Pathology_Robbins

Pathology_Robbins. Anti-phospholipid antibody syndrome has primary and secondary forms. Individuals with a well-defined autoimmune disease, such as systemic lupus erythematosus (Chapter 5), are designated as having secondary antiphospholipid syndrome (hence the earlier term lupus anticoagulant syndrome). In primary anti-phospholipid syndrome, patients exhibit only the manifestations of a hypercoagulable state and lack evidence of other autoimmune disorders; occasionally, it appears following exposure to certain drugs or infections. Therapy involves anticoagulation and immunosuppression. Although antiphospholipid antibodies are clearly associated with thrombotic diatheses, they have also been identified in 5% to 15% of apparently normal individuals, implying that they are necessary but not sufficient to cause the full-blown syndrome. http://ebooksmedicine.net


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Atautopsy,postmortem clots cansometimesbemistakenforvenousthrombi.However,theformeraregelatinousandbecauseofredcellsettlingtheyhaveadarkreddependentportionandayellow“chickenfat”upperportion;theyalsoareusuallynotattachedtotheunderlyingvesselwall.Bycontrast,redthrombitypicallyarefirm,focallyattachedtovesselwalls,andtheycontaingraystrandsofdepositedfibrin. Thrombionheartvalvesarecalledvegetations. Bacterialorfungalbloodborneinfectionscancausevalvedamage,leadingtothedevelopmentoflargethromboticmasses(infective endocarditis) (Chapter11).Sterilevegetationsalsocandeveloponnoninfectedvalvesinhypercoagulablestates—thelesionsofso-called“nonbacterial thrombotic endocarditis” (Chapter11).Lesscommonly,sterile,verrucous endocarditis (Libman-Sacks endocarditis) canoccurinthesettingofsystemiclupuserythematosus(Chapter5). (left side of photograph). Fate of the Thrombus


Pathology_Robbins

Pathology_Robbins. (left side of photograph). Fate of the Thrombus If a patient survives an initial thrombotic event, during the ensuing days to weeks the thrombus evolves through some combination of the following four processes: Propagation. The thrombus enlarges through the accretion of additional platelets and fibrin, increasing the odds of vascular occlusion or embolization. Embolization. Part or all of the thrombus is dislodged and transported elsewhere in the vasculature.


Pathology_Robbins

Pathology_Robbins. Embolization. Part or all of the thrombus is dislodged and transported elsewhere in the vasculature. Dissolution. If a thrombus is newly formed, activation of fibrinolytic factors may lead to its rapid shrinkage and complete dissolution. With older thrombi, extensive fibrin polymerization renders the thrombus substantially more resistant to plasmin-induced proteolysis, and lysis is ineffectual. This acquisition of resistance to lysis has clinical significance, as therapeutic administration of fibrinolytic agents (e.g., t-PA in the setting of acute coronary thrombosis) generally is not effective unless administered within a few hours of thrombus formation. Organization and recanalization. Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts (


Pathology_Robbins

Pathology_Robbins. Organization and recanalization. Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts ( Fig. 4.14 ). In time, capillary channels are formed that—to a limited extent—create conduits along the length of the thrombus, thereby reestablishing the continuity of the original lumen. Further recanalization can sometimes convert a thrombus into a http://ebooksmedicine.net Fig. 4.14 Anorganizedthrombus.Low-powerviewofathrombosedarterystainedforelastictissue.Theoriginallumenisdelineatedbytheinter-nalelasticlamina(arrows)andiscompletelyfilledwithorganizedthrombus.


Pathology_Robbins

Pathology_Robbins. Fig. 4.14 Anorganizedthrombus.Low-powerviewofathrombosedarterystainedforelastictissue.Theoriginallumenisdelineatedbytheinter-nalelasticlamina(arrows)andiscompletelyfilledwithorganizedthrombus. vascularized mass of connective tissue that is eventually incorporated into the wall of the remodeled vessel. Occasionally, instead of organizing, the center of a thrombus undergoes enzymatic digestion, presumably because of the release of lysosomal enzymes from entrapped leukocytes. If bacterial seeding occurs, the contents of degraded thrombi serve as an ideal culture medium, and the resulting infection may weaken the vessel wall, leading to the formation of a mycotic aneurysm (Chapter 10).


Pathology_Robbins

Pathology_Robbins. Thrombi are significant because they cause obstruction of arteries and veins and may give rise to emboli. The effect that is of the greatest clinical importance depends on the site of thrombosis. Thus, although venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, they are most worrisome because of their potential to embolize to the lungs and cause death. Conversely, whereas arterial thrombi can embolize and cause tissue infarction, their tendency to obstruct vessels (e.g., in coronary and cerebral vessels) is considerably more important.


Pathology_Robbins

Pathology_Robbins. Most venous thrombi occur in the superficial or the deep veins of the leg. Superficial venous thrombi usually arise in the saphenous system, particularly in the setting of varicosities; these rarely embolize but they can be painful and can cause local congestion and swelling from impaired venous outflow, predisposing the overlying skin to the development of infections and varicose ulcers. Deep venous thromboses (DVTs) in the larger leg veins at or above the knee joint (e.g., popliteal, femoral, and iliac veins) are more serious because they are prone to embolize. Although such DVTs may cause local pain and edema, collateral channels often circumvent the venous obstruction. Consequently, DVTs are entirely asymptomatic in approximately 50% of patients and are recognized only after they have embolized to the lungs. Lower-extremity DVTs are associated with stasis and hypercoagulable states, as described earlier (


Pathology_Robbins

Pathology_Robbins. Table 4.2 ). Thus, common predisposing factors include congestive heart failure, bed rest, and immobilization; the latter two factors reduce the milking action of leg muscles and thus slow venous return. Trauma, surgery, and burns not only immobilize a patient but also are associated with vascular injury, procoagulant release, increased hepatic synthesis of coagulation factors, and reduced t-PA production. Many factors contribute to the thrombotic diathesis of pregnancy; in addition to the potential for amniotic fluid infusion into the circulation at the time of delivery, pressure produced by the enlarging fetus and uterus can produce stasis in the veins of the legs, and late pregnancy and the postpartum period are associated with hypercoagulability. Tumor-associated procoagulant release is largely responsible for the increased risk of thromboembolic phenomena seen in disseminated cancers. These are sometimes referred to as migratory thrombophlebitis, because of the tendency to


Pathology_Robbins

Pathology_Robbins. is largely responsible for the increased risk of thromboembolic phenomena seen in disseminated cancers. These are sometimes referred to as migratory thrombophlebitis, because of the tendency to involve several different venous beds transiently, or as Trousseau syndrome, for the physician who both described the disorder and suffered from it. Regardless of the specific clinical setting, the risk of DVT is increased in persons older than 50 years.


Pathology_Robbins

Pathology_Robbins. Atherosclerosis is a major cause of arterial thromboses because it is associated with the loss of endothelial integrity and with abnormal blood flow ( Fig. 4.13B ). Myocardial infarction can predispose to cardiac mural thrombi by causing dyskinetic myocardial contraction and endocardial injury ( Fig. 4.13A ), and rheumatic heart disease may engender atrial mural thrombi by causing atrial dilation and fibrillation. Both cardiac and aortic mural thrombi are prone to embolization. Although any tissue can be affected, the brain, kidneys, and spleen are particularly likely targets because of their rich blood supply.


Pathology_Robbins

Pathology_Robbins. ThrombusdevelopmentisusuallyrelatedtooneormorecomponentsofVirchow’striad: endothelialinjury(e.g.,bytoxins,hypertension,inflammation,ormetabolicproducts) abnormalbloodflow,stasis,orturbulence(e.g.,resultingfromaneurysms,atheroscleroticplaque) hypercoagulability:eitherprimary(e.g.,factorVLeiden,increasedprothrombinsynthesis,anti-thrombinIIIdeficiency)orsecondary(e.g.,bedrest,tissuedamage,malignancy) Thrombimaypropagate,resolve,becomeorganized,orembolize. Thrombosiscausestissueinjurybylocalvascularocclusionorbydistalembolization. DIC is widespread thrombosis within the microcirculation that may be of sudden or insidious onset. It may be seen in disorders ranging from obstetric complications to advanced malignancy. To complicate matters, the widespread micro-vascular thrombosis consumes platelets and coagulation proteins (hence the synonym consumptive coagulopathy), and at the same time, fibrinolytic mechanisms are activated. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The net result is that excessive clotting and bleeding may co-exist in the same patient. It is discussed in greater detail along with other bleeding diatheses in Chapter 12.


Pathology_Robbins

Pathology_Robbins. An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction. The vast majority of emboli derive from a dislodged thrombus—hence the term thromboembolism. Less commonly, emboli are composed of fat droplets, bubbles of air or nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow, or amniotic fluid. Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion; depending on the site of origin, emboli can arrest anywhere in the vascular tree. The primary consequence of systemic embolization is ischemic necrosis (infarction) of downstream tissues, whereas embolization in the pulmonary circulation leads to hypoxia, hypotension, and right-sided heart failure.


Pathology_Robbins

Pathology_Robbins. Pulmonary emboli originate from deep venous thromboses and are responsible for the most common form of thromboembolic disease. The incidence of pulmonary embolism (PE) is 2 to 4 per 1000 hospitalized patients. Although the rate of fatal PE has declined considerably since the early 1990s, PE still causes about 100,000 deaths per year in the United States. In more than 95% of cases, venous emboli originate from thrombi within deep leg veins proximal to the popliteal fossa; embolization from lower leg thrombi is uncommon. Fragmented thrombi from DVTs are carried through progressively larger channels and usually pass through the right side of the heart before arresting in the pulmonary vasculature. Depending on size, a PE can occlude the main pulmonary artery, lodge at the bifurcation of the right and left pulmonary arteries (saddle embolus), or pass into the smaller, branching arterioles (


Pathology_Robbins

Pathology_Robbins. Fig. 4.15 ). Frequently, multiple emboli occur, either sequentially or as a shower of smaller emboli from a single large thrombus; a patient who has had one pulmonary embolus is at increased risk for having more. Rarely, an embolus passes through an atrial or ventricular defect and enters the systemic circulation (paradoxical embolism). A more complete discussion of PE is found in Chapter 13; the major clinical and pathologic features are the following: Most pulmonary emboli (60%–80%) are small and clinically silent. With time, they undergo organization and become incorporated into the vascular wall; in some cases, organization of thromboemboli leaves behind bridging fibrous webs. At the other end of the spectrum, a large embolus that blocks a major pulmonary artery can cause sudden death.


