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Pathology_Robbins. Pericarditis and Other Serosal Cavity Involvement. Inflammationoftheserosalliningmembranesmaybeacute,subacute,orchronic.Duringtheacutephase,themesothelialsurfacesaresometimescoveredwithfibrinousexudate.Latertheybecomethickened,opaque,andcoatedwithshaggyfibrous Fig. 5.25 Systemiclupuserythematosusinvolvingtheskin.(A)AnH&E-stainedsectionshowsliquefactivedegenerationofthebasallayeroftheepidermisandedemaatthedermoepidermaljunction.(B)AnimmunofluorescencemicrographstainedforIgGrevealsdepositsofIgalongthedermoepidermaljunction.(A,Courtesy of Dr. Jag Bhawan, Boston University School of Medicine, Boston, Massachusetts. B,Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas, Texas.) tissuethatmayleadtopartialortotalobliterationoftheserosalcavity.Pleuralandpericardialeffusionsmaybepresent.


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Pathology_Robbins. http://ebooksmedicine.net Fig. 5.26 Libman-Sacksendocarditisofthemitralvalveinlupuserythematosus.Thevegetationsattachedtothemarginofthethickenedvalveleafletareindicatedbyarrows. (Courtesy of Dr. Fred Schoen, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.) Spleen. Splenomegaly,capsularthickening,andfollicularhyperplasiaarecommonfeatures.Centralpenicilliaryarteriesmayshowconcentricintimalandsmoothmusclecellhyperplasia,producingso-calledonion-skin lesions. Lungs. Inadditiontopleuritisandaccompanyingpleural effusions,somecasesarecomplicatedbychronicinterstitial fibrosisandsecondarypulmonaryhypertension. Other Organs and Tissues. LE,orhematoxylin,bodiesinthebonemarroworotherorgansarestronglyindicativeofSLE.LymphnodesmaybeenlargedduetohyperplasiaofBcellfolliclesorevendemonstratenecrotizinglymphadenitisduetovasculitis.


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Pathology_Robbins. SLE is a highly variable multisystem disease, and its diagnosis relies on a constellation of clinical, serologic, and morphologic findings (see


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Pathology_Robbins. Table 5.10 ). It may be acute or insidious in its onset. Often, the patient is a young woman with some or all of the following features: a butterfly rash on the face; fever; pain without deformity in one or more joints; pleuritic chest pain; and photosensitivity. In many patients, however, the presentation is subtle and puzzling, taking forms such as fever of unknown origin, abnormal urinary findings, or joint disease masquerading as rheumatoid arthritis or rheumatic fever. Generic ANAs, detected by immunofluorescence assays, are found in virtually 100% of patients, but these are not specific for SLE. Renal involvement may produce a variety of findings, including hematuria, red blood cell casts, proteinuria, and nephrotic syndrome (Chapter 14). Anemia or thrombocytopenia are presenting manifestations in some patients and may be dominant clinical problems. In others, neuropsychiatric manifestations including psychosis or convulsions, or coronary artery disease may be prominent.


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Pathology_Robbins. manifestations in some patients and may be dominant clinical problems. In others, neuropsychiatric manifestations including psychosis or convulsions, or coronary artery disease may be prominent. Infections also are common, presumably because of the immune dysfunction that underlies SLE as well as treatment with immunosuppressive drugs.


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Pathology_Robbins. The course of SLE is variable and unpredictable. Rare acute cases result in death within weeks to months. More often, with appropriate therapy, SLE follows a relapsing and remitting course over a period of years or decades. During acute flares, increased formation of immune complexes results in complement activation, often leading to hypocomplementemia. Disease flares are usually treated with corticosteroids or other immunosuppressive drugs. Even without therapy, in some patients the disease runs an indolent course for years with relatively mild manifestations, such as skin changes and mild hematuria. The overall 5-year and 10-year survivals are approximately 90% and 80%, respectively. The most common causes of death are renal failure and intercurrent infections. Coronary artery disease also is becoming an important cause of death. Patients treated with steroids and immunosuppressive drugs incur the usual risks associated with such therapy.


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Pathology_Robbins. As mentioned earlier, involvement of skin along with multisystem disease is fairly common in SLE. The following sections describe two syndromes in which the cutaneous involvement is the exclusive or most prominent feature.


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Pathology_Robbins. 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, most often on the face and scalp, showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border. It progresses to SLE in 5% to 10% of patients, usually after many years. Conversely, some patients with SLE may have prominent discoid lesions in the skin. Approximately 35% of patients have a positive test for generic ANAs, 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.


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Pathology_Robbins. The term subacute cutaneous lupus erythematosus refers to a group intermediate between SLE and lupus erythematosus localized only to skin. The skin rash in this disease tends to be widespread and superficial. Most patients have mild systemic symptoms similar to those in SLE. There is a strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype. An SLE-like syndrome may develop in patients receiving a variety of drugs, including hydralazine, procainamide, isoniazid, and D-penicillamine. Surprisingly, anti-TNF therapy, which is effective in rheumatoid arthritis and other autoimmune diseases, also can cause drug-induced lupus. Many of these drugs are associated with the development of ANAs, especially antibodies specific for his-tones. The disease remits after withdrawal of the offending drug. http://ebooksmedicine.net SLEisasystemicautoimmunediseasecausedbyautoantibodiesproducedagainstnumerousselfantigensandtheformationofimmunecomplexes.


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Pathology_Robbins. Rheumatoid arthritis is an autoimmune disease that affects primarily the joints but also may involve extraarticular tissues such as the skin, blood vessels, lungs, and heart. Because the principal manifestations of the disease are in the joints, it is discussed in Chapter 21. 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). Rheumatoid arthritis is the most common associated disorder, while other patients have SLE, polymyositis, scleroderma, vasculitis, mixed connective tissue disease, or autoimmune thyroid disease.


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Pathology_Robbins. The lacrimal and salivary glands characteristically show dense lymphocytic infiltration consisting mainly of activated CD4+ helper T cells and some B cells, including plasma cells. Serologic studies frequently reveal autoantibodies. Antibodies against two ribonucleoprotein antigens, SS-A (Ro) and SS-B (La) (see Table 5.11 ), can be detected in as many as 90% of patients by sensitive techniques. High titers of antibodies to SS-A are associated with early disease onset, longer disease duration, and extraglandular manifestations, such as cutaneous vasculitis and nephritis. These autoantibodies also are present in a smaller percentage of patients with SLE and hence are not diagnostic of Sjögren syndrome. In addition, about 75% of patients have rheumatoid factor (an antibody reactive with self IgG), and 50% to 80% of patients have ANAs.


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Pathology_Robbins. The pathogenesis of Sjögren syndrome remains obscure, but the pathology and serology, as well as an association, albeit weak, with HLA alleles, all point to activation of autoreactive T cells and B cells. The initiating trigger may be a viral infection of the salivary glands, which causes local cell death and release of tissue self antigens. In genetically susceptible individuals, CD4+ T cells and B cells specific for these self antigens may escape tolerance and participate in immune reactions that lead to tissue damage and, eventually, fibrosis. However, the role of particular cytokines or T cell subsets, and the nature of the autoantigens recognized by these lymphocytes, remain mysterious.


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Pathology_Robbins. Sjögren syndrome occurs most commonly in women between 50 and 60 years of age. As might be expected, symptoms result from inflammatory destruction of the exocrine glands. Keratoconjunctivitis produces blurred vision, burning, and itching, and thick secretions that accumulate in the conjunctival sac. Xerostomia results in difficulty in swallowing solid foods, a decrease in taste, cracks and fissures in the mouth, and dryness of the buccal mucosa. Parotid gland enlargement is present in half the patients; dryness of the nasal mucosa, epistaxis, recurrent bronchitis, and pneumonitis are other symptoms. Manifestations of extraglandular disease are seen in one third of patients and include synovitis, pulmonary fibrosis, and peripheral neuropathy. In contrast to SLE, glomerular lesions are rare in Sjögren syndrome. Defects of tubular function, however, including renal tubular acidosis, uricosuria, and phosphaturia, often are seen and are associated with tubulointerstitial nephritis (Chapter


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Pathology_Robbins. in Sjögren syndrome. Defects of tubular function, however, including renal tubular acidosis, uricosuria, and phosphaturia, often are seen and are associated with tubulointerstitial nephritis (Chapter 14). About 60% of patients have another accompanying autoimmune disorder, such as rheumatoid arthritis.


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Pathology_Robbins. http://ebooksmedicine.net Fig. 5.27 Sjögrensyndrome.(A)Enlargementofthesalivarygland.(B)Intenselymphocyticandplasmacellinfiltrationwithductalepithelialhyperplasiainasalivarygland.(A,Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas,Texas. B,Courtesy of Dr. Dennis Burns,Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) Sjögrensyndromeisaninflammatorydiseasethatprimarilyaffectsthesalivaryandlacrimalglands,causingdrynessofthemouthandeyes. ThediseaseisbelievedtobecausedbyanautoimmuneT-cellreactionagainstanunknownselfantigenexpressedintheseglands,orimmunereactionsagainsttheantigensofavirusthatinfectsthetissues.


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Pathology_Robbins. ThediseaseisbelievedtobecausedbyanautoimmuneT-cellreactionagainstanunknownselfantigenexpressedintheseglands,orimmunereactionsagainsttheantigensofavirusthatinfectsthetissues. Systemic sclerosis is an immunologic disorder characterized by excessive fibrosis in multiple tissues, obliterative vascular disease, and evidence of autoimmunity, mainly the production of multiple autoantibodies. Although the term scleroderma is ingrained in clinical medicine, the name systemic sclerosis is preferred because excessive fibrosis is seen in multiple organs. Cutaneous involvement is the usual presenting manifestation and eventually appears in approximately 95% of cases, but it is the visceral involvement—of the gastrointestinal tract, lungs, kidneys, heart, and skeletal muscles—that is responsible for most of the morbidity and mortality. Disease limited to the skin is also called localized scleroderma. Systemic sclerosis is classified into two groups on the basis of its course:


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Pathology_Robbins. Systemic sclerosis is classified into two groups on the basis of its course: Diffuse systemic sclerosis, characterized by initial widespread skin involvement, with rapid progression and early visceral involvement Limited systemic sclerosis, with relatively mild skin involvement, often confined to the fingers and face. Involvement of the viscera occurs late, so the disease generally follows a fairly benign course. This presentation also is called CREST syndrome because of its frequent features of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. The cause of systemic sclerosis is not known, but the disease likely results from three interrelated processes— autoimmune responses, vascular damage, and collagen deposition ( Fig. 5.28


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Pathology_Robbins. The cause of systemic sclerosis is not known, but the disease likely results from three interrelated processes— autoimmune responses, vascular damage, and collagen deposition ( Fig. 5.28 Autoimmunity. It is proposed that CD4+ T cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that activate inflammatory cells and fibroblasts. Although inflammatory infiltrates in the affected skin typically are sparse, they include activated CD4+ TH2 cells. Several cytokines, including IL-13 produced by TH2 cells and TGF-β produced by macrophages and other cell types, stimulate synthesis of collagen and extracellular matrix proteins (e.g., fibronectin) in fibroblasts. Other cytokines recruit leukocytes and propagate the chronic inflammation.


