Robbins Essential Pathology PDF - Diseases of the Immune System
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This document, from Robbins Essential Pathology, focuses on diseases of the immune system, covering topics like pathogenesis, clinical features, and morphology. This is a medical textbook and not an exam paper.
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52 CHAPTER 4 Diseases of the Immune System A B...
52 CHAPTER 4 Diseases of the Immune System A B C Fig. 4.9 Systemic sclerosis. (A) Normal skin. (B) Skin biopsy from a patient with systemic sclerosis. Note the extensive deposition of dense collagen in the dermis with virtual absence of appendages (e.g., hair follicles) and foci of inflammation (arrow). (C) The extensive subcutaneous fibrosis has virtually immobilized the fingers, creating a clawlike flexion deformity. Loss of blood supply has led to cutaneous ulcerations. (C, Courtesy Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas.) Pathogeness. he dsease s oten assocaed w oer auommune Clncal Features. Because o desrucon o e acrma gands, ere dsorders and e presence o serum auoanbodes, supporng an s dr yness o e eyes and secondar y nlammaon and uceraon o auommune eoog y. O e varous auoanbodes, wo dreced e cornea (keraoconjuncvs scca). Lack o sava causes dr yness owards rbonuceoproen angens SS-A and SS-B are specc or o e mou (xerosoma). Nasa dr yness may ead o uceraon and, s dsease. he rggers or anbody ormaon are no known, and n some cases, peroraon o e sepum. Lesons ousde e gands, as even been suggesed a e dsease s naed by vra necon seen n abou a o paens, ncude synovs, perpera neuropay, o e savar y gands, w a perssen auommune T-ce reacon and pumonar y bross. More an a o e paens ave anoer deveopng subsequeny. auommune dsease, mos requeny reumaod arrs. REJECTION OF TRANSPLANTS Morphology. Te acr ma and s a var y g ands are e maj or ar- he repacemen o damaged or unconay mpared organs by rans- ges o e ds e as e, bu o er exo c r ne g ands , ncud ng o s e panaon o organs rom oer ndvduas as become sandard med- nng e respraor y and g as ro nes na rac s and e v ag na, ca pracce. Abou 30,000 organ ranspans are perormed yeary n a s o may be nvove d. T e a cr ma and s a var y g ands c on a n e Uned Saes, e mos common beng e kdney (accounng or dens e n raes o CD4+ T c e s (Fg. 4.10); n e arger s a var y amos a ), oowed by e ear, ver, ung, and pancreas. Trans- g ands, y mpod o ces w ger m na ceners , nd c a ve o a panaon o emaopoec sem ces s wdey used o rea bo B ce re ac on, may a s o be s e en. S a v ar y g ands may be v s by neopasc and nonneopasc dsorders o bood ces. Excep n rare en arge d. cases o denca wns, e grat donor and recpen are genecay CHAPTER 4 Diseases of the Immune System 53 A B Fig. 4.10 Sjögren syndrome. (A) Enlargement of the salivary gland. (B) Intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia in a salivary gland. (A, Courtesy Dr. Richard Sontheimer, Depart- ment of Dermatology, University of Texas Southwestern Medical School, Dallas. B, Courtesy Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School, Dallas.) dferen. Some o ese dferences are recognzed by e mmune sys- dferen ypes s a, aoug e paerns were dened on e bass em and are responsbe or mmune desrucon o e grat, caed o paoogc and cnca eaures, eac s caused by specc mmune rejecton. Grats excanged beween nondenca ndvduas o e mecansms. same speces are caed aograts. Hyperacue rejecon. hs s medaed by anbodes specc or donor angens a are presen n e recpen pror o ranspan- Immune Responses to Organ Allografts aon. I occurs ver y rapdy oowng connecon o e grat vas- The principal graft antigens recognized by the recipient’s immune cuaure o e os crcuaon, wen preormed anbodes lood system are histocompatibility molecules, which evoke both cellular e grat. hese anbodes bnd o grat endoeum, acvang e and humoral immune responses. compemen sysem and coaguaon cascade, causng rapd rom- As e name mpes, socompaby moecues were dscov- boss o e vesses and scemc necross o e grat (Fg. 4.11). In ered as e moecues a deermne weer or no ssue grats e pas, ABO bood group ncompaby was e greaes rsk or (so, ssue) excanged beween ndvduas woud be acceped yperacue rejecon, snce ndvduas ackng a parcuar ABO (compabe). he major socompaby compex (MHC, or HLA angen make anbodes agans a angen. Recpens wo ave n umans) s a coecon o gy poymorpc genes a d- been senszed by bood ransusons or prevous ranspan are aso er among ndvduas. he pysoogc uncon o MHC proens a rsk. Careu bood group macng o recpens and prospecve encoded by ese genes s o dspay pepde angens or recognon donors and cross-mac esng or serum anbodes n e recpen by T ces. I e grat donor expresses MHC moecues a dfer reacve w donor ssue ave argey emnaed s probem. rom ose n e recpen, e grat s recognzed as oregn by e Acue rejecon. hs orm o rejecon deveops days o weeks ater recpen’s T