Pathology_Robbins

Pathology_Robbins. At the other end of the spectrum, a large embolus that blocks a major pulmonary artery can cause sudden death. Embolic obstruction of medium-sized arteries and subsequent rupture of downstream capillaries rendered anoxic can cause pulmonary hemorrhage. Such emboli do not usually cause pulmonary infarction because the Fig. 4.15 Embolusderivedfromalower-extremitydeepvenousthrombuslodgedinapulmonaryarterybranch. area also receives blood through an intact bronchial circulation (dual circulation). However, a similar embolus in the setting of left-sided cardiac failure (and diminished bronchial artery perfusion) can lead to a pulmonary infarct. Embolism to small end-arteriolar pulmonary branches usually causes infarction. Multiple emboli occurring through time can cause pulmonary hypertension and right ventricular failure (cor pulmonale).


Pathology_Robbins

Pathology_Robbins. Embolism to small end-arteriolar pulmonary branches usually causes infarction. Multiple emboli occurring through time can cause pulmonary hypertension and right ventricular failure (cor pulmonale). Most systemic emboli (80%) arise from intracardiac mural thrombi; two-thirds of these are associated with left ventricular infarcts and another 25% with dilated left atria (e.g., secondary to mitral valve disease). The remainder originate from aortic aneurysms, thrombi overlying ulcerated atherosclerotic plaques, fragmented valvular vegetations (Chapter 11), or the venous system (paradoxical emboli); 10% to 15% of systemic emboli are of unknown origin.


Pathology_Robbins

Pathology_Robbins. By contrast with venous emboli, which lodge primarily in the lung, arterial emboli can travel virtually anywhere; their final resting place understandably depends on their point of origin and the relative flow rates of blood to the downstream tissues. Common arteriolar embolization sites include the lower extremities (75%) and central nervous system (10%); intestines, kidneys, and spleen are less common targets. The consequences of embolization depend on the caliber of the occluded vessel, the collateral supply, and the affected tissue’s vulnerability to anoxia; arterial emboli often lodge in end arteries and cause infarction.


Pathology_Robbins

Pathology_Robbins. Soft tissue crush injury or rupture of marrow vascular sinusoids (eg, due to a long bone fracture) release microscopic fat globules into the circulation. Fat and marrow emboli are common incidental findings after vigorous cardiopulmonary resuscitation but probably are of little clinical significance. Similarly, although fat and marrow embolism occurs in some 90% of individuals with severe skeletal injuries ( Fig. 4.16A ), less than 10% show any clinical findings. However, a minority of patients develop a http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 4.16 Unusualtypesofemboli.(A)Bonemarrowembolus.Theembolusiscomposedofhematopoieticmarrowandmarrowfatcells(clear spaces) attachedtoathrombus.(B)Amnioticfluidemboli.Twosmallpulmonaryarteriolesarepackedwithlaminatedswirlsoffetalsquamouscells.Thesurroundinglungisedematousandcongested.(Courtesy of Dr. Beth Schwartz, Baltimore, MD.) symptomatic fat embolism syndrome characterized by pulmonary insufficiency, neurologic symptoms, anemia, thrombocytopenia, and a diffuse petechial rash that is fatal in 10% of cases. Clinical signs and symptoms appear 1 to 3 days after injury as the sudden onset of tachypnea, dyspnea, tachycardia, irritability, and restlessness, which can progress rapidly to delirium or coma. Thrombocytopenia is attributed to platelet adhesion to fat globules and subsequent aggregation or splenic sequestration; anemia can result from similar red cell aggregation and/or hemolysis. A diffuse petechial rash (seen in 20%–50% of cases) is related to rapid onset of


Pathology_Robbins

Pathology_Robbins. subsequent aggregation or splenic sequestration; anemia can result from similar red cell aggregation and/or hemolysis. A diffuse petechial rash (seen in 20%–50% of cases) is related to rapid onset of thrombocytopenia and can be a useful diagnostic feature.


Pathology_Robbins

Pathology_Robbins. The pathogenesis of fat emboli syndrome involves both mechanical obstruction and biochemical injury. Fat microemboli occlude pulmonary and cerebral microvasculature, both directly and by triggering platelet aggregation. This deleterious effect is exacerbated by fatty acid release from lipid globules, which causes local toxic endothelial injury. Platelet activation and granulocyte recruitment (with free radical, protease, and eicosanoid release) (Chapter 3) complete the vascular assault. Because lipids are dissolved by the solvents used during tissue processing, microscopic demonstration of fat microglobules (i.e., in the absence of accompanying marrow elements) requires specialized techniques (frozen sections and fat stains).


Pathology_Robbins

Pathology_Robbins. Amniotic fluid embolism is an uncommon, grave complication of labor and the immediate postpartum period occurring in 1 in 40,000 deliveries. The mortality rate approaches 80%, making it the most common cause of maternal death in the developed world and the fifth most common cause of maternal death in the United States, accounting for 10% of maternal deaths in this country; 85% of survivors suffer some form of permanent neurologic deficit. Onset is characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. If the patient survives the initial crisis, pulmonary edema typically develops, along with (in about half the patients) disseminated intravascular coagulation secondary to release of thrombogenic substances from amniotic fluid. Indeed it is thought that morbidity and mortality in such cases results not from mechanical obstruction of pulmonary vessels but from biochemical activation of the coagulation system and the innate immune system


Pathology_Robbins

Pathology_Robbins. thought that morbidity and mortality in such cases results not from mechanical obstruction of pulmonary vessels but from biochemical activation of the coagulation system and the innate immune system caused by substances in the amniotic fluid.


Pathology_Robbins

Pathology_Robbins. The underlying cause is the entry of amniotic fluid (and its contents) into the maternal circulation via tears in the placental membranes and/or uterine vein rupture. Histologic analysis shows squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tracts in the maternal pulmonary microcirculation ( Fig. 4.16B ). Other findings include marked pulmonary edema, diffuse alveolar damage (Chapter 13), and systemic fibrin thrombi generated by disseminated intravascular coagulation. Gas bubbles within the circulation can coalesce and obstruct vascular flow and cause distal ischemic injury.


Pathology_Robbins

Pathology_Robbins. Gas bubbles within the circulation can coalesce and obstruct vascular flow and cause distal ischemic injury. Thus, a small volume of air trapped in a coronary artery during bypass surgery or introduced into the cerebral arterial circulation by neurosurgery performed in an upright “sitting position” can occlude flow, with dire consequences. Small venous gas emboli generally have no deleterious effects, but sufficient air can enter the pulmonary circulation inadvertently during obstetric or laproscopic procedures or as a consequence of a chest wall injury to cause hypoxia, and very large venous emboli may arrest in the heart and cause death.


Pathology_Robbins

Pathology_Robbins. A particular form of gas embolism called decompression sickness is caused by sudden changes in atmospheric pressure. Scuba divers, underwater construction workers, and persons in unpressurized aircraft who undergo rapid ascent are at risk. When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) become dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli, which cause tissue ischemia. Rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints is responsible for the painful condition called the bends (so named in the 1880s because the afflicted person arches the back in a manner reminiscent of a then-popular women’s fashion pose called the Grecian bend). Gas bubbles in the pulmonary vasculature cause edema, hemorrhages, and focal atelectasis or emphysema,


Pathology_Robbins

Pathology_Robbins. back in a manner reminiscent of a then-popular women’s fashion pose called the Grecian bend). Gas bubbles in the pulmonary vasculature cause edema, hemorrhages, and focal atelectasis or emphysema, leading to respiratory distress, the so-called “chokes”. Bubbles in the central nervous system can cause mental impairment and even sudden onset of coma. A more chronic form of decompression sickness is called caisson disease (named for pressurized underwater vessels used during bridge construction), in which recurrent or persistent gas emboli in the bones lead to multifocal ischemic necrosis; the heads of the femurs, tibiae, and humeri are most commonly affected.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Placing affected persons in a high-pressure chamber, to force the gas back into solution, treats acute decompression sickness. Subsequent slow decompression permits gradual gas resorption and exhalation so that obstructive bubbles do not re-form. Anembolusisasolid,liquid,orgaseousmasscarriedbythebloodtoasitedistantfromitsorigin;mostaredislodgedthrombi. Pulmonaryembolideriveprimarilyfromlower-extremitydeepveinthrombi.Theireffectsdependmainlyonthesizeoftheembolusandthelocationinwhichitlodges.Consequencesmayincluderight-sidedheartfailure,pulmonaryhemorrhage,pulmonaryinfarction,orsuddendeath. Systemicembolideriveprimarilyfromcardiacmuralorvalvularthrombi,aorticaneurysms,oratheroscleroticplaques;whetheranemboluscausestissueinfarctiondependsonthesiteofembolizationandthepresenceorabsenceofcollateralcirculation.


Pathology_Robbins

Pathology_Robbins. Fatembolismcanoccuraftercrushinginjuriestothebones;symptomsincludepulmonaryinsufficiencyandneurologicaldamage.Amnioticfluidembolismmayfollowchildbirthandcangiverisetofatalpulmonaryandcerebralmanifestations.Airembolismcanoccuruponrapiddecompression,mostcommonlyindivers;itresultsfromsuddenbubblingofnitrogendissolvedinbloodathigherpressures. An infarct is an area of ischemic necrosis caused by occlusion of the vascular supply to the affected tissue. Infarction primarily affecting the heart and the brain is a common and extremely important cause of clinical illness. Roughly 40% of all deaths in the United States are a consequence of cardiovascular disease, with most of these deaths stemming from myocardial or cerebral infarction. Pulmonary infarction is a common clinical complication, bowel infarction often is fatal, and ischemic necrosis of distal extremities (gangrene) causes substantial morbidity in the diabetic population.


Pathology_Robbins

Pathology_Robbins. Arterial thrombosis or arterial embolism underlies the vast majority of infarctions. Less common causes of arterial obstruction include vasospasm, expansion of an atheroma secondary to intraplaque hemorrhage, and extrinsic compression of a vessel, such as by tumor, a dissecting aortic aneurysm, or edema within a confined space (e.g., in anterior tibial compartment syndrome). Other uncommon causes of tissue infarction include vessel twisting (e.g., in testicular torsion or bowel volvulus), traumatic vascular rupture, and entrapment in a hernia sac. Although venous thrombosis can cause infarction, the more common outcome is simply congestion; typically, bypass channels rapidly open to provide sufficient outflow to restore the arterial inflow. Infarcts caused by venous thrombosis thus usually occur only in organs with a single efferent vein (e.g., testis or ovary). tion.Thus,infarctsmaybeeitherred (hemorrhagic) orwhite (anemic) andmaybeeitherseptic orbland.