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Pathology_Robbins. The presence of various autoantibodies, notably ANAs, provides diagnostic and prognostic information. It has been postulated that these antibodies stimulate fibrosis, but the evidence in support of this idea is not convincing.


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Pathology_Robbins. Vascular damage. Microvascular disease is consistently present early in the course of systemic sclerosis. Telltale signs of endothelial activation and injury and increased platelet activation have been noted. However, the cause of the vascular injury is not known; it could be the initiating event or the result of chronic inflammation, with mediators released by inflammatory cells inflicting damage on microvascular endothelium. Repeated cycles of endothelial injury followed by platelet aggregation lead to release of platelet and endothelial factors (e.g., PDGF, TGF-β) that trigger endothelial proliferation and intimal and perivascular fibrosis. Eventually, widespread narrowing of the microvasculature leads to ischemic injury and scarring. The pulmonary vasculature is frequently involved, and the resulting pulmonary hypertension is a serious complication of the disease.


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Pathology_Robbins. Fibrosis. The progressive fibrosis characteristic of the disease may be the culmination of multiple abnormalities, including the accumulation of alternatively http://ebooksmedicine.net EXTERNAL STIMULI? GENETIC SUSCEPTIBILITY EXTERNAL STIMULI?


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Pathology_Robbins. EXTERNAL STIMULI? GENETIC SUSCEPTIBILITY EXTERNAL STIMULI? Fig. 5.28 Amodelforthepathogenesisofsystemicsclerosis.Unknownexternalstimulicausevascularabnormalitiesandimmuneactivationingeneticallysusceptibleindividuals,andbothcontributetotheexcessivefibrosis.Endothelial injury Pulmonary arterial hypertension Synthesis of extracellular matrix proteins: fibrosis involving skin and parenchymal organs Ischemia, repair Proliferative and obliterative vasculopathy Tand B-cell activation Production of pro-fibrotic cytokines (e.g., TGF-˜, IL-13, PDGF) Autoantibodies T B activated macrophages, actions of fibrogenic cytokines produced by infiltrating leukocytes, hyperresponsiveness of fibroblasts to these cytokines, and scarring following ischemic damage caused by the vascular lesions. Studies with cultured fibroblasts from patients have suggested an intrinsic abnormality that causes the cells to produce excessive amounts of collagen.


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Pathology_Robbins. http://ebooksmedicine.net Fig. 5.29 Systemicsclerosis.(A)Normalskin.(B)Skinbiopsyfromapatientwithsystemicsclerosis.Notetheextensivedepositionofdensecollageninthedermis,thevirtualabsenceofappendages(e.g.,hairfollicles),andfociofinflammation(arrow). (C)Theextensivesubcutaneousfibrosishasvirtuallyimmobilizedthefingers,creatingaclawlikeflexiondeformity.Lossofbloodsupplyhasledtocutaneousulcerations.(C,Courtesy of Dr. Richard Sontheimer, Department of Dermatology,University of Texas Southwestern Medical School,Dallas,Texas.)


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Pathology_Robbins. Systemic sclerosis has a female-to-male ratio of 3:1 and a peak incidence in the 50to 60-year age group. Although systemic sclerosis shares features with SLE, rheumatoid arthritis (Chapter 21), and polymyositis (Chapter 22), it is distinguished by the striking cutaneous changes, notably skin thickening. Raynaud phenomenon, caused by episodic vasoconstriction of the arteries and arterioles of the extremities, is seen in virtually all patients and precedes other symptoms in 70% of cases. Progressive collagen deposition in the skin leads to increasing stiffness, especially of the hands, with eventually complete immobilization of the joints. Nailfold capillary loops are distorted early in the disease, and later disappear. Dysphagia attributable to esophageal fibrosis and its resultant hypomotility are present in more than 50% of patients. Eventually, destruction of the esophageal wall leads to atony and dilation, especially at its lower end. Abdominal pain, intestinal obstruction, or


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Pathology_Robbins. are present in more than 50% of patients. Eventually, destruction of the esophageal wall leads to atony and dilation, especially at its lower end. Abdominal pain, intestinal obstruction, or malabsorption syndrome reflect involvement of the small intestine. Respiratory difficulties caused by the pulmonary fibrosis may result in right-sided cardiac dysfunction, and myocardial fibrosis may cause either arrhythmias or cardiac failure. Mild proteinuria occurs in as many as 30% of patients, but rarely is severe enough to cause nephrotic syndrome. The most ominous manifestation is malignant hypertension, with the subsequent development of fatal renal failure (Chapter 14), but in its absence progression of the disease may be slow. In most patients the disease pursues a steady downhill course over the span of many years, although life span is improving with better treatment of the complications. The disease tends to be more severe in blacks, especially black women. As treatment of the renal


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Pathology_Robbins. the span of many years, although life span is improving with better treatment of the complications. The disease tends to be more severe in blacks, especially black women. As treatment of the renal complications has improved, pulmonary and cardiac complications have become the major cause of death.


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Pathology_Robbins. Virtually all patients have ANAs that react with a variety of nuclear antigens (see Table 5.11 ). Two ANAs are strongly associated with systemic sclerosis. One directed against DNA topoisomerase I (anti-Scl 70) is highly specific and is associated with a greater likelihood of pulmonary fibrosis and peripheral vascular disease. The other, an anticentromere antibody, is associated with a higher likelihood of CREST syndrome. Patients with this syndrome have relatively limited skin disease, often confined to fingers, forearms and face, and subcutaneous calcifications. Involvement of the viscera, including esophageal lesions, pulmonary hypertension, and biliary cirrhosis, may not occur at all or occur late. In general, these patients live longer than those with systemic sclerosis with diffuse visceral involvement from the outset. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Systemicsclerosis(commonlycalledscleroderma)ischaracterizedbyprogressivefibrosisinvolvingtheskin,gastrointestinaltract,andothertissues. FibrosismaybetheresultofactivationoffibroblastsbycytokinesproducedbyTcells,butwhattriggersTcellresponsesisunknown. Endothelialinjuryandmicrovasculardiseasearecommonlypresentinthelesionsofsystemicsclerosis,perhapscausingchronicischemia,butthepathogenesisofvascularinjuryisnotknown. Inflammatory myopathies comprise an uncommon, heterogeneous group of disorders characterized by injury and inflammation of mainly the skeletal muscles that are probably immunologically mediated. Based on clinical, morphologic, and immunologic features, three disorders— polymyositis, dermatomyositis, and inclusion body myositis—have been described. Each may occur alone or with other immune-mediated diseases, particularly systemic sclerosis. These diseases are described in Chapter 22.


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Pathology_Robbins. Mixed connective tissue disease is a disorder with clinical features that overlap those of SLE, systemic sclerosis, and polymyositis. The disease is characterized serologically by high titers of antibodies to U1 ribonucleoprotein. Typically, it presents with synovitis of the fingers, Raynaud phenomenon, and mild myositis. Renal involvement is modest, and there is a favorable response to corticosteroids, at least in the short term. Because these clinical features are shared with other diseases, mixed connective tissue disease may not be a distinct entity, and in fact it may evolve over time into classic SLE or systemic sclerosis. However, progression to other autoimmune disorders is not universal, and there may be a form of mixed connective tissue disease that is distinct from other autoimmune diseases. Serious complications of mixed connective tissue disease include pulmonary hypertension, interstitial lung disease, and renal disease.


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Pathology_Robbins. Polyarteritis nodosa belongs to a group of disorders characterized by necrotizing inflammation of the walls of blood vessels that show strong evidence of an immunologic basis. Any type of vessel may be involved—arteries, arterioles, veins, or capillaries. These vasculitides are discussed in Chapter 10. IgG4-related disease (IgG4-RD) is a newly recognized constellation of fibro-inflammatory disorders characterized by tissue infiltrates rich in IgG4 antibody-producing plasma cells and lymphocytes, particularly T cells, associated with fibrosis and obliterative phlebitis (


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Pathology_Robbins. Fig. 5.30 ). The disorder is often, but not always, associated with elevated serum IgG4 concentrations. Increased numbers of IgG4-producing plasma cells in tissue are a sine qua non of this disorder. IgG4-related disease has now been described in virtually every organ system, including the biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin. Many conditions long viewed as disorders of single organs are now part of the IgG4-RD spectrum. These include Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal glands), Riedel thyroiditis, idiopathic retroperitoneal fibrosis, autoimmune pancreatitis, and inflammatory pseudotumors of the orbit, lungs, and kidneys, to name a few. The disease most often affects middle-aged and older men.


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Pathology_Robbins. The pathogenesis of this condition is not understood, and although IgG4 production in lesions is a hallmark of the disease, it is not known if this antibody type contributes to the pathology. The key role of B cells is supported by clinical trials in which depletion of B cells by anti–B-cell reagents such as rituximab provided clinical benefit. A major barrier to transplantation is the process of rejection, in which the recipient’s immune system recognizes the graft as foreign and attacks it. The key to successful transplantation has been the development of therapies that prevent or minimize rejection. Transplant rejection is discussed here because it involves several of the immunologic reactions that underlie immune-mediated inflammatory diseases. Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react against and destroy the grafts. We next discuss how this occurs. Recognition of Graft Alloantigens


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Pathology_Robbins. The major antigenic differences between a donor and recipient that result in rejection of transplants are differences in HLA alleles. Grafts exchanged between individuals of the same species are called allografts. Because HLA genes are highly polymorphic, there are always some differences between individuals (except, of course, identical twins). Following transplantation, the recipient’s T cells recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways. The graft antigens are either presented directly to recipient T cells by graft APCs, or the graft antigens are picked up by host APCs, processed (like any other foreign antigen), and presented to host T cells. These are called the direct and indirect pathways of recognition of alloantigens. Both lead to the activation of CD8+ T cells, which develop into CTLs, and CD4+ T cells, which become cytokine-producing effector cells, mainly TH1 cells. We do not know the relative importance of these


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Pathology_Robbins. lead to the activation of CD8+ T cells, which develop into CTLs, and CD4+ T cells, which become cytokine-producing effector cells, mainly TH1 cells. We do not know the relative importance of these pathways in the rejection of allografts. The direct pathway may be most important for CTL-mediated acute rejection, and the indirect pathway may play a greater role in chronic rejection, described later.


