. Properties of Amyloid Proteins • Physical Nature of Amyloid • Chemical Nature of Amyloid Pathogenesis of Amyloidosis • results from abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function two general categories: (1) normal proteins that have an inherent tendency to fold improperly, associate and form fibrils, and do so when they are produced in increased amounts (2) mutant proteins that are prone to misfolding and subsequent aggregation. Classification of Amyloidosis: • Primary Amyloidosis: Immunocyte Dyscrasias with Amyloidosis • Reactive Systemic Amyloidosis • Hemodialysis-Associated Amyloidosis • Heredofamilial Amyloidosis • Localized Amyloidosis • Endocrine Amyloid • Amyloid of Aging