Pathology_Robbins

Pathology_Robbins. tion.Thus,infarctsmaybeeitherred (hemorrhagic) orwhite (anemic) andmaybeeitherseptic orbland. (Fig.4.17A )occur(1)asaresultofvenousocclusions(suchasinovariantorsion);(2)inloosetissues(e.g.,lung)wherebloodcancollectininfarctedzones;(3)intissueswithdualcirculationssuchaslungandsmallintestine,wherepartial,albeit (B)Sharplydemarcatedpaleinfarctinthespleen(white infarct). Fig. 4.17 Redandwhiteinfarcts.(A)Hemorrhagic,roughlywedge-shapedpulmonaryinfarct(red infarct). ABthe painful condition called the bends (so named in the 1880s because the afflicted person arches the back in a manner reminiscent of a then-popular women’s fashion pose called the Grecian bend). Gas bubbles in the pulmo inadequateperfusionbycollateralarterialsuppliesistypical;(4)inpreviouslycongestedtissues(asaconsequenceofsluggishvenousoutflow);and(5)whenflowisreestablishedafterinfarctionhasoccurred(e.g.,afterangioplastyofanarterialobstruction).


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig. 4.18 Remotekidneyinfarct,nowreplacedbyalargefibroticscar. The effects of vascular occlusion range from inconsequential to tissue necrosis leading to organ dysfunction and sometimes death. The range of outcomes is influenced by the following three variables:


Pathology_Robbins

Pathology_Robbins. Anatomy of the vascular supply. The presence or absence of an alternative blood supply is the most important factor in determining whether occlusion of an individual vessel causes damage. The dual supply of the lung by the pulmonary and bronchial arteries means that obstruction of the pulmonary arterioles does not cause lung infarction unless the bronchial circulation also is compromised. Similarly, the liver, which receives blood from the hepatic artery and the portal vein, and the hand and forearm, with its parallel radial and ulnar arterial supply, are resistant to infarction. By contrast, the kidney and the spleen both have end-arterial circulations, and arterial obstruction generally leads to infarction in these tissues.


Pathology_Robbins

Pathology_Robbins. Rate of occlusion. Slowly developing occlusions are less likely to cause infarction because they allow time for the development of collateral blood supplies. For example, small interarteriolar anastomoses, which normally carry minimal blood flow, interconnect the three major coronary arteries. If one coronary artery is slowly occluded (e.g., by encroaching atherosclerotic plaque), flow in this collateral circulation may increase sufficiently to prevent infarction—even if the original artery becomes completely occluded. Tissue vulnerability to hypoxia. Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells, although hardier than neurons, still die after only 20 to 30 minutes of ischemia. By contrast, fibroblasts within myocardium remain viable after many hours of ischemia.


Pathology_Robbins

Pathology_Robbins. Infarctsareareasofischemicnecrosismostcommonlycausedbyarterialocclusion(typicallyresultingfromthrombosisorembolization);venousoutflowobstructionisalessfrequentcause. Infarctscausedbyvenousocclusionoroccurringinspongytissuestypicallyarehemorrhagic(red);thosecausedbyarterialocclusionincompacttissuestypicallyarepale(white). Whetherornotvascularocclusioncausestissueinfarctionisinfluencedbycollateralbloodsupplies,therateatwhichanobstructiondevelops,intrinsictissuesusceptibilitytoischemicinjury,andbloodoxygenation. Shock is a state in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia. At the outset, the cellular injury is reversible; however, prolonged shock eventually leads to irreversible tissue injury and is often fatal. http://ebooksmedicine.net Table 4.3 Three Major Types of Shock Type of Shock Clinical Examples Principal Pathogenic Mechanisms


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Table 4.3 Three Major Types of Shock Type of Shock Clinical Examples Principal Pathogenic Mechanisms Arrhythmia Failure of myocardial pump resulting from intrinsic myocardial damage, extrinsic pressure, or obstruction to outfow Shock may complicate severe hemorrhage, extensive trauma improvements in care, the mortality remains at a stagger- or burns, myocardial infarction, pulmonary embolism, and microbial sepsis. Its causes fall into three general categories ( Table 4.3 Cardiogenic shock results from low cardiac output as a result of myocardial pump failure. It may be caused by myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tamponade) (Chapter 12), or outflow obstruction (e.g., pulmonary embolism). Hypovolemic shock results from low cardiac output due to loss of blood or plasma volume (e.g., resulting from hemorrhage or fluid loss from severe burns).


Pathology_Robbins

Pathology_Robbins. Hypovolemic shock results from low cardiac output due to loss of blood or plasma volume (e.g., resulting from hemorrhage or fluid loss from severe burns). Septic shock is triggered by microbial infections and is associated with severe systemic inflammatory response syndrome (SIRS). In addition to microbes, SIRS may be triggered by a variety of insults, including burns, trauma, and/or pancreatitis. The common pathogenic mechanism is a massive outpouring of inflammatory mediators from innate and adaptive immune cells that produce arterial vasodilation, vascular leakage, and venous blood pooling. These cardiovascular abnormalities result in tissue hypoperfusion, cellular hypoxia, and metabolic derangements that lead to organ dysfunction and, if severe and persistent, organ failure and death. The pathogenesis of shock is discussed in detail below.


Pathology_Robbins

Pathology_Robbins. Less commonly, shock can result from a loss of vascular tone associated with anesthesia or secondary to a spinal cord injury (neurogenic shock). Anaphylactic shock results from systemic vasodilation and increased vascular permeability that is triggered by an immunoglobulin E–mediated hypersensitivity reaction (Chapter 5). Septic shock is responsible for 2% of all hospital admissions in the United States. Of these, 50% require treatment in intensive care units. The number of cases in the United States exceeds 750,000/year and the incidence is rising, which is ironically due to improvements in life support for critically ill patients, as well as the growing ranks of immunocompromised hosts (because of chemotherapy, immunosuppression, advanced age, or human immunodeficiency virus infection) and the increasing prevalence of multidrugresistant organisms in the hospital setting. Despite ing 20% to 30%.


Pathology_Robbins

Pathology_Robbins. Septic shock is most frequently triggered by gram-positive bacterial infections, followed by gram-negative bacteria and fungi. Hence, an older synonym, “endotoxic shock,” is no longer appropriate. The ability of diverse microorganisms to cause septic shock is consistent with the idea that a variety of microbial constituents can trigger the process. As mentioned in Chapter 3, macrophages, neutrophils, dendritic cells, endothelial cells, and soluble components of the innate immune system (e.g., complement) recognize and are activated by several substances derived from microorganisms. After activation, these cells and factors initiate a number of inflammatory responses that interact in a complex, incompletely understood fashion to produce septic shock and multiorgan dysfunction ( Fig. 4.19


Pathology_Robbins

Pathology_Robbins. Factors believed to play major roles in the pathophysiology of septic shock include the following: • Inflammatory and counterinflammatory responses. In sepsis, various microbial cell wall constituents engage receptors on cells of the innate immune system, triggering proinflammatory responses. Likely initiators of inflammation in sepsis are signaling pathways that lie downstream of Toll-like receptors (TLRs) (Chapter 5), which recognize a host of microbe-derived substances containing so-called “pathogen-associated molecular patterns” (PAMPs), as well as G-protein–coupled receptors that detect bacterial peptides, and C-type lectin receptors such as Dectins. On activation, innate immune cells produce numerous cytokines, including TNF, IL-1, IFNγ, IL-12, and IL-18, as well as other inflammatory mediators such as high-mobility group box 1 protein (HMGB1). Markers of acute inflammation such as C-reactive protein and procalcitonin are also elevated. The latter is a clinically useful


Pathology_Robbins

Pathology_Robbins. mediators such as high-mobility group box 1 protein (HMGB1). Markers of acute inflammation such as C-reactive protein and procalcitonin are also elevated. The latter is a clinically useful indicator of septic shock. Reactive oxygen species and lipid mediators such as prostaglandins and platelet-activating factor (PAF) are also elaborated. These effector molecules induce endothelial cells (and other cell types) to upregulate adhesion molecule expression and further stimulate cytokine and chemokine production. The complement cascade is also activated by microbial components, both directly and through the proteolytic activity of plasmin (Chapter 3), resulting in the production of anaphylotoxins (C3a, C5a), chemotactic fragments (C5a), and opsonins (C3b), all of which contribute to the proinflammatory state. In addition, microbial components can activate coagulation directly through factor XII and indirectly through altered endothelial function (discussed later). The accompanying


Pathology_Robbins

Pathology_Robbins. proinflammatory state. In addition, microbial components can activate coagulation directly through factor XII and indirectly through altered endothelial function (discussed later). The accompanying widespread activation of thrombin may further augment inflammation by triggering protease activated receptors on inflammatory cells.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net TISSUE ISCHEMIA Procoagulant Anti-fibrinolytic Adrenal insufficiency MULTIORGAN FAILURE IL-10, apoptosis, STNFR Secondary anti-inflammatory mediators IL-6, IL-8, NO, PAF, reactive oxygen species, etc. Microbial products (PAMPs) Factor XII TNF, IL-1, HMGB1 Endothelial activation Neutrophil and monocyte activation Cytokines and cytokine-like mediators Complement activation Direct and indirect MICROVASCULAR THROMBOSIS (DIC) IMMUNOSUPPRESSION VASODILATION INCREASED PERMEABILITY DECREASED PERFUSION SYSTEMIC EFFECTS Fever, diminished myocardial contractility, metabolic abnormalities TFPI, thrombomodulin, protein C TF PAI-1 C3 C3a


Pathology_Robbins

Pathology_Robbins. Fig. 4.19 Majorpathogenicpathwaysinsepticshock.Microbialproductsactivateendothelialcellsandcellularandhumoralelementsoftheinnateimmunesystem,initiatingacascadeofeventsthatleadtoend-stagemultiorganfailure.Additionaldetailsareprovidedinthetext.DIC, Disseminatedintravascularcoagulation;HMGB1, high-mobilitygroupbox1protein;NO, nitricoxide;PAF, platelet-activatingfactor;PAI-1, plasminogenactivatorinhibitor-1;PAMP, pathogen-associatedmolecularpattern;STNFR, solubletumornecrosisfactorreceptor;TF, tissuefactor;TFPI, tissuefactorpathwayinhibitor.