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Pathology_Robbins. http://ebooksmedicine.net A 1.0 cm B C D Fig. 5.30 IgG4-relateddisease:representativelesions.(A)Bileductshowingsclerosingcholangitis.(B)Scleroticareaofthebileductwithstoriformfibrosis.(C)Submandibularglandwithinfiltratesoflymphocytesandplasmacellsandwhorlsoffibrosis.(D)SectionofaninvolvedlacrimalglandstainedwithanantibodyagainstIgG4,showinglargenumbersofIgG4-producingplasmacells.(From Kamisawa T,Zen Y,Pillai S,et al:IgG4-related disease. Lancet385:1460, 2015.) The frequency of T cells that can recognize the foreign antigens in a graft is much higher than the frequency of T cells specific for any microbe. For this reason, immune responses to allografts are stronger than responses to pathogens. Predictably, these strong reactions can destroy grafts rapidly, and their control requires powerful immunosuppressive agents. Mechanisms of Graft Rejection


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Pathology_Robbins. Mechanisms of Graft Rejection Graft rejection is classified into hyperacute, acute, and chronic, on the basis of clinical and pathologic features. This classification was devised by nephrologists and pathologists based on rejection of kidney allografts, and has stood the test of time remarkably well. Each type of rejection is mediated by a particular kind of immune response. In the following discussion, the description of the morphology of rejection is limited to kidney allografts, but similar changes are seen in other organ transplants.


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Pathology_Robbins. • Hyperacute rejection is mediated by preformed antibodies specific for antigens on graft endothelial cells. The preformed antibodies may be natural IgM antibodies specific for blood group antigens, or may be antibodies specific for allogeneic MHC molecules that were induced by prior exposure through blood transfusions, pregnancy, or organ transplantation. Immediately after the graft is implanted and blood flow is restored, the antibodies bind to antigens on the graft http://ebooksmedicine.net Blood vessel Endothelial cell Circulating alloantigen-specific antibody Complement activation, endothelial damage, inflammation and thrombosis Alloantigen (e.g., blood group antigen) Fig. 5.31 Hyperacuterejection.(A)Depositionofantibodyonendotheliumandactivationofcomplementcausesthrombosis.(B)Hyperacuterejectionofakidneyallograftshowingplateletfibrinthrombiandsevereischemicinjuryinaglomerulus.


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Pathology_Robbins. endothelium and activate the complement and clotting systems, leading to endothelial injury, thrombus for mation, and ischemic necrosis of the graft (Fig. 5.31A ). Hyperacute rejection is not a common problem, because every donor and recipient are matched for blood type and potential recipients are tested for antibodies against the cells of the prospective donor, a test called a cross-match. MORPHOLOGYInhyperacuterejection,theaffectedkidneyrapidlybecomescyanotic,mottled,andanuric.Virtuallyallarteriolesandarteriesexhibitacutefibrinoidnecrosisoftheirwallsandnarrowingorcompleteocclusionoftheirlumensbythrombi( Fig.5.31B ).Neutrophilsrapidlyaccumulatewithinarterioles,glomeruli,andperitubularcapillaries.Asthesechangesintensifyandbecomediffuse,theglomerularcapillariesalsoundergothromboticocclusion,andeventuallythekidneycortexundergoesoutrightnecrosis(infarction).Affectedkidneysarenonfunctionalandhavetoberemoved.


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Pathology_Robbins. • Acute rejection is mediated by T cells and antibodies that are activated by alloantigens in the graft. It occurs within days or weeks after transplantation, and is the principal cause of early graft failure. It also may appear suddenly months or even years later, after immunosuppression is tapered or terminated. Based on the role of T cells or antibodies, acute rejection is divided into two types, although in most rejecting grafts, both patterns are present. In acute cellular rejection, CD8+ CTLs may directly destroy graft cells, or CD4+ cells secrete cytokines and induce inflammation, which damages the graft ( Fig. 5.32A ). T cells also may react against graft vessels, leading to vascular damage. Current immunosuppressive therapy is designed mainly to prevent and reduce acute rejection by blocking the activation of alloreactive T cells. MORPHOLOGYAcutecellular(Tcell-mediated)rejectionmayproducetwodifferentpatternsofinjury.


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Pathology_Robbins. MORPHOLOGYAcutecellular(Tcell-mediated)rejectionmayproducetwodifferentpatternsofinjury. Inthetubulointerstitial pattern (sometimescalledtypeI),thereisextensiveinterstitialinflammationandtubularinflammation(tubulitis)associatedwithfocaltubularinjury( Fig.5.32B ).Asmightbeexpected,theinflammatoryinfiltratescontainactivatedCD4+ andCD8+ Tlymphocytes. Fig.5.32C )andsometimesnecrosisofvesselwalls(typeIII).Theaffectedvesselshaveswollenendothelialcells,andatplaceslymphocytesareseenbetweentheendotheliumandthevesselwall,afindingtermedendotheliitis orintimal arteritis.Therecognitionofcellularrejectionisimportantbecause,intheabsenceofaccompanyinghumoralrejection,mostpatientsrespondwelltoimmunosuppressivetherapy. In acute antibody-mediated (vascular or humoral) rejection, antibodies bind to vascular endothelium and activate complement via the classical pathway ( Fig. 5.33A ). The resultant inflammation and endothelial damage cause graft failure.


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Pathology_Robbins. Fig. 5.33A ). The resultant inflammation and endothelial damage cause graft failure. MORPHOLOGYAcuteantibody-mediatedrejectionismanifestedmainlybydamagetoglomeruliandsmallbloodvessels.Typically,thereisinflammationofglomeruliandperitubularcapillaries( Fig.5.33B )associatedwithdepositionofcomplementproducts,whichisduetoactivationofthecomplementsystembytheantibody-dependentclassicalpathway( Fig.5.33C ).Smallvesselsalsomayshowfocalthrombosis. • Chronic rejection is an indolent form of graft damage that occurs over months or years, leading to progressive loss of graft function. Chronic rejection manifests http://ebooksmedicine.net Recruitment of macrophages and neutrophils


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Pathology_Robbins. Fig. 5.32 Acute cellular rejection. (A) Destruction of graft cells by T cells. Acute T cell–mediated rejection involves direct killing of graft cells by CD8+ CTLs and inflammation caused by cytokines produced by CD4 T cells. (B) Acute cellular rejection of a kidney graft, manifested by inflammatory cells in the interstitium and between epithelial cells of the tubules (tubulitis). Collapsed tubules are outlined by wavy basement membranes. (C) Rejection vasculitis in a kidney graft. An arteriole is shown with inflammatory cells attacking and undermining the endothelium (endotheliitis) (arrow). (Courtesy of Drs. Zoltan Laszik and Kuang-Yu Jen, Department of Pathology, University of California, San Francisco, California.) as interstitial fibrosis and gradual narrowing of graft blood vessels (graft arteriosclerosis). In both lesions, the culprits are believed to be T cells that react against graft alloantigens and secrete cytokines, which stimulate the proliferation and activities of


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Pathology_Robbins. (graft arteriosclerosis). In both lesions, the culprits are believed to be T cells that react against graft alloantigens and secrete cytokines, which stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft (


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Pathology_Robbins. Fig. 5.34A ). Alloantibodies also contribute to chronic rejection. Although treatments to prevent or curtail acute rejection have steadily improved, leading to longer than 1-year survival of transplants, chronic rejection is refractory to most therapies and is becoming the principal cause of graft failure. Chronic rejection is dominated by vascular changes, often with intimal thickening and vascular occlusion ( Fig. 5.34B ). Chronically rejecting kidney grafts show glomerulopathy, with duplication of the basement membrane, likely secondary to chronic endothelial injury ( Fig. 5.34C ) and peritubular capillaritis with multilayering of peritubular capillary basement membranes. Interstitial fibrosis and tubular atrophy with loss of renal parenchyma may occur secondary to the vascular lesions ( Fig. 5.34D ). Interstitial mononuclear cell infiltrates are typically sparse. Methods of Increasing Graft Survival


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Pathology_Robbins. Fig. 5.34D ). Interstitial mononuclear cell infiltrates are typically sparse. Methods of Increasing Graft Survival Because HLA molecules are the major targets in transplant rejection, better matching of the donor and the recipient improves graft survival. HLA matching is more beneficial for living related kidney transplants than for other kinds of transplants, and survival improves with increasing number of loci matched. However, as drugs for immunosuppression have improved, HLA matching is no longer done for heart, lung, liver, and islet transplantation; in such instances, the recipient often needs a transplant urgently and other considerations, such as anatomic compatibility, are of greater importance.


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Pathology_Robbins. Immunosuppression of the recipient is a necessity in all organ transplantation, except in the case of identical twins. At present, drugs such as cyclosporine, the related FK506, mofetil mycophenolate (MMF), rapamycin, azathioprine, corticosteroids, anti-thymocyte globulin, and monoclonal antibodies (e.g., monoclonal anti-CD3) are used. Cyclosporine and FK506 suppress T cell–mediated immunity by inhibiting transcription of cytokine genes, in particular, the gene for IL-2. Although immunosuppression has made transplantation of many organs feasible, it has its own problems. Suppression of the immune system results in increased susceptibility to opportunistic fungal, viral, and other infections. Reactivation of latent viruses, such as cytomegalovirus (CMV) and polyoma virus, are frequent complications. Immunosuppressed patients also are at increased risk for developing virus-induced tumors, such as Epstein-Barr virus (EBV)–induced lymphomas and human papillomavirus (HPV)–induced squamous


Pathology_Robbins

Pathology_Robbins. Immunosuppressed patients also are at increased risk for developing virus-induced tumors, such as Epstein-Barr virus (EBV)–induced lymphomas and human papillomavirus (HPV)–induced squamous cell carcinomas. To circumvent the untoward effects of immunosuppression, much effort is being devoted to induce donor-specific tolerance in host T cells. One strategy is to prevent host T cells from receiving costimulatory signals from donor DCs during the initial phase of sensitization. This can be accomplished by administration of agents that block the interaction of the B7 molecules on the DCs of the graft and the CD28 receptor on host T cells, which, by interrupting the second signal for T cell activation, induces either T cell apoptosis or anergy. Other approaches include injecting into recipients regulatory T cells enriched for cells specific for donor alloantigens; these trials are in their infancy.