Pathology_Robbins

Pathology_Robbins. The hyperinflammatory state, initiated by sepsis, triggers counterregulatory immunosuppressive mechanisms, which may involve both innate and adaptive immune cells. As a result, septic patients may oscillate between hyperinflammatory and immunosuppressed states during their clinical course. Proposed mechanisms for the immune suppression include a shift from proinflammatory (TH1) to anti-inflammatory (TH2) cytokines (Chapter 5), production of anti-inflammatory mediators (e.g., soluble TNF receptor, IL-1 receptor antagonist, and IL-10), lymphocyte apoptosis, the immunosuppressive effects of apoptotic cells, and the induction of cellular anergy. In some patients the counterregulatory mechanisms overshoot the inflammatory responses and the resultant immune suppression renders such patients susceptible to superinfections.


Pathology_Robbins

Pathology_Robbins. • Endothelial activation and injury. The proinflammatory state and endothelial cell activation associated with edema, which have deleterious effects on both nutrient delivery and waste removal. One effect of inflammatory cytokines is to loosen endothelial cell tight junctions, making vessels leaky and resulting in the accumulation of protein-rich edema fluid throughout the body. This alteration impedes tissue perfusion and may be exacerbated by attempts to support the patient with intravenous fluids. Activated endothelium also upregulates production of nitric oxide (NO) and other vasoactive inflammatory mediators (e.g., C3a, C5a, and PAF), which may contribute to vascular smooth muscle relaxation and systemic hypotension.


Pathology_Robbins

Pathology_Robbins. • Induction of a procoagulant state. The derangement in coagulation is sufficient to produce the formidable complication of disseminated intravascular coagulation in up to half of septic patients. Sepsis alters the expression of many factors so as to favor coagulation. Proinflammatory cytokines increase tissue factor production by monocytes and possibly endothelial cells as well, and decrease the production of endothelial anti-coagulant factors, such as tissue factor pathway inhibitor, thrombomodulin, and protein C (see Fig. 4.11 ). They also dampen fibrinolysis by increasing plasminogen activator inhibitor-1 expression (see Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 4.11 ). They also dampen fibrinolysis by increasing plasminogen activator inhibitor-1 expression (see Fig. 4.10 ). The vascular leak and tissue edema decrease blood flow at the level sepsis lead to widespread vascular leakage and tissue of small vessels, producing stasis and diminishing the http://ebooksmedicine.net washout of activated coagulation factors. Acting in concert, these effects lead to systemic activation of thrombin and the deposition of fibrin-rich thrombi in small vessels, often throughout the body, further compromising tissue perfusion. In full-blown disseminated intravascular coagulation, the consumption of coagulation factors and platelets is so great that deficiencies of these factors appear, leading to concomitant bleeding and hemorrhage (Chapter 12).


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Pathology_Robbins. Metabolic abnormalities. Septic patients exhibit insulin resistance and hyperglycemia. Cytokines such as TNF and IL-1, stress-induced hormones (such as glucagon, growth hormone, and glucocorticoids), and catecholamines all drive gluconeogenesis. At the same time, the proinflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues, likely by impairing the surface expression of GLUT-4, a glucose transporter. Hyperglycemia decreases neutrophil function—thereby suppressing bactericidal activity—and causes increased adhesion molecule expression on endothelial cells. Although sepsis is initially associated with an acute surge in glucocorticoid production, this phase may be followed by adrenal insufficiency and a functional deficit of glucocorticoids. This may stem from depression of the synthetic capacity of intact adrenal glands or frank adrenal necrosis resulting from disseminated intravascular dissemination


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Pathology_Robbins. deficit of glucocorticoids. This may stem from depression of the synthetic capacity of intact adrenal glands or frank adrenal necrosis resulting from disseminated intravascular dissemination (Waterhouse-Friderichsen syndrome) (Chapter 20). Finally, cellular hypoxia and diminished oxidative phosphorylation lead to increased lactate production and lactic acidosis.


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Pathology_Robbins. Organ dysfunction. Systemic hypotension, interstitial edema, and small vessel thrombosis all decrease the delivery of oxygen and nutrients to the tissues that, because of cellular hypoxia, fail to properly use those nutrients that are delivered. Mitochondrial damage resulting from oxidative stress impairs oxygen use. High levels of cytokines and secondary mediators diminish myocardial contractility and cardiac output, and increased vascular permeability and endothelial injury can lead to the acute respiratory distress syndrome (Chapter 13). Ultimately, these factors may conspire to cause the failure of multiple organs, particularly the kidneys, liver, lungs, and heart, culminating in death.


Pathology_Robbins

Pathology_Robbins. The severity and outcome of septic shock are likely dependent on the extent and virulence of the infection; the immune status of the host; the presence of other comorbid conditions; and the pattern and level of mediator production. The multiplicity of factors and the complexity of the interactions that underlie sepsis explain why most attempts to intervene therapeutically with antagonists of specific mediators have not been effective and may even have had deleterious effects in some cases. The standard of care remains antibiotics to treat the underlying infection and intravenous fluids, pressors, and supplemental oxygen to maintain blood pressure and limit tissue hypoxia. Suffice it to say that even in the best of clinical centers, septic shock remains an obstinate clinical challenge.


Pathology_Robbins

Pathology_Robbins. An additional group of secreted bacterial proteins called superantigens also cause a syndrome similar to septic shock (e.g., toxic shock syndrome). Superantigens are polyclonal T-lymphocyte activators that induce the release of high levels of cytokines that result in a variety of clinical manifestations, ranging from a diffuse rash to vasodilation, hypotension, shock, and death.


Pathology_Robbins

Pathology_Robbins. Shock is a progressive disorder that leads to death if the underlying problems are not corrected. The exact mechanisms of sepsis-related death are still unclear; aside from increased lymphocyte and enterocyte apoptosis, cellular necrosis is minimal. Death typically follows the failure of multiple organs, which usually offer no morphological clues to explain their dysfunction. For hypovolemic and cardiogenic shock, however, the pathways leading to a patient’s demise are reasonably well understood. Unless the insult is massive and rapidly lethal (e.g., exsanguination from a ruptured aortic aneurysm), shock tends to evolve through three general (albeit somewhat artificial) stages. These stages have been documented most clearly in hypovolemic shock but are common to other forms as well: An initial nonprogressive stage during which reflex compensatory mechanisms are activated and vital organ perfusion is maintained,


Pathology_Robbins

Pathology_Robbins. An initial nonprogressive stage during which reflex compensatory mechanisms are activated and vital organ perfusion is maintained, A progressive stage characterized by tissue hypo-perfusion and onset of worsening circulatory and metabolic derangement, including acidosis, An irreversible stage in which cellular and tissue injury is so severe that even if the hemodynamic defects are corrected, survival is not possible.


Pathology_Robbins

Pathology_Robbins. In the early nonprogressive phase of shock, various neurohumoral mechanisms help maintain cardiac output and blood pressure. These mechanisms include baroreceptor reflexes, release of catecholamines and anti-diuretic hormone, activation of the renin-angiotensin-aldersterone axis, and generalized sympathetic stimulation. The net effect is tachycardia, peripheral vasoconstriction, and renal fluid conservation; cutaneous vasoconstriction causes the characteristic “shocky” skin coolness and pallor (notably, septic shock can initially cause cutaneous vasodilation, so the patient may present with warm, flushed skin). Coronary and cerebral vessels are less sensitive to sympathetic signals and maintain relatively normal caliber, blood flow, and oxygen delivery. Thus, blood is shunted away from the skin to the vital organs such as the heart and the brain.


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Pathology_Robbins. If the underlying causes are not corrected, shock passes imperceptibly to the progressive phase, which as noted is characterized by widespread tissue hypoxia. In the setting of persistent oxygen deficit, intracellular aerobic respiration is replaced by anaerobic glycolysis with excessive production of lactic acid. The resultant metabolic lactic acidosis lowers the tissue pH, which blunts the vasomotor response; arterioles dilate, and blood begins to pool in the microcirculation. Peripheral pooling not only worsens the cardiac output but also puts endothelial cells at risk for the development of anoxic injury with subsequent DIC. With widespread tissue hypoxia, vital organs are affected and begin to fail.


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Pathology_Robbins. In the absence of appropriate intervention, or in severe cases, the process eventually enters an irreversible stage. Widespread cell injury is reflected in lysosomal enzyme leakage, further aggravating the shock state. Myocardial contractile function worsens, in part because of increased NO synthesis. The ischemic bowel may allow intestinal flora to enter the circulation, and thus bacteremic shock may be superimposed. Commonly, further progression to renal failure occurs as a consequence of ischemic injury of the kidney (Chapter 14), and despite the best therapeutic interventions, the downward spiral frequently culminates in death. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net MORPHOLOGYThecellularandtissueeffectsofshockareessentiallythoseofhypoxicinjury(Chapter2)andarecausedbyacombinationofhypoperfusion andmicrovascular thrombosis. Althoughanyorgancanbeaffected,thebrain,heart,kidneys,adrenals,andgastrointestinaltractaremostcommonlyinvolved.Fibrin thrombi canforminanytissuebuttypicallyaremostreadilyvisualizedinkidneyglomeruli.Adrenal cortical cell lipid depletion isakintothatseeninallformsofstressandreflectsincreaseduseofstoredlipidsforsteroidsynthesis.Whereasthelungsareresistanttohypoxicinjuryinhypovolemicshockoccurringafterhemorrhage,sepsisortraumacanprecipitatediffusealveolardamage(Chapter13),leadingtoso-called“shock lung.” Exceptforneuronalandcardiomyocyteloss,affectedtissuescanrecovercompletelyifthepatientsurvives.


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Pathology_Robbins. The clinical manifestations of shock depend on the precipitating insult. In hypovolemic and cardiogenic shock, patients exhibit hypotension, a weak rapid pulse, tachypnea, and cool, clammy, cyanotic skin. As already noted, in septic shock, the skin may be warm and flushed owing to peripheral vasodilation. The primary threat to life is the underlying initiating event (e.g., myocardial infarction, severe hemorrhage, bacterial infection). However, the cardiac, cerebral, and pulmonary changes rapidly aggravate the situation. If patients survive the initial period, worsening renal function can provoke a phase dominated by progressive oliguria, acidosis, and electrolyte imbalances. Prognosis varies with the origin of shock and its duration. Thus, more than 90% of young, otherwise healthy patients with hypovolemic shock survive with appropriate management; by comparison, septic or cardiogenic shock is associated with substantially worse outcomes, even with state-of-the-art care.


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Pathology_Robbins. •Shockisdefinedasastateofsystemictissuehypoperfusionresultingfromreducedcardiacoutputand/orreducedeffectivecirculatingbloodvolume. Themajortypesofshockarecardiogenic(e.g.,myocardialinfarction),hypovolemic(e.g.,bloodloss),andseptic(e.g.,infections). Shockofanyformcanleadtohypoxictissueinjuryifnotcorrected. Septicshockiscausedbythehostresponsetobacterialorfungalinfections;itischaracterizedbyendothelialcellactivation,vasodilation,edema,disseminatedintravascularcoagulation,andmetabolicderangements. Akhtar S: Fat embolism, Anesthesiol Clin 27:533, 2009. [Recent overview of the pathogenesis and clinical issues in fat embolism syndrome.] Alberelli MA, De Candia E: Functional role of protease activated receptors in vascular biology, Vascul Pharmacol 62:72–81, 2014. [An exhaustive review of the role played by PARs in hemostasis.]


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Pathology_Robbins. Alberelli MA, De Candia E: Functional role of protease activated receptors in vascular biology, Vascul Pharmacol 62:72–81, 2014. [An exhaustive review of the role played by PARs in hemostasis.] Angus DC, van der Poll T: Severe sepsis and septic shock, N Engl J Med 840:2013. [An excellent review of clinical features, pathogenesis, and outcome of septic shock.] Benson MD: Current concepts of immunology and diagnosis in amniotic fluid embolism, Clin Dev Immunol doi:10.1155/2012/946576: 2012. [Discussion of the pathophysiology of amniotic fluid embolism.] Cawcutt KA, Peters SG: Severe sepsis and septic shock: clinical overview and update on management, Mayo Clin Proc 89:1572, 2014. [A brief clinical review of sepsis.] Chapman JC, Hajjar KA: Fibrinolysis and the control of blood coagulation, Blood Rev 29:17, 2015. [An updated discussion of fibrinolysis and its role in the regulation of coagulation.]


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Pathology_Robbins. Chapman JC, Hajjar KA: Fibrinolysis and the control of blood coagulation, Blood Rev 29:17, 2015. [An updated discussion of fibrinolysis and its role in the regulation of coagulation.] Chaturvedi S, McCrae KR: Recent advances in the antiphospholipid antibody syndrome, Curr Opin Hematol 21:371, 2014. [A discussion of the pathophysiology of this important and complex entity.] Coleman DM, Obi A, Henke PK: Update in venous thromboembolism: pathophysiology, diagnosis, and treatment for surgical patients, Curr Probl Surg 52:233, 2015. [An exhaustive review of this common clinical condition.] Ellery PE, Adams MJ: Tissue factor pathway inhibitor: then and now, Semin Thromb Hemost 40:881, 2014. [Advances in understanding the role of tissue factor in coagulation.] Esmon CT, Esmon NL: The link between vascular features and thrombosis, Annu Rev Physiol 2011. [An excellent review of the interactions of endothelium, blood flow, and hemostasis/thrombosis.]


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Pathology_Robbins. Esmon CT, Esmon NL: The link between vascular features and thrombosis, Annu Rev Physiol 2011. [An excellent review of the interactions of endothelium, blood flow, and hemostasis/thrombosis.] Greinacher A: Heparin induced thrombocytopenia, N Engl J Med 373:3, 2015. [A nice review on this common and enigmatic condition.] Osinbowale O, Ali L, Chi YW: Venous thromboembolism: a clinical review, Postgrad Med 122:54, 2010. [Good review at a medical student/ house officer level.] Rao LVM, Esom CT, Pendurthi UR: Endothelial cell protein C receptor: a multiliganded and multifunctional receptor, Blood 124:1553, 2014. [A discussion of this novel receptor in limiting coagulation.] Renne T, Schmaier AH, Nickel KF, et al: In vivo roles of factor XII, Blood 120:4296–4303, 2012. [A review summarizing new insights into the still-uncertain in vivo functions of factor XII in thrombosis and vascular biology.]


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Pathology_Robbins. Versteeg HH, Heemskerk JWM, Levi M, et al: New fundamentals in hemostasis, Physiol Rev 93:327, 2013. [An update in several issues in hemostasis.] http://ebooksmedicine.net studentconsult.com Diseases of the Immune System Capture and Display of Antigens Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Intracellular Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular Microbes Decline of Immune Responses and Immunologic Hypersensitivity:ImmunologicallyMediatedTissueInjury Causes of Hypersensitivity Reactions Classification of Hypersensitivity Reactions Mechanisms of Autoimmunity: General Recognition and Rejection of Allografts Transplantation of Hematopoietic Stem Cells Properties of HIV Pathogenesis of HIV Infection and AIDS Natural History and Course of HIV Clinical Features of AIDS Pathogenesis of Amyloid Deposition Classification of Amyloidosis and Mechanisms of Amyloid Formation


Pathology_Robbins

Pathology_Robbins. Natural History and Course of HIV Clinical Features of AIDS Pathogenesis of Amyloid Deposition Classification of Amyloidosis and Mechanisms of Amyloid Formation Immunity refers to protection against infections. The immune system is the collection of cells and molecules that are responsible for defending the body against the countless pathogens that individuals encounter. Defects in the immune system render individuals easy prey to infections and are the cause of immunodeficiency diseases. But the immune system is itself capable of causing tissue injury and disease, which are often referred to as hypersensitivity disorders.


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Pathology_Robbins. This chapter is devoted to diseases caused by too little immunity or too much immunologic reactivity. We also consider amyloidosis, a disease in which an abnormal protein, usually derived from fragments of antibodies or produced during chronic inflammatory disorders, is deposited in tissues. First, we review some important features of normal immune responses, to provide a foundation for understanding the abnormalities that give rise to immunologic diseases. Defense against pathogens consists of two types of reactions ( Fig. 5.1 ). Innate immunity (also called natural, or native, immunity) is mediated by cells and proteins that are always present (hence the term innate), poised to react against infectious pathogens. These mechanisms are called into action immediately in response to infection, and thus provide the first line of defense. Some of these mechanisms also are involved in clearing damaged cells and tissues. A major reaction of innate immunity is inflammation (Chapter 3).


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Pathology_Robbins. Many pathogens have evolved to resist innate immunity, and protection against these infections requires the more specialized and powerful mechanisms of adaptive immunity (also called acquired, or specific, immunity). Adaptive immunity is normally silent and responds (or adapts) http://ebooksmedicine.net Fig. 5.1 The principal components and kinetics of response of the innate and adaptive immune systems. NK cells, Natural killer cells. to the presence of infectious agents by generating potent mechanisms for neutralizing and eliminating the pathogens. By convention, the terms immune system and immune response generally refer to adaptive immunity.


Pathology_Robbins

Pathology_Robbins. The major components of innate immunity are epithelial barriers that block the entry of microbes, phagocytic cells (mainly neutrophils and macrophages), dendritic cells (DCs), natural killer (NK) cells and other innate lymphoid cells, and several plasma proteins, including the proteins of the complement system. The various cells are discussed later in this chapter; the complement system was discussed in Chapter 3.


Pathology_Robbins

Pathology_Robbins. Phagocytes, dendritic cells and many other cells, such as epithelial cells, express receptors that sense the presence of infectious agents and substances released from dead cells. The microbial structures recognized by these receptors are called pathogen-associated molecular patterns; they are shared among microbes of the same type, and they are essential for the survival and infectivity of the microbes (so the microbes cannot evade innate immune recognition by mutating these molecules). The substances released from injured and necrotic cells are called damage-associated molecular patterns. The cellular receptors that recognize these molecules are often called pattern recognition receptors. It is estimated that innate immunity uses about 100 different receptors to recognize 1000 molecular patterns. Receptors of Innate Immunity


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Pathology_Robbins. Receptors of Innate Immunity Pattern recognition receptors are located in all the cellular compartments where pathogens may be present: plasma membrane receptors detect extracellular pathogens, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm ( Fig. 5.2 ). Several classes of these receptors have been identified. NOD-like receptor Nucleic acids of ingested Bacterial microbes peptidoglycan; products of TLR damaged cells


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Pathology_Robbins. Fig. 5.2 ). Several classes of these receptors have been identified. NOD-like receptor Nucleic acids of ingested Bacterial microbes peptidoglycan; products of TLR damaged cells Fig. 5.2 Cellular receptors for microbes and products of cell injury. Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the presence of microbes and dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as other cytoplasmic and plasma membrane receptors, recognize products of different classes of microbes. The major classes of innate immune receptors are TLRs, NOD-like receptors in the cytosol (NLRs), C-type lectin receptors, RIG-like receptors for viral RNA, named after the founding member RIG-I, and cytosolic DNA sensors.


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Pathology_Robbins. The best known of the pattern recognition receptors are the Toll-like receptors (TLRs). There are 10 TLRs in mammals that recognize a wide range of microbial molecules. The plasma membrane TLRs recognize bacterial products such as lipopolysaccharide (LPS), and endosomal TLRs recognize viral and bacterial RNA and DNA (see Fig. 5.2 ). Recognition of microbes by these receptors activates transcription factors that stimulate the production of several secreted and membrane proteins, including mediators of inflammation, anti-viral cytokines (interferons), and proteins that promote lymphocyte activation and the even more potent adaptive immune responses.


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Pathology_Robbins. NOD-like receptors (NLRs) are cytosolic receptors named after the founding members NOD-1 and NOD-2. They recognize a wide variety of substances, including products of necrotic cells (e.g., uric acid and released ATP), ion disturbances (e.g., loss of K+), and some microbial products. How this family of sensors detects so many diverse signs of danger or damage is not known. Several of the NLRs signal via a cytosolic multiprotein complex called the inflammasome, which activates an enzyme (caspase-1) that cleaves a precursor form of the cytokine interleukin-1 (IL-1) to generate the biologically active form (


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Pathology_Robbins. Fig. 5.3 ). As discussed in Chapter 3, IL-1 is a mediator of inflammation that recruits leukocytes and induces fever. Gain-offunction mutations in one of the NLRs result in periodic fever syndromes, called autoinflammatory syndromes,which respond very well to treatment with IL-1 antagonists. The NLR-inflammasome pathway also may play a role in a number of chronic disorders marked by inflammation. For example, recognition of urate crystals by a class of NLRs underlies the inflammation associated with gout. These receptors may detect and respond to lipids and cholesterol crystals that are deposited in abnormally large amounts in tissues; the resulting inflammation may contribute to obesity-associated type 2 diabetes and atherosclerosis, respectively.