Pathology_Robbins

Pathology_Robbins. Fig. 5.33 Acuteantibody-mediated(humoral)rejection.(A)Graftdamagecausedbyantibodydepositioninvessels.(B)Lightmicrographshowinginflammation(capillaritis)inperitubularcapillaries(arrows) inakidneygraft.(C)ImmunoperoxidasestainshowsC4ddepositioninperitubularcapillariesandaglomerulus.(Courtesy of Dr. Zoltan Laszik, Department of Pathology, University of California, San Francisco, California.)


Pathology_Robbins

Pathology_Robbins. Use of hematopoietic stem cell (HSC) transplants for hematologic malignancies, bone marrow failure syndromes (such as aplastic anemia), and disorders caused by inherited HSC defects (such as sickle cell anemia, thalassemia, and immunodeficiency states) is increasing in number each year. Transplantation of genetically “reengineered” hematopoietic stem cells obtained from affected patients may be useful in treating inherited forms of immunodeficiency. Historically, HSCs were obtained from the bone marrow, but now they usually are harvested from peripheral blood after they are mobilized from the bone marrow by administration of hematopoietic growth factors, or from the umbilical cord blood of newborn infants, a rich source of HSCs. In most of the conditions in which HSC transplantation is indicated, the recipient is irradiated or treated with chemotherapy to destroy the immune system (and sometimes, cancer cells) and to “open up” niches in the micro-environment of the marrow that nurture


Pathology_Robbins

Pathology_Robbins. the recipient is irradiated or treated with chemotherapy to destroy the immune system (and sometimes, cancer cells) and to “open up” niches in the micro-environment of the marrow that nurture HSCs, thus allowing the transplanted HSCs to engraft. Two major problems complicate this form of transplantation and distinguish it from solid organ transplants: graft-versus-host disease and immune deficiency.


Pathology_Robbins

Pathology_Robbins. GVHD occurs when immunologically competent cells or their precursors are transplanted into immunologically crippled recipients, and the transferred cells recognize alloantigens in the host and attack host tissues. It is seen most commonly in the setting of HSC transplantation but, rarely, may occur following transplantation of solid organs rich in lymphoid cells (e.g., the liver). On receiving allogeneic HSCs, an immunologically compromised host cannot reject the graft, but T cells present in the http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 5.34 Chronic rejection. (A) Graft arteriosclerosis caused by T-cell cytokines and antibody deposition. (B) Graft arteriosclerosis in a cardiac transplant. (C) Transplant glomerulopathy, the characteristic manifestation of chronic antibody-mediated rejection in the kidney. The glomerulus shows inflammatory cells within the capillary loops (glomerulitis), accumulation of mesangial matrix, and duplication of the capillary basement membrane. (D) Interstitial fibrosis and tubular atrophy, resulting from arteriosclerosis of arteries and arterioles in a chronically rejecting kidney allograft. In this trichrome stain, the blue area (asterisk) shows fibrosis, contrasted with the normal kidney (top right). An artery showing prominent arteriosclerosis is shown (bottom right). (B, Courtesy of Dr. Richard Mitchell, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts. C and D, Courtesy of Dr. Zoltan Laszik, Department of Pathology, University of California, San


Pathology_Robbins

Pathology_Robbins. of Dr. Richard Mitchell, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts. C and D, Courtesy of Dr. Zoltan Laszik, Department of Pathology, University of California, San Francisco, California.) donor graft perceive the host’s tissue as foreign and react There are two forms of GVHD. against it. This results in the activation of donor CD4+ and • Acute GVHD (occurring days to weeks after transplanCD8+ T cells, ultimately causing inflammation and killing tation) causes epithelial cell necrosis in three principal recipient cells. To try to minimize GVHD, HSC transplants target organs: liver, skin, and gut. Destruction of small are done between donor and recipient that are carefully bile ducts gives rise to jaundice, and mucosal ulcerHLA-matched using precise DNA sequencing–based ation of the gut results in bloody diarrhea. Cutanemethods. ous involvement (


Pathology_Robbins

Pathology_Robbins. Fig. 5.35 ) manifests as a rash, which Fig. 5.35 Acute graft-versus-host disease (GVHD) involving the skin. (A) Patchy epithelial cell death and dermal infiltrates of mononuclear cells (lymphocytes and macrophages). (B) Focally dead epithelial cells (arrows). characteristically appears first on the neck, ears, and palms of the hands and soles of the feet and then becomes generalized. • Chronic GVHD may follow the acute syndrome or may occur insidiously. Patients develop skin lesions resembling those of systemic sclerosis (discussed earlier) and manifestations mimicking other autoimmune disorders.


Pathology_Robbins

Pathology_Robbins. Because GVHD is mediated by T lymphocytes contained in the transplanted donor cells, depletion of donor T cells before transplantation virtually eliminates the disease. This approach, however, has proven to be a mixed blessing: GVHD is ameliorated, but the recurrence of tumor in leukemic patients as well as the incidence of graft failures and EBV-related B-cell lymphoma increase. It seems that the multifaceted T cells not only mediate GVHD but also are required for engraftment of the transplanted HSCs, suppression of EBV-infected B-cell clones, and control of leukemia cells.


Pathology_Robbins

Pathology_Robbins. These are often of prolonged duration in recipients of HSC transplants. Among the many reasons for this impairment is the slow reconstitution of the adaptive immune system (derived from donor HSC), after the recipient’s immune system is destroyed or suppressed to allow the graft to take. During the many months that may be needed for immune reconstitution, recipients are susceptible to a variety of infections, mostly with viruses, such as CMV and EBV. RejectionofsolidorgantransplantsisinitiatedmainlybyhostTcellsthatrecognizetheforeignHLAantigensofthegraft,eitherdirectly(onAPCsinthegraft)orindirectly(afteruptakeandpresentationbyhostAPCs). Typesandmechanismsofrejectionofsolidorgangraftsareasfollows: Hyperacute rejection: Preformedanti-donorantibodiesbindtograftendotheliumimmediatelyaftertransplantation,leadingtothrombosis,ischemicdamage,andrapidgraftfailure. Acute cellular rejection: Tcellsdestroygraftparenchyma(andvessels)bycytotoxicityandinflammatoryreactions.


Pathology_Robbins

Pathology_Robbins. Acute cellular rejection: Tcellsdestroygraftparenchyma(andvessels)bycytotoxicityandinflammatoryreactions. Acute antibody-mediated (humoral) rejection:Antibodiesdamagegraftvasculature. Chronic rejection: Dominatedbyarteriosclerosis,thistypeiscausedbyTcellactivationandantibodies.TheTcellsmaysecretecytokinesthatinduceproliferationofvascularsmoothmusclecells,andtheantibodiescauseendothelialinjury.ThevascularlesionsandTcellreactionscauseparenchymalfibrosis. Treatmentofgraftrejectionreliesonimmunosuppressivedrugs,whichinhibitimmuneresponsesagainstthegraft. Transplantationofhematopoieticstemcells(HSCs)requirescarefulmatchingofdonorandrecipientandisoftencomplicatedbygraft-vs-hostdisease(GVHD)andimmunedeficiency.


Pathology_Robbins

Pathology_Robbins. Transplantationofhematopoieticstemcells(HSCs)requirescarefulmatchingofdonorandrecipientandisoftencomplicatedbygraft-vs-hostdisease(GVHD)andimmunedeficiency. Immune deficiencies can be divided into primary (or congenital) immunodeficiency disorders, which are genetically determined, and secondary (or acquired) immunodeficiencies, which may arise as complications of cancers, infections, malnutrition, or side effects of immunosuppression, irradiation, or chemotherapy for cancer and other diseases.


Pathology_Robbins

Pathology_Robbins. Immunodeficiencies are manifested clinically by increased infections, which may be newly acquired or reactivation of latent infections. The primary immunodeficiency syndromes are accidents of nature that provide valuable insights into some of the molecules critical in the development of the immune system. Paradoxically, several immunodeficiencies also are associated with autoimmune disorders, perhaps because the deficiency results in loss of regulatory mechanisms or persistence of infections that promote autoimmunity. Here we briefly discuss the more important and best-defined primary immunodeficiencies, to be followed by a more detailed description of acquired immunodeficiency syndrome (AIDS), the most devastating example of secondary immunodeficiency.


Pathology_Robbins

Pathology_Robbins. Primary immunodeficiency diseases are inherited genetic disorders that impair mechanisms of innate immunity (phagocytes, NK cells, or complement) or the humoral and/or cellular arms of adaptive immunity (mediated by B lymphocytes and T lymphocytes, respectively). These immunodeficiencies are usually detected in infancy, between 6 months and 2 years of age, the telltale signs being susceptibility to recurrent infections. With advances in genetic analyses, the mutations responsible for many of these diseases are now known ( Fig. 5.36). Here we present selected examples of immunodeficiencies, beginning with the more common defects in the maturation and activation of B lymphocytes and T lymphocytes, followed by disorders of innate immunity.


Pathology_Robbins

Pathology_Robbins. Severe combined immunodeficiency (SCID) spans a constellation of genetically distinct syndromes, all having in common impaired development of mature T lymphocytes and/or B lymphocytes and defects in both humoral and cell-mediated immunity. Affected infants present with thrush (oral candidiasis), severe diaper rash, and failure to thrive. Some infants develop a generalized rash shortly after birth because maternal T cells are transferred across the placenta and attack the fetus, causing GVHD. Children with SCID are extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, Pneumocystis jiroveci, Pseudomonas, cytomegalovirus, varicella, and a whole host of bacteria. Without HSC transplantation, death occurs within the first year of life. The overall prevalence of the disease is approximately 1 in 65,000 to 1 in 100,000, but it is 20 to 30 times more frequent in some Native American populations.


Pathology_Robbins

Pathology_Robbins. Despite the common clinical manifestations, of different forms of SCID the underlying defects are quite varied. http://ebooksmedicine.net Fig. 5.36 Primary immune deficiency diseases. Shown are the principal pathways of lymphocyte development and the blocks in these pathways in selected primary immune deficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA, Adenosine deaminase; CD40L, CD40 ligand (also known as CD154); CVID, common variable immunodeficiency; SCID, severe combined immunodeficiency. Often, the defect resides in the T-cell compartment, with a secondary impairment of humoral immunity. Two major forms are described next.


Pathology_Robbins

Pathology_Robbins. Often, the defect resides in the T-cell compartment, with a secondary impairment of humoral immunity. Two major forms are described next. X-linked SCID. Approximately half of the cases of SCID are X-linked; these are caused by mutations in the gene encoding the common γ (γc) chain shared by the receptors for the cytokines IL-2, IL-4, IL-7, IL-9, and IL-15. Of these cytokines, defective IL-7 signaling is the most important underlying basis of SCID because this cytokine is responsible for stimulating the survival and expansion of immature B and T cell precursors in the generative lymphoid organs.


Pathology_Robbins

Pathology_Robbins. Autosomal recessive SCID. Another 40% to 50% of SCID cases follow autosomal recessive pattern of inheritance, with approximately half of these caused by mutations in adenosine deaminase (ADA), an enzyme involved in purine metabolism. ADA deficiency results in accumulation of adenosine and deoxyadenosine triphosphate metabolites, which inhibit DNA synthesis and are toxic to lymphocytes. Other autosomal recessive forms of SCID result variously from defects in another purine metabolic pathway, primary failure of class II MHC expression, or mutations in genes encoding the recombinase responsible for the rearrangement of lymphocyte antigen-receptor genes.


Pathology_Robbins

Pathology_Robbins. The histologic findings in SCID depend on the underlying defect. In the two most common forms (γc mutation and ADA deficiency), the thymus is small and devoid of lymphoid cells. In X-linked SCID, the thymus contains lobules of undifferentiated epithelial cells resembling fetal thymus, whereas in SCID caused by ADA deficiency, remnants of Hassall’s corpuscles can be found. In both diseases, other lymphoid tissues are hypoplastic as well, with marked depletion of T cell areas and in some cases both T cell and B cell zones.


Pathology_Robbins

Pathology_Robbins. Currently, HSC transplantation is the mainstay of treatment. X-linked SCID is the first disease in which gene therapy has been successful. For gene therapy, a normal γc gene is expressed using a viral vector in HSCs taken from patients, and the cells are then transplanted back into the patients. The clinical experience is small, but some patients have shown reconstitution of their immune systems for several years after therapy. Unfortunately, however, about 20% of patients receiving a first-generation viral vector developed T cell acute lymphoblastic leukemia (T-ALL), highlighting the dangers of this particular approach to gene therapy. The uncontrolled T-cell proliferation is likely the result of the virus integrating into the genome close to an oncogene, leading to the activation of the oncogene, and possibly also because of the growth advantage conferred by the introduced normal γc gene. Current trials are using new vectors with safety features built in. Patients with ADA


Pathology_Robbins

Pathology_Robbins. of the oncogene, and possibly also because of the growth advantage conferred by the introduced normal γc gene. Current trials are using new vectors with safety features built in. Patients with ADA deficiency also have been treated with HSC transplantation and, more recently, with administration of the enzyme or gene therapy involving the introduction of a normal ADA gene into T-cell precursors.


Pathology_Robbins

Pathology_Robbins. X-linked agammaglobulinemia (XLA), or Bruton disease, is characterized by the failure of pre–B cells to differentiate into mature B cells and, as the name implies, a resultant absence of antibodies (gamma globulin) in the blood.


Pathology_Robbins

Pathology_Robbins. It is one of the more common forms of primary immunodeficiency, occurring at a frequency of about 1 in 100,000 male infants. During normal B-cell maturation, immunoglobulin (Ig) heavy chain genes are rearranged first, followed by light chain genes. At each stage, signals are received from the expressed components of the antigen receptor that drive maturation to the next stage; these signals act as quality controls, to ensure that the correct receptor proteins are being produced. In XLA, B-cell maturation stops after the initial heavy chain gene rearrangement because of mutations in a tyrosine kinase that is associated with the pre–B-cell receptor and is involved in pre-B-cell signal transduction. This kinase is called Bruton tyrosine kinase (BTK). When BTK is nonfunctional, the pre– B-cell receptor cannot signal the cells to proceed along the maturation pathway. As a result, Ig light chains are not produced, and the complete Ig molecule containing heavy and light chains cannot be


Pathology_Robbins

Pathology_Robbins. receptor cannot signal the cells to proceed along the maturation pathway. As a result, Ig light chains are not produced, and the complete Ig molecule containing heavy and light chains cannot be assembled and transported to the cell membrane, although free heavy chains can be found in the cytoplasm. Because the BTK gene is on the X chromosome, the disorder is only seen in males. Sporadic cases with the same features have been described in females, possibly due to mutations in other genes that function in the same pathway.


Pathology_Robbins

Pathology_Robbins. Classically, the disease is characterized by a profound reduction in the number of B cells in the blood and secondary lymphoid organs and an absence of germinal centers and plasma cells in these organs. T-cell numbers and responses may be normal.


Pathology_Robbins

Pathology_Robbins. The disease usually does not become apparent until about 6 months of age, as maternal antibodies that were transported via the placenta are depleted. In most cases, recurrent bacterial infections of the respiratory tract, such as acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia, call attention to the underlying immune defect. Almost always, the causative organisms are Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus, organisms that are normally opsonized by antibodies and cleared by phagocytosis. Because antibodies are important for neutralizing certain infectious viruses, individuals with this disease also are susceptible to some viral infections, especially those caused by enteroviruses. These viruses infect the gastrointestinal tract, and from there they can disseminate to the nervous system via the blood. Thus, immunization with live poliovirus carries the risk for paralytic poliomyelitis, and infections with echovirus can


Pathology_Robbins

Pathology_Robbins. tract, and from there they can disseminate to the nervous system via the blood. Thus, immunization with live poliovirus carries the risk for paralytic poliomyelitis, and infections with echovirus can cause fatal encephalitis. For similar reasons, Giardia lamblia, an intestinal protozoan that is normally resisted by secreted IgA, causes persistent infections in individuals with this disorder. Many intracellular viral, fungal, and protozoal infections are handled quite well by the intact T cell–mediated immunity. For unclear reasons, autoimmune diseases (such as rheumatoid arthritis and dermatomyositis) occur in as many as 35% of patients with this disease.


Pathology_Robbins

Pathology_Robbins. The treatment of X-linked agammaglobulinemia is replacement therapy with intravenous immunoglobulin (IVIG) from pooled human serum. DiGeorge syndrome is caused by a congenital defect in thymic development resulting in deficient T-cell maturation. T cells are absent in the lymph nodes, spleen, and peripheral blood, and infants with this defect are extremely vulnerable to viral, fungal, and protozoal infections. Patients also are susceptible to infection with intracellular bacteria, because of defective T cell–mediated immunity. B cells and serum immunoglobulins are generally unaffected.


Pathology_Robbins

Pathology_Robbins. The disorder is a consequence of a developmental malformation affecting the third and fourth pharyngeal pouches, structures that give rise to the thymus, parathyroid glands, and portions of the face and aortic arch. Thus, in addition to the thymic and T-cell defects, there may be parathyroid gland hypoplasia, resulting in hypocalcemic tetany, as well as additional midline developmental abnormalities. In 90% of cases of DiGeorge syndrome, there is a deletion affecting chromosomal region 22q11, discussed in Chapter 7. Transplantation of thymic tissue has successfully treated some affected infants. In patients with partial defects, immunity may improve spontaneously with age.


Pathology_Robbins

Pathology_Robbins. This disease is characterized by the production of normal (or even supranormal) levels of IgM antibodies and decreased levels of the IgG, IgA, and IgE isotypes; the underlying defect is an inability of T cells to activate B cells. As discussed earlier, many of the functions of CD4+ helper T cells require the engagement of CD40 on B cells, macrophages, and dendritic cells by CD40L (also called CD154) expressed on antigen-activated T cells. This interaction triggers Ig class switching and affinity maturation in the B cells, and stimulates the microbicidal functions of macrophages. Approximately 70% of individuals with hyper-IgM syndrome have the X-linked form of the disease, caused by mutations in the gene encoding CD40L located on Xq26. In the remaining patients, the disease is inherited in an autosomal recessive pattern caused by loss-offunction mutations involving either CD40 or an enzyme called activation-induced cytidine deaminase (AID), a DNA-editing enzyme that is required for Ig


Pathology_Robbins

Pathology_Robbins. an autosomal recessive pattern caused by loss-offunction mutations involving either CD40 or an enzyme called activation-induced cytidine deaminase (AID), a DNA-editing enzyme that is required for Ig class switching and affinity maturation.


Pathology_Robbins

Pathology_Robbins. Patients present with recurrent pyogenic infections because of low levels of opsonizing IgG antibodies. Those with CD40L mutations also are susceptible to pneumonia caused by the intracellular organism Pneumocystis jiroveci, because CD40L-mediated macrophage activation, a key reaction of cell-mediated immunity, is compromised. Occasionally, the IgM antibodies react with blood cells, giving rise to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. In older patients, there may be a proliferation of IgM-producing plasma cells that infiltrate the mucosa of the gastrointestinal tract. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net This relatively frequent but poorly defined entity encompasses a heterogeneous group of disorders in which the common feature is hypogammaglobulinemia, generally affecting all the antibody classes but sometimes only IgG. The diagnosis of common variable immunodeficiency is based on exclusion of other well-defined causes of decreased antibody production. The estimated prevalence of the disease is about 1 in 50,000.


Pathology_Robbins

Pathology_Robbins. Although most patients have normal numbers of mature B cells, plasma cells are absent, suggesting a block in B-cell differentiation. In keeping with this idea, B cell areas of the lymphoid tissues (i.e., lymphoid follicles in nodes, spleen, and gut) tend to be hyperplastic. The enlargement of B cell areas may reflect incomplete activation, such that B cells can proliferate in response to antigen but do not differentiate into antibody-producing plasma cells. The defective antibody production has been variably attributed to intrinsic B-cell defects, deficient T-cell help, or excessive T-cell suppressive activity. Paradoxically, these patients are prone to develop a variety of autoimmune disorders (hemolytic anemia, pernicious anemia) as well as lymphoid tumors. Common variable immunodeficiency may be genetic or acquired. Different genetic causes have been discovered, including mutations in a receptor for BAFF, a cytokine that promotes the survival and differentiation of B cells, and in


Pathology_Robbins

Pathology_Robbins. may be genetic or acquired. Different genetic causes have been discovered, including mutations in a receptor for BAFF, a cytokine that promotes the survival and differentiation of B cells, and in a molecule called ICOS (inducible costimulator), a homologue of CD28 that contributes to the function of T follicular helper cells. However, in the majority of cases, the genetic basis is unknown.


Pathology_Robbins

Pathology_Robbins. Patients typically present with recurrent sinopulmonary bacterial infections. About 20% of patients have recurrent herpesvirus infections, and serious enterovirus infections causing meningoencephalitis also may occur. Individuals with this disorder also are prone to the development of persistent diarrhea caused by G. lamblia. In contrast to X-linked agammaglobulinemia, common variable immunodeficiency affects both sexes equally, and the onset of symptoms is later, in childhood or adolescence. As in X-linked agammaglobulinemia, these patients have a high frequency of autoimmune diseases (approximately 20%), including rheumatoid arthritis. The risk for lymphoid malignancy also is increased, and an increase in gastric cancer has been reported.