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Pathology_Robbins. C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and DCs detect fungal glycans and elicit inflammatory reactions to fungi. Several cytosolic receptors detect the nucleic acids of viruses that replicate in the cytoplasm of infected cells, and stimulate the production of anti-viral cytokines. G protein–coupled receptors on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N-formylmethionyl residues. Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are initiated by N-formylmethionine, this receptor enables neutrophils to detect bacterial proteins and stimulates chemotactic responses. Mannose receptors recognize microbial sugars (which often contain terminal mannose residues, unlike mammalian glycoproteins) and induce phagocytosis of the microbes. In addition, two families of cytosolic receptors, one named after the founding member RIG-I and the


Pathology_Robbins

Pathology_Robbins. terminal mannose residues, unlike mammalian glycoproteins) and induce phagocytosis of the microbes. In addition, two families of cytosolic receptors, one named after the founding member RIG-I and the other called cytosolic DNA sensors, recognize microbial RNA and DNA, respectively.


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Pathology_Robbins. Signals from TLRs, other receptors Fig.5.3 Theinflammasome.Theinflammasomeisaproteincomplexthat recognizesproductsofdeadcellsandsomemicrobesandinducesthesecretionofbiologicallyactiveinterleukin-1.Itisacomplexofmultiplecopiesof asensorprotein(aleucine-richproteincalledNLRP3),anadapter,andthe enzyme caspase-1, which is converted from an inactive toanactive form. The structure of the inflammasome as shown is simplified from known crystal structures.The formation of the inflammasome complex proceeds byaprion-likemechanismofpropagation,inwhichoneproteinalteredby activation induces conformational changes in other proteins of the same type.The net result is the activation and assembly of a large number of identicalpolypeptides,formingfilament-likebundlesofadaptersandenzymes. Reactions of Innate Immunity The innate immune system provides host defense by the following two main reactions:


Pathology_Robbins

Pathology_Robbins. Reactions of Innate Immunity The innate immune system provides host defense by the following two main reactions: Inflammation. Cytokines and products of complement activation, as well as other mediators, are produced during innate immune reactions and trigger the vascular and cellular components of inflammation. The recruited leukocytes destroy pathogens and ingest and eliminate damaged cells. This reaction was described in Chapter 3. Anti-viral defense. Type I interferons produced in response to viruses act on infected and uninfected cells and activate enzymes that degrade viral nucleic acids and inhibit viral replication. In addition to these defensive functions, the innate immune system generates signals that stimulate the subsequent, more powerful adaptive immune response. Some of these signals are described later.


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Pathology_Robbins. In addition to these defensive functions, the innate immune system generates signals that stimulate the subsequent, more powerful adaptive immune response. Some of these signals are described later. The adaptive immune system consists of lymphocytes and their products, including antibodies. In contrast to the limited repertoire of the innate immune system, the adaptive immune system can recognize a vast array of foreign substances.


Pathology_Robbins

Pathology_Robbins. There are two types of adaptive immunity: humoral immunity, mediated by soluble proteins called antibodies that are produced by B lymphocytes (also called B cells), and cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells). Antibodies provide protection against extracellular pathogens in the blood, mucosal surfaces, and tissues. T lymphocytes are important in defense against intracellular microbes. They work by either directly killing infected cells (accomplished by cytotoxic T lymphocytes) or by activating phagocytes to kill ingested microbes, via the production of soluble protein mediators called cytokines (made by helper T cells). We next turn to the main properties and functions of the cells of the immune system.


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Pathology_Robbins. The cells of the immune system consist of lymphocytes, most of which have specific receptors for antigens and mount adaptive immune responses; specialized APCs, which capture and display microbial and other antigens to the lymphocytes; and various effector cells, whose function is to eliminate microbes and other antigens. Some of the remarkable features of the immune system are the expression of highly diverse and specific antigen receptors on B and T cells, the specialization of the cells that that enable them to perform many different functions, and the precise control mechanisms that permit useful responses when needed and prevent potentially harmful ones. Lymphocytes are present in the circulation and in various lymphoid organs. Although all lymphocytes are morphologically similar, they actually consist of several functionally and phenotypically distinct populations (


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Pathology_Robbins. Fig. 5.4 ). Lymphocytes develop from precursors in the generative (primary) lymphoid organs; T lymphocytes mature in the thymus, whereas B lymphocytes mature in the bone marrow. Each T or B lymphocyte and its progeny, which constitute a clone, express a single antigen receptor, and the total population of lymphocytes (numbering about 1012 in humans) can recognize tens or hundreds of millions of antigens. The enormous diversity of antigen receptors is encoded by variant DNA sequences that are created during lymphocyte maturation by the joining and diversification of different gene segments to form functional antigen receptor genes, a process that occurs only in B cells and T cells. Hence the presence of rearranged antigen receptor genes is a reliable marker of these cells. As already mentioned, the antigen receptors that are expressed in B cells are called antibodies, while their T-cell counterparts are called T-cell receptors.


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Pathology_Robbins. Mature T and B lymphocytes recirculate through peripheral (secondary) lymphoid organs—the lymph nodes, spleen and mucosal tissues—and reside in these organs and in most tissues. Foreign antigens are concentrated in these organs, where they bind to and activate the clones of lymphocytes that express receptors for those antigens, a process known as clonal selection. All mature lymphocytes go through distinct phases during their lives— naïve lymphocytes express antigen receptors but have not responded to antigens and do not serve any functions; effector lymphocytes are induced by lymphocyte activation and perform the functions that eliminate microbes; and memory lymphocytes, induced during activation, survive in a functionally silent state even after the antigen is eliminated and respond rapidly upon subsequent encounters with the antigen.


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Pathology_Robbins. Thymus-derived T lymphocytes develop into the effector cells of cellular immunity and “help” B cells to produce antibodies against protein antigens. T cells constitute 60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones. T cells cannot recognize free or circulating antigens; instead, the vast majority (>95%) of T cells sense only peptide fragments of proteins displayed by molecules of the major histocompatibility complex (MHC), discussed in more detail later. Because T cell antigen receptors have evolved to see MHC-bound peptides on cell surfaces, T cells only recognize antigens presented by other cells. The outcome of this interaction varies dramatically depending on the type of T cell that is involved and the identity of the other interacting cell, ranging from the killing of virus-infected cells to the activation of phagocytes or B lymphocytes that have ingested protein


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Pathology_Robbins. of T cell that is involved and the identity of the other interacting cell, ranging from the killing of virus-infected cells to the activation of phagocytes or B lymphocytes that have ingested protein antigens.


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Pathology_Robbins. Peptide antigens presented by MHC molecules are recognized by the T-cell receptor (TCR), a heterodimer that in most T cells is composed of disulfide-linked α and β protein chains ( Fig. 5.5). Each chain has a variable region that participates in binding a particular peptide antigen and a constant region that interacts with associated signaling molecules. TCRs are noncovalently linked to a cluster of five invariant polypeptide chains, the γ, δ, and ε proteins of the CD3 molecular complex and two ζ chains (see Fig. 5.5 ). The CD3 proteins and ζ chains do not bind antigens; instead, they are attached to the TCR and initiate intracellular biochemical signals after TCR recognition of antigen.


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Pathology_Robbins. Fig. 5.5 ). The CD3 proteins and ζ chains do not bind antigens; instead, they are attached to the TCR and initiate intracellular biochemical signals after TCR recognition of antigen. T cells also express a number of other molecules that serve important functions in immune responses. CD4 and CD8 are expressed on distinct T-cell subsets and act as coreceptors during T-cell activation. During antigen recognition, CD4 molecules on T cells bind to invariant portions of class II MHC molecules (described later) on selected antigen-presenting cells (APCs); in an analogous fashion, CD8 binds to class I MHC molecules. CD4 is expressed on 50% to 60% of T cells, whereas CD8 is expressed on about 40% of T cells. The CD4-and CD8-expressing T cells— called CD4+ and CD8+ cells, respectively—perform different but overlapping functions. CD4+ T cells are called helper T cells because they secrete soluble molecules http://ebooksmedicine.net


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Pathology_Robbins. Neutralization of microbe, B lymphocyte B + phagocytosis, complement activation Activation of macrophages Microbial antigen presented by antigen-presenting cells Activation (proliferation B T and differentiation) of B T T and B lymphocytes Killing of infected cell (CTL) T Regulatory Suppression of T lymphocyte T immune response Killing of infected cell cell Fig. 5.4 The principal classes of lymphocytes and their functions. B lymphocytes and T lymphocytes are cells of adaptive immunity, and natural killer (NK) cells are cells of innate immunity. Several more classes of lymphocytes have been identified, including NK-T cells and so-called “innate lymphoid cells” (ILCs); the functions of these cells are not established.


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Pathology_Robbins. (cytokines) that help B cells to produce antibodies and also help macrophages to destroy phagocytosed microbes. The central role of CD4+ helper cells in immunity is highlighted by the severe compromise that results from destruction of these cells by human immunodeficiency virus (HIV) infection (described later). CD8+ T cells also can secrete cytokines, but their most important role is to directly kill virus-infected cells and tumor cells; hence, they are called cytotoxic T lymphocytes (CTLs). Other important invariant proteins on T cells include CD28, which functions as the receptor for molecules called costimulators that are induced on APCs by microbes, and various adhesion molecules that strengthen the bond between the T cells and APCs and control the migration of the T cells to different tissues. T cells that function to suppress immune responses are called regulatory T lymphocytes. This cell type is described later, in the context of tolerance of self antigens.


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Pathology_Robbins. While most T cells express TCRs composed of α and β chains, a minority of peripheral blood T cells and many T cells associated with mucosal surfaces (e.g., lung, gastrointestinal tract) express TCRs that are composed of γ and δ chains, which are similar but not identical to α and β chains. Such γδ T cells, which do not express CD4 or CD8, recognize nonprotein molecules (e.g., bacterial lipoglycans), but their functional roles are not well understood. Another small population of T cells expresses markers of both T cells and NK cells. These so-called NKT cells recognize microbial glycolipids and may play a role in defense against some infections. The antigen receptors of γδ T cells and NKT cells recognize antigens independently of MHC molecules, and are much less diverse than the receptors of the more abundant CD4+ and CD8+ T cells. We will not discuss these rare lymphocyte populations further.