Pathology_Robbins

Pathology_Robbins. This is the most common primary immune deficiency disease, affecting about 1 in 700 whites. As noted previously, IgA is the major immunoglobulin in mucosal secretions and is thus involved in defending the airways and the gastrointestinal tract. Weakened mucosal defenses due to IgA deficiency predispose patients to recurrent sinopulmonary infections and diarrhea. There also is a significant (but unexplained) association with autoimmune diseases. The pathogenesis of IgA deficiency seems to involve a block in the terminal differentiation of IgA-secreting B cells to plasma cells; IgM and IgG subclasses of antibodies are present in normal or even supranormal levels. The molecular basis for this defect is not understood.


Pathology_Robbins

Pathology_Robbins. Many rare cases of lymphocyte activation defects have been described that affect antigen receptor signaling and various biochemical pathways. Defects in TH1 responses are associated with atypical mycobacterial infections, and defective TH17 responses are the cause of chronic mucocutaneous candidiasis as well as bacterial infections of the skin (a disorder called Job syndrome). In some inherited systemic disorders, immune deficiency is a prominent clinical problem. Two representative examples of such diseases are described next.


Pathology_Robbins

Pathology_Robbins. Wiskott-Aldrich syndrome is an X-linked disease characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection that results in early death. The thymus is normal, at least early in the disease course, but there is progressive loss of T lymphocytes from the blood and the T cell zones (paracortical areas) of lymph nodes, with variable defects in cellular immunity. Patients do not make antibodies to polysaccharide antigens, and the response to protein antigens is poor. IgM levels in the serum are low, but levels of IgG are usually normal and, paradoxically, IgA and IgE are often elevated. The syndrome is caused by mutations in an X-linked gene encoding Wiskott-Aldrich syndrome protein (WASP). WASP belongs to a family of signaling proteins that link membrane receptors, such as antigen receptors, to cytoskeletal elements. The WASP protein is involved in cytoskeleton-dependent responses, including cell migration and signal transduction, but how this contributes


Pathology_Robbins

Pathology_Robbins. such as antigen receptors, to cytoskeletal elements. The WASP protein is involved in cytoskeleton-dependent responses, including cell migration and signal transduction, but how this contributes to the functions of lymphocytes and platelets is unclear. The only treatment is HSC transplantation.


Pathology_Robbins

Pathology_Robbins. Ataxia telangiectasia is an autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), neurologic deficits, increased incidence of tumors, and immunodeficiency. The immunologic defects are of variable severity and may affect both B cells and T cells. The most prominent humoral immune abnormalities are defective production of isotype-switched antibodies, mainly IgA and IgG2. The T-cell defects are usually less pronounced, and may be associated with thymic hypoplasia. Patients experience upper and lower respiratory tract bacterial infections, multiple autoimmune phenomena, and increasingly frequent cancers, particularly lymphoid tumors, with advancing age. The gene responsible for this disorder encodes a protein called ATM (ataxia telangiectasia mutated), a sensor of DNA damage that activates cell cycle checkpoints and apoptosis in cells with damaged DNA. Lack of ATM also leads to abnormalities in antigen gene recombination (and


Pathology_Robbins

Pathology_Robbins. mutated), a sensor of DNA damage that activates cell cycle checkpoints and apoptosis in cells with damaged DNA. Lack of ATM also leads to abnormalities in antigen gene recombination (and therefore defects in the generation of antigen receptors) and abnormal antibody isotype switching.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Inherited defects in the early innate immune response typically affect leukocyte functions or the complement system and lead to increased vulnerability to infections ( 5.13 ). Some defects whose molecular bases are defined are summarized next. Leukocyte adhesion deficiencies (LADs) stem from inherited defects in adhesion molecules that impair leukocyte recruitment to sites of infection, resulting in recurrent bacterial infections. LAD1 is caused by defects in the β2 chain that is shared by the integrins LFA-1 and Mac-1, while LAD2 is caused by a defect in a fucosyl transferase that is required to synthesize functional sialyl-Lewis X, the ligand for Eand P-selectins.


Pathology_Robbins

Pathology_Robbins. Chronic granulomatous disease results from inherited defects in the genes encoding components of phagocyte oxidase, the phagolysosomal enzyme that generates ROS such as superoxide (O2 • ), resulting in defective bacterial killing and susceptibility to recurrent bacterial infection. The name of this disease comes from the macrophage-rich chronic inflammatory reaction that Table 5.13 Common Inherited Immune Deficiencies of Phagocytic Leukocytes and the Complement System C2,C4deficiencyDefectiveclassicalpathwayactivation;resultsinreducedresistancetoinfectionandreducedclearanceofimmunecomplexes ModifiedinpartfromGallinJI:Disordersofphagocyticcells.InGallinJI,etal,editors:Inflammation: basic principles and clinical correlates, ed2,NewYork,1992,RavenPress,pp860–861. appears at sites of infection if the initial neutrophil defense is inadequate. These collections of activated macrophages form granulomas in an effort to wall off the microbes.


Pathology_Robbins

Pathology_Robbins. appears at sites of infection if the initial neutrophil defense is inadequate. These collections of activated macrophages form granulomas in an effort to wall off the microbes. Chédiak-Higashi syndrome is characterized by defective fusion of phagosomes and lysosomes, resulting in defective phagocyte function and susceptibility to infections. The main leukocyte abnormalities are neutropenia, defective degranulation, and delayed microbial killing. The affected leukocytes contain giant granules, which are readily seen in peripheral blood smears and are thought to result from aberrant phagolysosome fusion. In addition, there are abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders). The gene associated with this disorder encodes a large cytosolic protein called LYST, which is believed to regulate lysosomal trafficking.


Pathology_Robbins

Pathology_Robbins. TLR defects are rare but informative. Mutations in TLR3, a receptor for viral RNA, result in recurrent herpes simplex encephalitis, and mutations in MYD88, an adaptor protein needed for signaling downstream of multiple TLRs, are associated with destructive bacterial pneumonias. Deficiencies Affecting the Complement System


Pathology_Robbins

Pathology_Robbins. Deficiency of several complement components have been described, with C2 deficiency being the most common. Deficiencies of C2 or C4, early components of the classical pathway, are associated with increased bacterial or viral infections; however, many patients are asymptomatic, presumably because the alternative complement pathway is able to control most infections. Surprisingly, in some patients with C2, C4, or C1q deficiency, the dominant manifestation is an SLE-like autoimmune disease, possibly because these factors are involved in clearance of immune complexes. Deficiency of C3 is rare. It is associated with severe pyogenic infections as well as immune complex–mediated glomerulonephritis. Deficiency of the late components C5 to C9 results in increased susceptibility to recurrent neisserial (gonococcal and meningococcal) infections, as Neisseria bacteria have thin cell walls and are especially susceptible to the lytic actions of complement.


Pathology_Robbins

Pathology_Robbins. Defects in complement regulatory proteins result in excessive inflammation or cell injury. A deficiency of C1 inhibitor (C1 INH) gives rise to an autosomal dominant disorder called hereditary angioedema, C1 INH is an inhibitor of many proteases, including kallikrein and coagulation factor XII, both of which are involved in the production of vasoactive peptides such as bradykinin. Therefore, defective C1 INH activity leads to over-production of bradykinin, which is a potent vasodilator. Affected patients have episodes of edema affecting skin and mucosal surfaces such as the larynx and the gastrointestinal tract. Acquired deficiencies of other complement regulatory proteins are the cause of paroxysmal nocturnal hemoglobinuria (Chapter 12), while some cases of hemolytic uremic syndrome (Chapter 14) stem from inherited defects in complement regulatory proteins. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Thesediseasesarecausedbyinheritedmutationsingenesinvolvedinlymphocytematurationorfunction,orininnateimmunity. Someofthemorecommondisordersaffectinglymphocytesandtheadaptiveimmuneresponseare: X-SCID: FailureofTcellandBcellmaturation;mutationinthecommonγ chainofacytokinereceptor,leadingtofailureofIL-7signalinganddefectivelymphopoiesis Autosomal recessive SCID: FailureofTcelldevelopment;secondarydefectinantibodyresponses;approximately50%ofcasescausedbymutationinthegeneencodingADA,leadingtoaccumulationoftoxicmetabolitesduringlymphocytematurationandproliferation X-linked agammaglobulinemia (XLA): FailureofB-cellmaturation,absenceofantibodies;causedbymutationsintheBTK gene,whichencodesB-celltyrosinekinase,requiredformaturationsignalsfromthepre–B-cellandB-cellreceptors Di George syndrome: Failureofdevelopmentofthymus,withTcelldeficiency


Pathology_Robbins

Pathology_Robbins. Di George syndrome: Failureofdevelopmentofthymus,withTcelldeficiency X-linked hyper-IgM syndrome: Failuretoproduceisotypeswitchedhigh-affinityantibodies(IgG,IgA,IgE);mutationsingenesencodingCD40Loractivation-inducedcytosinedeaminase Common variable immunodeficiency: Defectsinantibodyproduction;causeunknowninmostcases. Selective IgA deficiency: FailureofIgAproduction;causeunknown Deficienciesininnateimmunityincludedefectsofleukocytefunction,complement,andinnateimmunereceptors. Thesediseasespresentclinicallywithincreasedsusceptibilitytoinfectionsinearlylife. Secondary (acquired) immune deficiencies may be encountered in individuals with cancer, diabetes and other metabolic diseases, malnutrition, chronic infection, and in patients receiving chemotherapy or radiation therapy for cancer, or immunosuppressive drugs to prevent graft rejection or to treat autoimmune diseases ( Table 5.14).


Pathology_Robbins

Pathology_Robbins. Table 5.14). As a group, the secondary immune deficiencies are more common than the disorders of primary genetic origin. Discussed next is perhaps the most important secondary immune deficiency disease, AIDS, which has become one of the great scourges of humankind. AIDS is a disease caused by the retrovirus human immunodeficiency virus (HIV) and is characterized by profound immunosuppression that leads to opportunistic


Pathology_Robbins

Pathology_Robbins. Table 5.14 Causes of Secondary (Acquired) Immunodeficiencies infections, secondary neoplasms, and neurologic manifestations. Although AIDS was first recognized as a distinct entity as recently as the 1980s, it has become one of the most devastating afflictions in history. Of the estimated 36 million HIV-infected individuals worldwide, about 70% are in Africa and 20% in Asia. More than 25 million deaths are attributable to HIV/AIDS, with 1 to 2 million deaths annually. Effective anti-retroviral drugs have been developed, but the infection continues to spread in parts of the world where these therapies are not widely available, and in some African countries, more than 30% of the population is HIV infected. Despite the remarkable progress in drug therapy of AIDS, cure is still a distant goal. The advent of these drugs also raises its own tragic concern; because more individuals are living with HIV, the risk of spreading the infection will increase if vigilance is relaxed.


Pathology_Robbins

Pathology_Robbins. The enormous medical and social burden of AIDS has led to an explosion of research aimed at understanding this modern plague and its remarkable ability to cripple host defenses. The literature on HIV and AIDS is vast. Here we summarize the currently available data on the epidemiology, pathogenesis, and clinical features of HIV infection. Epidemiologic studies in the United States have identified five groups of adults at high risk for developing AIDS. Homosexual or bisexual men constitute the largest group, accounting for about 50% of the reported cases. This includes about 5% who also are intravenous drug abusers. Heterosexual contacts of members of other high-risk groups constituted about 20% of infections from 2001 to 2004. In Africa and Asia, this is by far the largest group of patients with new infections, most of which occur in women who are infected by male partners.


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Pathology_Robbins. Intravenous drug abusers with no previous history of homosexuality represented about 20% of infected individuals and 9% of new cases in 2009. Surviving hemophiliacs, especially those who received large amounts of factor VIII or factor IX concentrates before 1985, make up about 0.5% of all cases. Other recipients of HIV-infected whole blood or components (e.g., platelets, plasma) account for about 1% of patients. http://ebooksmedicine.net HIV infection of the newborn. Close to 2% of all AIDS cases occur in this pediatric population. The vast majority acquires the infection by transmission of the virus from mother to child (discussed later). In approximately 5% of cases, the risk factors cannot be determined.


Pathology_Robbins

Pathology_Robbins. In approximately 5% of cases, the risk factors cannot be determined. It should be apparent from the preceding discussion that transmission of HIV occurs under conditions that facilitate exchange of blood or body fluids containing the virus or virus-infected cells. The three major routes of transmission are sexual contact, parenteral inoculation, and passage of the virus from infected mothers to their newborns.


Pathology_Robbins

Pathology_Robbins. Sexual transmission is the dominant mode of infection worldwide, accounting for more than 75% of all cases of HIV transmission. Because most infected individuals in the United States are men who have sex with men, sexual transmission has mainly occurred among homosexual men. The virus is carried in the semen, and it enters the recipient’s body through abrasions in rectal or oral mucosa or by direct contact with mucosal lining cells. Viral spread occurs in two ways: (1) direct inoculation into the blood vessels breached by trauma and (2) infection of DCs or CD4+ cells within the mucosa. Sexual transmission of HIV is enhanced by coexisting sexually transmitted diseases, especially those associated with genital ulceration.


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Pathology_Robbins. Parenteral transmission of HIV has occurred in intravenous drug abusers, hemophiliacs who received contaminated factor VIII and factor IX concentrates, and other recipients of contaminated blood products. In the United States at present, parenteral transmission is common only among intravenous drug users. Transmission occurs by sharing of needles, syringes, and other paraphernalia contaminated with HIV-containing blood. Transmission of HIV by transfusion of blood or blood products, such as lyophilized factor VIII and factor IX concentrates, has been virtually eliminated by public health measures, including screening of donated blood and plasma for antibody to HIV, stringent purity criteria for factor VIII and factor IX preparations, and screening of donors on the basis of history. An extremely small risk for acquiring AIDS through transfusion of seronegative blood persists, because a recently infected individual may be antibody-negative. Currently, this risk is estimated to be 1 in


Pathology_Robbins

Pathology_Robbins. small risk for acquiring AIDS through transfusion of seronegative blood persists, because a recently infected individual may be antibody-negative. Currently, this risk is estimated to be 1 in more than 2 million units of blood transfused.


Pathology_Robbins

Pathology_Robbins. As alluded to earlier, mother-to-infant transmission is the major cause of pediatric AIDS. Infected mothers can transmit the infection to their offspring by three routes: (1) in utero by transplacental spread; (2) during delivery through an infected birth canal; and (3) after birth by ingestion of breast milk. Of these, transmission during birth (intrapartum) and in the immediate period thereafter (peripartum) is considered to be the most common mode in the United States. The reported transmission rates vary from 7% to 49% in different parts of the world. Higher risk of transmission is associated with high maternal viral load and low CD4+ T cell counts as well as chorioamnionitis. Fortunately, anti-retroviral therapy given to infected pregnant women in the United States has virtually eliminated mother-to-child transmission, but it remains a major source of infection in areas where these treatments are not available.


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Pathology_Robbins. Much concern has arisen in the lay public and among healthcare workers about the spread of HIV infection outside the high-risk groups. Extensive studies indicate that HIV infection cannot be transmitted by casual personal contact in the household, workplace, or school. Spread by insect bites is virtually impossible. Regarding transmission of HIV infection to healthcare workers, an extremely small but definite risk is present. Seroconversion has been documented after accidental needle-stick injury or exposure of nonintact skin to infected blood in laboratory accidents. After needle-stick accidents, the risk for seroconversion is believed to be about 0.3%, and antiretroviral therapy given within 24 to 48 hours of a needle stick can greatly reduce the risk of infection. By comparison, approximately 30% of those accidentally exposed to hepatitis B–infected blood become seropositive.


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Pathology_Robbins. HIV is 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. Two genetically different but related forms of HIV, called HIV-1 and HIV-2, have been isolated from patients. HIV-1 is the most common type associated with AIDS in the United States, Europe, and Central Africa, whereas HIV-2 causes a similar disease principally in West Africa and India. The ensuing discussion relates primarily to HIV-1, but is generally applicable to HIV-2 as well. Structure of HIV Similar to most retroviruses, the HIV-1 virion is spherical and contains an electron-dense, cone-shaped core surrounded by a lipid envelope derived from the host cell membrane (


Pathology_Robbins

Pathology_Robbins. Structure of HIV Similar to most retroviruses, the HIV-1 virion is spherical and contains an electron-dense, cone-shaped core surrounded by a lipid envelope derived from the host cell membrane ( Fig. 5.37 ). The virus core contains (1) the major capsid protein p24; (2) nucleocapsid protein p7/p9; (3) two copies of viral genomic RNA; and (4) the three viral enzymes (protease, reverse transcriptase, and integrase). p24 is the most abundant viral antigen and is the antigen detected by an assay widely used to diagnose HIV infection. The viral core is surrounded by a matrix protein called p17, which lies underneath the virion envelope. Studding the viral envelope are two viral glycoproteins, gp120 and gp41, which are critical for HIV infection of cells.


Pathology_Robbins

Pathology_Robbins. The HIV-1 RNA genome contains the gag, pol, and env genes, which are typical of retroviruses. The products of the gag and pol genes are large precursor proteins that are cleaved by the viral protease to yield the mature proteins. In addition to these three standard retroviral genes, HIV contains several accessory genes, including tat, rev, vif, nef, vpr, and vpu, which regulate the synthesis and assembly of infectious viral particles and the pathogenicity of the virus. Molecular analysis of different HIV-1 isolates has revealed considerable variability in certain parts of the viral genome, mostly within sequences that encode particular regions of the envelope glycoproteins. Because the http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 5.37 Thestructureofthehumanimmunodeficiencyvirus(HIV)-1virion.Theviralparticleiscoveredbyalipidbilayerderivedfromthehostcellandstuddedwithviralglycoproteinsgp41andgp120.gp120 Lipid bilayer p24 capsid Protease Integrase RNA Reverse transcriptase antibody response against HIV-1 is targeted against its envelope, such variability poses problems for the development of a single-antigen vaccine. Based on genetic variation, HIV-1 can be divided into three subgroups, designated M (major), O (outlier), and N (neither M nor O). Group M viruses are the most common form worldwide, and they are further divided into several subtypes, or clades, designated A through K. Various subtypes differ in their geographic distribution; for example, subtype B is the most common form in western Europe and the United States, whereas subtype E is the most common clade in Thailand. Currently, clade C is the fastest spreading clade worldwide, being present in India, Ethiopia, and Southern Africa.


Pathology_Robbins

Pathology_Robbins. While HIV can infect many tissues, the two major targets of HIV infection are the immune system and the central nervous system. The effects of HIV infection on each of these two systems are discussed separately. Profound immune deficiency, primarily affecting cell-mediated immunity, is the hallmark of AIDS. This results chiefly from infection and subsequent loss of CD4+ T cells as well as impaired function of surviving helper T cells and other immune cells. We first describe the mechanisms involved in viral entry into T cells and macrophages and the replicative cycle of the virus within cells. This is followed by a more detailed review of the interaction between HIV and its cellular targets. Life Cycle of HIV The life cycle of HIV consists of infection of cells, integration of the provirus into the host cell genome, activation of viral replication, and production and release of infectious virus (


Pathology_Robbins

Pathology_Robbins. The life cycle of HIV consists of infection of cells, integration of the provirus into the host cell genome, activation of viral replication, and production and release of infectious virus ( Fig. 5.38 ). The molecules and mechanisms of each of these steps are understood in considerable detail. HIV infects cells by using the CD4 molecule as a receptor and various chemokine receptors as coreceptors (see Fig.


Pathology_Robbins

Pathology_Robbins. HIV infects cells by using the CD4 molecule as a receptor and various chemokine receptors as coreceptors (see Fig. 5.38 ). Binding of HIV gp120 to CD4 is essential for infection and accounts for the tropism of the virus for CD4+ T cells and for CD4+ monocytes/macrophages and DCs. However, binding to CD4 is not sufficient for infection, as HIV gp120 also must bind to other cell surface molecules (coreceptors) for entry into the cell. Chemokine receptors, particularly CCR5 and CXCR4, serve this role. HIV isolates can be distinguished by their use of these coreceptors: R5 strains use CCR5, X4 strains use CXCR4, and some strains (R5X4) are dual-tropic. R5 strains preferentially infect cells of the monocyte/macrophage lineage and are thus referred to as M-tropic, whereas X4 strains are T-tropic, preferentially infecting T cells, but these distinctions are not absolute.


Pathology_Robbins

Pathology_Robbins. Polymorphisms in the gene encoding CCR5 are associated with altered susceptibility to HIV infection. About 1% of white Americans inherit two mutated copies of the CCR5 gene and are resistant to R5 HIV isolates. About 20% of individuals are heterozygous for this protective CCR5 allele; these individuals are not protected from AIDS, but the onset of their disease after infection is delayed. Only rare homozygotes for the mutation have been found in African and East Asian populations.