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Pathology_Robbins. Fig. 5.5 TheT-cellreceptor(TCR)complexandothermoleculesinvolvedinT-cellactivation.TheTCRheterodimer,consistingofanα chainandaβ chain,recognizesantigen(intheformofpeptide-MHCcomplexesexpressedonantigen-presentingcells),andthelinkedCD3complexandζ chainsinitiateactivatingsignals.CD4andCD28arealsoinvolvedinT-cellactivation.(NotethatsomeTcellsexpressCD8andnotCD4;thesemoleculesserveanalogousroles.)Thesizesofthemoleculesarenotdrawntoscale.MHC, Majorhistocompatibilitycomplex. Major Histocompatibility Complex Molecules: The Peptide Display System of Adaptive Immunity


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Pathology_Robbins. Major Histocompatibility Complex Molecules: The Peptide Display System of Adaptive Immunity MHC molecules are fundamental to T-cell recognition of antigens, and genetic variations in MHC molecules are associated with many immunologic diseases; hence, it is important to review the structure and function of these molecules. The MHC was discovered on the basis of studies of graft rejection and acceptance (tissue, or “histo,” compatibility). It is now known that the normal function of MHC molecules is to display peptides for recognition by CD4+ and CD8+ T lymphocytes. In each person, T cells recognize only peptides displayed by that person’s MHC molecules, which, of course, are the only MHC molecules that the T cells normally encounter. This phenomenon is called MHC restriction. The human MHC, known as the human leukocyte antigen (HLA) complex, consists of a cluster of genes on chromosome 6 (


Pathology_Robbins

Pathology_Robbins. The human MHC, known as the human leukocyte antigen (HLA) complex, consists of a cluster of genes on chromosome 6 ( Fig. 5.6 ). On the basis of their chemical structure, tissue distribution, and function, MHC gene products fall into two main categories: • Class I MHC molecules are expressed on all nucleated cells and are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C (see


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Pathology_Robbins. Fig. 5.6 ). Each of these molecules consists of a polymorphic α chain noncovalently associated with an invariant β2microglobulin polypeptide (encoded by a separate gene on chromosome 15). The extracellular portion of the α chain contains a cleft where the polymorphic residues are located and where foreign peptides bind to MHC molecules for presentation to T cells, and a conserved region that binds CD8, ensuring that only CD8+ T cells can respond to peptides displayed by class I molecules. In general, class I MHC molecules bind and display peptides derived from protein antigens present in the cytosol of the cell (e.g., viral and tumor antigens). Class II MHC molecules are encoded by genes in the HLA-D region, which contains three subregions: DP, DQ, and DR. Class II molecules are heterodimers of noncovalently linked α and β subunits (see


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Pathology_Robbins. Class II MHC molecules are encoded by genes in the HLA-D region, which contains three subregions: DP, DQ, and DR. Class II molecules are heterodimers of noncovalently linked α and β subunits (see Fig. 5.6 ). Unlike class I MHC molecules, which are expressed on all nucleated cells, expression of class II MHC molecules is restricted to a few cell types, mainly APCs (notably, dendritic cells), macrophages, and B cells. The extracellular portion of class II MHC molecules contains a cleft for the binding of antigenic peptides and a region that binds CD4. In general, class II MHC molecules bind to peptides derived from extracellular proteins synthesized outside the cell, for example, from microbes that are ingested and then broken down inside the cell. This property allows CD4+ T cells to recognize the presence of extracellular pathogens. Several other proteins are encoded in the MHC locus, including complement components (C2, C3, and Factor


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Pathology_Robbins. Several other proteins are encoded in the MHC locus, including complement components (C2, C3, and Factor B) and the cytokines tumor necrosis factor (TNF) and lymphotoxin.


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Pathology_Robbins. HLA genes are highly polymorphic; that is, there are alternative forms (alleles) of each gene at each locus (estimated to number over 10,000 for all HLA genes and over 3500 for HLA-B alleles alone). Each individual expresses only one set of HLA genes. It is believed that the polymorphism of MHC genes evolved to enable display of and response to any conceivable microbial peptide encountered in the environment. As a result of the polymorphism, a virtually infinite number of combinations of HLA molecules exists in the population. The HLA genes are closely linked on chromosome 6, so they are passed from parent to offspring en bloc and behave like a single locus with respect to their inheritance patterns. Each set of maternal and paternal HLA genes is referred to as an HLA haplotype. Because of this mode of inheritance, the probability that siblings will share the same two HLA haplotypes is 25%. By contrast, in most populations the probability that an unrelated donor will share the same


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Pathology_Robbins. of this mode of inheritance, the probability that siblings will share the same two HLA haplotypes is 25%. By contrast, in most populations the probability that an unrelated donor will share the same two HLA haplotypes is very low. The implications of HLA polymorphism for transplantation are obvious; because each person has HLA alleles that differ to some extent from those of every other unrelated individual, grafts from unrelated donors will elicit immune responses in the recipient and be rejected. Only identical twins can accept grafts from one another, without fear of rejection. Even grafts from a donor to a sibling with the same HLA haplotype may be rejected because of differences in so-called “minor histocompatibility loci”, other sets of polymorphic genes that are likely to differ by chance. (The only exception to this rule, of course, are identical twins) In fact, HLA molecules were discovered in the course of early attempts at tissue transplantation, because HLA molecules of


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Pathology_Robbins. by chance. (The only exception to this rule, of course, are identical twins) In fact, HLA molecules were discovered in the course of early attempts at tissue transplantation, because HLA molecules of the graft evoke immune responses that eventually lead to graft destruction http://ebooksmedicine.net


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Pathology_Robbins. Class II MHC Complement Cytokines Class I MHC molecules proteins, others molecules Fig. 5.6 The human leukocyte antigen (HLA) complex and the structure of HLA molecules. (A) The location of genes in the HLA complex. The relative locations, sizes, and distances between genes are not to scale. Genes that encode several proteins involved in antigen processing (the TAP transporter, components of the proteasome, and HLA-DM) are located in the class II region (not shown). (B) Schematic diagrams and crystal structures of class I and class II HLA molecules. (Crystal structures are courtesy of Dr. P. Bjorkman, California Institute of Technology, Pasadena, California.) (discussed later). This ability of MHC molecules to trigger immune responses is the reason these molecules are often called antigens.


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Pathology_Robbins. The inheritance of particular MHC alleles influences both protective and harmful immune responses. The ability of any given MHC allele to bind the peptide antigens generated from a particular pathogen will determine whether a specific person’s T cells can recognize and mount a protective response to that pathogen. Conversely, if the antigen is ragweed pollen and the response is an allergic reaction, inheritance of some HLA genes may make individuals susceptible to hay fever, the colloquial name for ragweed allergy. Finally, many autoimmune diseases are associated with particular HLA alleles. We return to a discussion of these associations when we consider autoimmunity. B (bone marrow–derived) lymphocytes are the cells that produce antibodies, the mediators of humoral immunity. B cells make up 10% to 20% of the circulating peripheral lymphocyte population. They also are present in bone marrow and in the follicles of peripheral (secondary) lymphoid organs.


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Pathology_Robbins. B cells recognize antigen by means of membrane-bound antibody of the immunoglobulin M (IgM) class, expressed on the surface together with signaling molecules to form the B-cell receptor (BCR) complex ( Fig. 5.7 ). Whereas T cells recognize only MHC-associated peptides, B cells recognize and respond to many more chemical structures, including soluble or cell-associated proteins, lipids, polysaccharides, nucleic acids, and small chemicals, without a requirement for the MHC. As with TCRs, each antibody has a unique amino acid sequence. This sequence diversity is a consequence of the rearrangement and assembly of a multitude of immunoglobulin (Ig) gene segments, a process that creates functional Ig genes. B cells express several invariant molecules that are responsible for signal transduction and B-cell activation (see


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Pathology_Robbins. Fig. 5.7 ). Some are signaling molecules attached to the BCR; another example is CD21 (also known as the type 2 complement receptor, or CR2), which recognizes a complement breakdown product that frequently is deposited on microbes and promotes B-cell responses to microbial antigens. Interestingly, the ubiquitous Epstein-Barr virus has cleverly evolved to use CD21 as a receptor for binding to B cells and infecting them. After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies. There are five classes, or isotypes, of immunoglobulins: IgG, IgM, and IgA constitute more than 95% of circulating antibodies. IgA is the major isotype in mucosal secretions; IgE is present in


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Pathology_Robbins. Fig. 5.7 StructureofantibodiesandtheB-cellantigenreceptor.(A)TheB-cellantigenreceptorcomplexiscomposedofmembraneimmunoglobulinM(IgM;orIgD,not shown),whichrecognizesantigens,andtheassociatedsignalingproteinsIgα andIgβ.CD21isareceptorforacomplementcomponentthatalsopromotesB-cellactivation.(B)CrystalstructureofasecretedIgGmolecule,showingthearrangementofthevariable(V)andconstant(C)regionsoftheheavy(H)andlight(L)chains.(Courtesy of Dr. Alex McPherson, University of California, Irvine, California.) the circulation at very low concentrations and also is found attached to the surfaces of tissue mast cells; and IgD is expressed on the surfaces of B cells but is secreted at very low levels. These isotypes differ in their ability to activate complement and recruit inflammatory cells, and thus have different roles in host defense and disease states.


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Pathology_Robbins. NK cells are lymphocytes that arise from the same common lymphoid progenitor that gives rise to T lymphocytes and B lymphocytes. However, NK cells are innate immune cells, as they are functional without prior activation and do not express highly variable and clonally distributed receptors for antigens. Instead, NK cells have two types of receptors—inhibitory and activating. Inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells, whereas activating receptors recognize molecules that are expressed or upregulated on stressed or infected cells. Normally, the effects of inhibitory receptors dominate over those of activating receptors, preventing spontaneous activation of the NK cells. Infections (especially viral infections) and stress are associated with reduced expression of class I MHC molecules and increased expression of proteins that engage activating receptors. The net result is that the NK cells are activated and the infected or stressed


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Pathology_Robbins. with reduced expression of class I MHC molecules and increased expression of proteins that engage activating receptors. The net result is that the NK cells are activated and the infected or stressed cells are killed and eliminated. NK cells also secrete cytokines such as interferon-γ (IFN-γ), which activates macrophages to destroy ingested microbes, and thus NK cells provide early defense against intracellular microbial infections.


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Pathology_Robbins. Innate lymphoid cells (ILCs) are populations of lymphocytes that lack TCRs but produce cytokines similar to those that are made by T cells. They are classified into three groups, which produce IFN-γ, IL-5, or IL-17, cytokines that are characteristic of TH1, TH2, and TH17 subsets of T cells, respectively (described later). NK cells are related to group 1 ILCs based on their production of IFN-γ, a cytokine also made by TH1 cells. Because ILCs mostly reside in tissues, they are thought to provide early defense against infections in the tissues, before T cells are activated and can migrate into tissues. ILCs also may be early participants in inflammatory diseases.