Pathology_Robbins

Pathology_Robbins. Molecular details of the deadly handshake between HIV glycoproteins and their cell surface receptors have been elucidated. The HIV envelope contains two noncovalently associated glycoproteins, surface gp120 and the transmembrane protein gp41. The initial step in infection is the binding of the gp120 envelope glycoprotein to CD4 molecules, which leads to a conformational change that creates a new recognition site on gp120 for the coreceptors CCR5 or CXCR4. Binding to the coreceptors induces conformational changes in gp41 that exposes a hydrophobic region called the fusion peptide at the tip of gp41. This peptide inserts into the cell membrane of the target cells (e.g., T cells or macrophages), leading to fusion of the virus with the host cell. After fusion, the virus core containing the HIV genome enters the cytoplasm of the cell.


Pathology_Robbins

Pathology_Robbins. Once internalized, the RNA genome of the virus undergoes reverse transcription, leading to the synthesis of double-stranded complementary DNA (cDNA; proviral DNA) (see Fig. 5.38 ). In quiescent T cells, HIV cDNA may remain in the cytoplasm in a linear episomal form. In dividing T cells, the cDNA circularizes, enters the nucleus, and is then integrated into the host genome. After integration, the pro-virus may be silent for months or years, a form of latent infection. Alternatively, proviral DNA may be transcribed, leading to the expression of viral proteins that are required for the formation of complete viral particles. HIV infects memory cells and activated T cells but is inefficient at productively infecting naïve (resting) T cells.


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Pathology_Robbins. Completion of the viral life cycle in latently infected cells occurs only after cell activation, and in the case of most CD4+ T cells, virus activation results in death of the infected cells. Activation of T cells by antigens or cytokines upregulates several transcription factors, including NF-κB, which moves from the cytosol into the nucleus. In http://ebooksmedicine.net Budding and release of mature virion


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Pathology_Robbins. Fig. 5.38 The life cycle of HIV showing the steps from viral entry to production of infectious virions. (Adapted from Wain-Hobson S: HIV. One on one meets two. Nature 384:117, 1996.) the nucleus, NF-κB binds to regulatory sequences within several genes, including genes for cytokines and other immune mediators, promoting their transcription. The long-terminal-repeat sequences that flank the HIV genome also contain NF-κB–binding sites, so binding of the transcription factor activates viral gene expression. Imagine now a latently infected CD4+ cell that encounters an environmental antigen. Induction of NF-κB in such a cell (a physiologic response) activates the transcription of HIV proviral DNA (a pathologic outcome) and leads ultimately to the production of virions and to cell death. Furthermore, TNF and other cytokines produced by activated macrophages also stimulate NF-κB activity and thus lead to production of HIV RNA. Thus, it seems that HIV thrives when the host T cells and


Pathology_Robbins

Pathology_Robbins. Furthermore, TNF and other cytokines produced by activated macrophages also stimulate NF-κB activity and thus lead to production of HIV RNA. Thus, it seems that HIV thrives when the host T cells and macrophages are physiologically activated, a situation that can be described as “subversion from within.” Such activation in vivo may result from antigenic stimulation by HIV itself or by other infecting microorganisms. HIV-positive individuals are at increased risk for recurrent infections, which leads to increased lymphocyte activation and production of proinflammatory cytokines. These, in turn, stimulate more HIV production, loss of additional CD4+ T cells, and more infections. Thus, it is easy to see how HIV infection sets up a vicious cycle that culminates in inexorable destruction of the immune system.


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Pathology_Robbins. Mechanism of T-Cell Depletion in HIV Infection Loss of CD4+ T cells is mainly caused by the direct cytopathic effects of the replicating virus. In infected individuals, approximately 100 billion new viral particles are produced and 1 to 2 billion CD4+ T cells die each day. Death of these cells is a major cause of the relentless, and eventually profound, T cell immunodeficiency. Up to a point, the immune system can replace the dying T cells, but as the disease progresses, renewal of CD4+ T cells cannot keep up with their loss. Possible mechanisms by which the virus directly kills infected cells include increased plasma membrane permeability associated with budding of virus particles and defects in protein synthesis stemming from interference by viral proteins involved in viral replication. In addition to direct killing of cells by the virus, other mechanisms may contribute to the loss or functional impairment of T cells. These include:


Pathology_Robbins

Pathology_Robbins. In addition to direct killing of cells by the virus, other mechanisms may contribute to the loss or functional impairment of T cells. These include: Chronic activation of uninfected cells, responding to HIV itself or to infections that are common in individuals with AIDS, leading to apoptosis of these cells. HIV infection of cells in lymphoid organs (spleen, lymph nodes, tonsils) causing progressive destruction of the architecture and cellular composition of lymphoid tissues. Fusion of infected and uninfected cells, leading to formation of syncytia (giant cells). In tissue culture the gp120 expressed on productively infected cells binds to CD4 molecules on uninfected T cells, followed by cell fusion. Fused cells usually die within a few hours.


Pathology_Robbins

Pathology_Robbins. Qualitative defects in T cell function. Even in asymptomatic HIV-infected individuals, defects have been reported, including a reduction in antigen-induced T cell proliferation, a decrease in TH1-type responses relative to the TH2 type, defects in intracellular signaling, and many more. The loss of TH1 responses results in a profound deficiency in cell-mediated immunity. There also is a selective loss of the memory subset of CD4+ helper T cells early in the course of disease, which explains poor recall responses to previously encountered antigens.


Pathology_Robbins

Pathology_Robbins. Low-level chronic or latent infection of T cells is an important feature of HIV infection. Integrated provirus, without viral gene expression (latent infection), can persist in cells for months or years. Even with potent antiviral therapy, which practically sterilizes the peripheral blood, latent virus lurks within CD4+ cells (both T cells and macrophages) in lymph nodes. According to some estimates, 0.05% of CD4+ T cells in the lymph nodes are latently infected. Because most of these CD4+ T cells are memory cells, they are long-lived, with a life span of months to years, and thus provide a persistent reservoir of virus. HIV Infection of Non–T Immune Cells In addition to infection and loss of CD4+ T cells, infection of macrophages and DCs also is important in the pathogenesis of HIV infection.


Pathology_Robbins

Pathology_Robbins. HIV Infection of Non–T Immune Cells In addition to infection and loss of CD4+ T cells, infection of macrophages and DCs also is important in the pathogenesis of HIV infection. Macrophages. Similar to T cells, most macrophages infected by HIV are found in tissues, and in certain tissues, such as the lungs and brain, as many as 10% to 50% of macrophages are infected. Although cell division is required for nuclear entry and replication of most retroviruses, HIV-1 can infect and multiply in terminally differentiated nondividing macrophages, which may contain large numbers of virus particles. Even though macrophages allow viral replication, they are quite resistant to the cytopathic effects of HIV, in contrast to CD4+ T cells. Thus, macrophages may be reservoirs of infection, and in late stages of HIV infection, when CD4+ T-cell numbers decline greatly, macrophages may be an important site of continued viral replication.


Pathology_Robbins

Pathology_Robbins. Dendritic Cells. Mucosal DCs may be infected by the virus and transport it to regional lymph nodes, where the virus is transmitted to CD4+ T cells. Follicular DCs in the germinal centers of lymph nodes also are potential reservoirs of HIV. Although some follicular DCs may be susceptible to HIV infection, most virus particles are found on the surface of their dendritic processes. B Cell Function in HIV Infection. Although B cells cannot be infected by HIV, they may show profound abnormalities. Paradoxically, there is spontaneous B-cell activation and hypergammaglobulinemia in association with an inability to mount antibody responses to newly encountered antigens. The defective antibody responses may be due to lack of T-cell help as well as acquired defects in B cells. Pathogenesis of Central Nervous System Involvement


Pathology_Robbins

Pathology_Robbins. Pathogenesis of Central Nervous System Involvement Like the lymphoid system, the nervous system is a target of HIV infection. Macrophages and microglia, cells in the CNS that belong to the macrophage lineage, are the predominant cell types in the brain that are infected with HIV. It is believed that HIV is carried into the brain by infected monocytes. In keeping with this, the HIV isolates from the brain are almost exclusively M-tropic. The mechanism of HIV-induced damage of the brain, however, remains obscure. Because neurons are not infected and the extent of neuropathologic changes is often less than might be expected from the severity of neurologic symptoms, most clinicians believe that the neurologic deficit is caused indirectly by viral products and by soluble factors produced by infected microglia, such as the cytokines IL-1, TNF, and IL-6.


Pathology_Robbins

Pathology_Robbins. Virus entry into cells: RequiresCD4andcoreceptors,whicharereceptorsforchemokines;involvesbindingofviralgp120andfusionwiththecellmediatedbyviralgp41protein;maincellulartargets:CD4+ helperTcells,macrophages,DCs Viral replication: IntegrationofprovirusgenomeintohostcellDNA;triggeringofviralgeneexpressionbystimulithatactivateinfectedcells(e.g.,infectiousmicrobes,cytokinesproducedduringnormalimmuneresponses) Progression of infection: AcuteinfectionofmucosalTcellsandDCs;viremiawithdisseminationofvirus;latentinfectionofcellsinlymphoidtissue;continuingviralreplicationandprogressivelossofCD4+ Tcells Mechanisms of immune deficiency: LossofCD4+ Tcells:Tcelldeathduringviralreplicationandbudding(similartoothercytopathicinfections);apoptosisoccurringasaresultofchronicstimulation;decreasedthymicoutput;functionaldefects http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. HIV disease begins with acute infection, which is only partly controlled by the host immune response, and advances to chronic progressive infection of peripheral lymphoid tissues ( Figs. 5.39 5.40 • Acute phase. Virus typically enters through mucosal surfaces, and acute (early) infection is characterized by infection of memory CD4+ T cells (which express CCR5) in mucosal lymphoid tissues, and the death of many of these 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. At this stage, few infected cells are detectable in the blood and other tissues.


Pathology_Robbins

Pathology_Robbins. Mucosal infection is followed by dissemination of the virus and the development of host immune responses. DCs in epithelia at sites of virus entry capture the virus and then migrate into the lymph nodes. Once in lymphoid tissues, DCs pass HIV on to CD4+ T cells through direct cell–cell contact. Within days after the first exposure to HIV, viral replication can be detected in lymph nodes. This replication leads to viremia, during which high numbers of HIV particles are present in the patient’s blood. The virus disseminates throughout the body and infects helper T cells, macrophages, and DCs in peripheral lymphoid tissues.


Pathology_Robbins

Pathology_Robbins. Within 3 to 6 weeks after initial infection, 40% to 90% of infected individuals develop an acute HIV syndrome, which is triggered by the initial spread of the virus and the host response. This phase is associated with a self-limited acute illness with nonspecific symptoms, including sore throat, myalgias, fever, weight loss, and fatigue, resembling a flulike syndrome. Rash, lymphadenopathy, diarrhea, and vomiting also may occur. This typically resolves spontaneously in 2 to 4 weeks.