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Pathology_Robbins. The immune system contains several cell types that are specialized to capture antigens and display these to lymphocytes. Foremost among these APCs are dendritic cells, the major cells for displaying protein antigens to naïve T cells. Several other cell types present antigens to lymphocytes at various stages of immune responses. Dendritic cells (DCs) are the most important antigen-presenting cells for initiating T-cell responses against protein antigens. These cells have numerous fine cytoplasmic processes that resemble dendrites, from which they derive their name. Several features of DCs account for their key role in antigen capture and presentation. These cells are located at the right place to capture antigens—under epithelia, the common site of entry of microbes and foreign antigens, and in the interstitia of all tissues, where antigens may be produced. DCs within the epidermis are called Langerhans cells.


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Pathology_Robbins. DCs express many receptors for capturing and responding to microbes (and other antigens), including TLRs and C-type lectin receptors. In response to microbes, DCs are recruited to the T-cell zones of lymphoid organs, where they are ideally positioned to present antigens to T cells. DCs express high levels of MHC and other molecules needed for antigen presentation and activation of T cells. One subset of DCs is called plasmacytoid DCs because of their resemblance to plasma cells. These cells are present in the blood and lymphoid organs, and are major sources of the anti-viral cytokine type I interferon, produced in response to many viruses. A second type of cell with dendritic morphology is present in the germinal centers of lymphoid follicles in the spleen and lymph nodes and is called the follicular dendritic cell (FDC). These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or http://ebooksmedicine.net


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Pathology_Robbins. Table 5.1 Distribution of Lymphocytes in Tissues *Approximate numbers of lymphocytes in different tissues in a healthy adult. complement proteins. These cells display antigens to B lymphocytes in lymphoid follicles and promote antibody responses, but are not involved in capturing antigens for display to T cells. Macrophages (Chapter 3) ingest microbes and other particulate antigens and display peptides for recognition by T lymphocytes. These T cells in turn activate the macrophages to kill the microbes, the central reaction of cell-mediated immunity. B cells present peptides to helper T cells and receive signals that stimulate antibody responses to protein antigens, critical steps in humoral immune responses.


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Pathology_Robbins. The tissues of the immune system consist of the generative (also called primary, or central) lymphoid organs, in which T lymphocytes and B lymphocytes mature and become competent to respond to antigens, and the peripheral (or secondary) lymphoid organs, in which adaptive immune responses to microbes are initiated. The principal generative lymphoid organs are the thymus, where T cells develop, and the bone marrow, the site of production of all blood cells and where B lymphocytes mature. The major peripheral organs are briefly described in the following sections. The peripheral lymphoid organs are organized to concentrate antigens, APCs, and lymphocytes in a way that optimizes interactions among these cells and the development of adaptive immune responses. Most of the body’s lymphocytes are located in these organs ( Table 5.1


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Pathology_Robbins. Table 5.1 Lymph nodes are encapsulated, highly organized collections of lymphoid cells and innate immune cells that are located along lymphatic channels throughout the body ( Fig. 5.8A ). As lymph passes through lymph nodes, resident APCs are able to sample antigens that are carried to the node in lymph derived from the interstitial fluids of tissues. In addition, DCs transport antigens from nearby epithelial surfaces and tissues by migrating through lymphatic vessels to the lymph nodes. Thus, antigens (e.g., of microbes that enter through epithelia or colonize tissues) become concentrated in draining lymph nodes. The spleen has an important role in immune responses to bloodborne antigens. Blood entering the spleen flows through a network of sinusoids, which enables the


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Pathology_Robbins. The spleen has an important role in immune responses to bloodborne antigens. Blood entering the spleen flows through a network of sinusoids, which enables the Fig. 5.8 Morphology of a lymph node. (A) The histology of a lymph node, with an outer cortex containing follicles and an inner medulla. (B) The segregation of B cells and T cells in different regions of the lymph node, illustrated schematically. (C) The location of B cells (stained green, using the immunofluorescence technique) and T cells (stained red) in a lymph node. (Courtesy of Drs. Kathryn Pape and Jennifer Walter, University of Minnesota School of Medicine, Minneapolis, Minnesota.) trapping of bloodborne antigens by resident DCs and macrophages.


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Pathology_Robbins. • The cutaneous and mucosal lymphoid systems are located under the epithelia of the skin and the gastrointestinal and respiratory tracts, respectively. They respond to antigens that enter through breaches in the epithelium. Pharyngeal tonsils and Peyer’s patches of the intestine are two anatomically defined mucosal lymphoid tissues. The large number of lymphocytes in mucosal organs (second only to lymph nodes) reflects the huge surface area of these organs. Within the peripheral lymphoid organs, T lymphocytes and B lymphocytes are segregated into different regions (


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Pathology_Robbins. Within the peripheral lymphoid organs, T lymphocytes and B lymphocytes are segregated into different regions ( Fig. 5.8B, C ). In lymph nodes, the B cells are concentrated in discrete structures, called follicles, located around the periphery, or cortex, of each node. If the B cells in a follicle have recently responded to an antigen, the follicle develops a central pale-staining region called a germinal center. The T lymphocytes are concentrated in the parafollicular cortex. The follicles contain the FDCs that are involved in the activation of B cells, and the paracortex contains the DCs that present antigens to T lymphocytes. In the spleen, T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding small arterioles, and B cells reside in the follicles.


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Pathology_Robbins. Lymphocytes constantly travel between tissues and home to particular sites. Naive lymphocytes circulate through peripheral lymphoid organs where antigens are concentrated and immune responses are initiated, and effector lymphocytes migrate to sites of infection. The process of lymphocyte recirculation is most important for T cells, because naïve T cells have to “patrol” widely distributed peripheral lymphoid organs to find antigens, and effector T cells have to home to sites of infection to eliminate microbes. In contrast, plasma cells do not need to migrate to sites of infection because they secrete antibodies that are transported via the blood and lymph to distant tissues. Cytokines: Messenger Molecules of the Immune System


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Pathology_Robbins. Cytokines: Messenger Molecules of the Immune System Cytokines are secreted proteins that mediate immune and inflammatory reactions. Molecularly defined cytokines are called interleukins, a name implying a role in communication between leukocytes. Most cytokines have a wide spectrum of effects, and some are produced by several different cell types. The majority of these cytokines act on the cells that produce them or on neighboring cells, but some (like IL-1) have systemic effects. Different cytokines contribute to specific types of immune responses. In innate immune responses, cytokines are produced rapidly after microbes and other stimuli are encountered, and function to induce inflammation and inhibit virus replication. These cytokines include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines (Chapter 3). Their major sources are macrophages, DCs, ILCs, and NK cells, but endothelial and epithelial cells also can produce them.


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Pathology_Robbins. In adaptive immune responses, cytokines are produced principally by CD4+ T lymphocytes activated by antigen and other signals, and function to promote lymphocyte proliferation and differentiation and to activate effector cells. The main ones in this group are IL-2, IL-4, IL-5, IL-17, and IFN-γ; their roles in immune responses are described later. Some cytokines serve mainly to limit and terminate immune responses; these include TGF-β and IL-10. • Some cytokines stimulate hematopoiesis and are called colony-stimulating factors because they stimulate formation of blood cell colonies from bone marrow progenitors (Chapter 12). Their functions are to increase leukocyte numbers during immune and inflammatory responses, and to replace leukocytes that are consumed during such responses. They are produced by marrow stromal cells, T lymphocytes, macrophages, and other cells. Examples include GM-CSF and IL-7.


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Pathology_Robbins. The knowledge gained about cytokines has numerous practical therapeutic applications. Inhibiting cytokine production or actions can control the harmful effects of inflammation and tissue-damaging immune reactions. Patients with rheumatoid arthritis often show dramatic responses to TNF antagonists, an elegant example of rationally designed and molecularly targeted therapy. Many other cytokine antagonists are now approved for the treatment of various inflammatory disorders. Conversely, administration of cytokines is used to boost reactions that are normally dependent on these proteins, such as hematopoiesis and defense against some viruses.


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Pathology_Robbins. Adaptive immune responses develop in steps, consisting of: antigen recognition; activation, proliferation and differentiation of specific lymphocytes into effector and memory cells; elimination of the antigen; and decline of the response, with memory cells being the long-lived survivors. The major events in each step are summarized next; these general principles apply to protective responses against microbes as well as pathologic responses that injure the host. Microbes and other foreign antigens can enter the body virtually anywhere, and it is obviously impossible for lymphocytes of every specificity to patrol every possible portal of antigen entry. To overcome this problem, microbes and their protein antigens in epithelia and other tissues are captured by resident dendritic cells, which then carry their antigenic cargo to draining lymph nodes through which T cells constantly recirculate (


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Pathology_Robbins. Fig. 5.9 ). Here the antigens are processed and displayed complexed with MHC molecules on the cell surface, where the antigens are recognized by T cells. Similarly, soluble antigens are captured and concentrated in follicles in lymph nodes and the spleen, where they may be recognized by B cells via their antigen receptors. At the same time as microbial antigens are recognized by T lymphocytes and B lymphocytes, the microbe http://ebooksmedicine.net MACROPHAGE ACTIVATION, KILLING OF KILLING OF INGESTED MICROBES INFECTED CELLS


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Fig.

Pathology_Robbins. Fig.


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Pathology_Robbins. 5.9 Cell-mediated immunity. Dendritic cells (DCs) capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes. During this process, the DCs mature, and express high levels of MHC molecules and costimulators. Naïve T cells recognize MHC-associated peptide antigens displayed on DCs. The T cells are activated to proliferate and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. CD4+ effector T cells of the TH1 subset recognize the antigens of microbes ingested by phagocytes, and activate the phagocytes to kill the microbes; other subsets of effector cells enhance leukocyte recruitment and stimulate different types of immune responses. CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Some activated T cells remain in the lymphoid organs and help B cells to produce antibodies, and some T cells differentiate into long-lived m


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Pathology_Robbins. ) kill infected cells harboring microbes in the cytoplasm. Some activated T cells remain in the lymphoid organs and help B cells to produce antibodies, and some T cells differentiate into long-lived memory cells (not


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shown). APC, Antigen-presenting cell.

Pathology_Robbins. shown). APC, Antigen-presenting cell.