ces. MHC moecues n e grat may be presened on ranspanaon and eads o grat aure. In acue ceuar rejecon, grat ces (parencyma ces and APCs) and be recognzed by recp- CD8+ CTLs k grat parencyma ces (Fg. 4.12). A e same en T ces (drec recognon), or grat MHC moecues may be aken me, CD4+ T ces smuae nlammaon n e grat, wc up by e recpen’s APCs and presened o T ces (ndrec recogn- exacerbaes e damage. In acue umora (or vascuar) rejecon, on). In bo cases, e recpen’s CD4+ and CD8+ T ces specc anbodes are produced agans donor angens, bnd o grat endo- or grat angens are acvaed, mgrae back no e ranspan, and eum, and cause damage many by compemen-dependen cause s rejecon. Recpen B ces aso recognze moecues n e mecansms (Fg. 4.13). Oten, e ceuar and umora reacons grat as oregn, resung n e producon o anbodes specc or coexs. Immunosuppressve erapy as been more successu n ese moecues. reang acue rejecon an any oer orm. Cronc rejecon. W ncreasngy efecve erapy o acue rejec- Mechanisms of Rejection of Solid-Organ Allografts on, cronc rejecon, wc deveops over mons o years, as Rejection of allografts is mediated by T cells and antibodies. become e major cause o grat aure. Cronc rejecon s carac- CD4+ T ces specc or grat angens secree cyoknes a nduce erzed by vascuar njur y and nma bross, eadng o narrowng nlammaon n e grat; CD8+ CTLs k grat ces; and anbodes o vesses and scema, and nersa bross due o proonged bnd o grat ssues (noaby endoeum because s e mos access- nlammaon and scemc ssue njur y (Fg. 4.14). be o crcuang anbodes), acvae compemen, and cause njury o e ssues. A ree mecansms may be nvoved smuaneousy, bu as Treatment of Graft Rejection s dscussed aer, ey pay domnan roes n dferen ypes o rejecon. In a excep denca wns, mmunosuppresson s needed o proong The major patterns of rejection reect different mechanisms of grat sur vva. Corcoserods, an–T-ce anbodes, and drugs a graft injury and have different morphologic and clinical features. nb T-ce uncon are e mansays o reamen. Immunosuppres- hese paerns were rs descrbed and are bes esabsed or son carres e rsk o opporunsc unga and vra necons. Reac- kdney ranspans, bu e same prncpes appy o e rejecon o vaon o aen vruses (e.g., poyomavrus and cyomegaovrus), as a sod organ ranspans. he uy o cassyng rejecon no 54 CHAPTER 4 Diseases of the Immune System Complement activation, endothelial damage, Blood Endothelial inflammation and thrombosis vessel cell Alloantigen Circulating alloantigen- (e.g., blood group antigen) specific antibody A B Fig. 4.11 Hyperacute rejection. (A) Deposition of antibody on endothelium and activation of complement causes thrombosis. (B) Hyperacute rejection of a kidney allograft showing platelet and fibrin thrombi, early neutrophil infiltration, and severe ischemic injury (necrosis) in a glomerulus. + + A Alloantigen-specific CD8 and CD4 T cells + Direct CD8 + Cytokines CD4 killing Recruitment of macrophages Parenchymal cells and neutrophils B + CD8 Neutrophil + CD8 Macrophage Parenchymal cell damage Interstitial inflammation C Fig. 4.12 Acute cellular rejection. (A) Destruction of graft cells by T cells. Acute T cell–mediated rejection involves direct killing of graft cells by CD8+ CTLs and inflammation caused by cytokines produced by CD4+ T cells. (B) Acute cellular rejection of a kidney graft, manifested by inflammatory cells in the interstitium and between epithelial cells of the tubules (tubulitis). (C) Acute cellular rejection involving an artery with inflamma- tory cells damaging the endothelium (arrow). we as an ncreased rsk o cancers, are aso seen n mmunosuppressed he process was sorcay caed bone marrow ranspanaon paens. because e HSCs were soaed rom e donor’s bone marrow, bu now ese sem ces are mobzed rom e marrow o donors by rea- Hematopoietic Stem Cell Transplantation men w grow acors or agens a nb bndng o HSCs o The transplantation of hematopoietic stem cells (HSCs) is used to er marrow “nce”, aowng HSCs o be ar vesed n mos nsances treat leukemias and other hematologic malignancies, and to cor- rom e perpera bood. rect numerical or functional deciencies of blood cells. Recpens o HSCs need “condonng” o abae er own mmune sysem (o preven grat rejecon), creae “space” or e ranspaned Blood Endothelial cell vessel Alloreactive antibody Endotheliitis Complement activation A B C Fig. 4.13 Acute antibody-mediated (humoral) rejection. (A) Graft damage caused by antibody deposition in vessels. (B) Light micrograph showing inflammation (capillaritis) in peritubular capillaries (arrows) in a kidney graft. (C) Immunoperoxidase staining shows C4d deposition in peritubular capillaries and a glomerulus. (Cour- tesy Dr. Zoltan Laszik, Department of Pathology, University of California San Francisco.) Blood vessel Antibody binding Chronic inflammatory reaction to endothelial in vessel wall antigens Intimal smooth muscle proliferation Cytokines Vessel occlusion + CD4 Alloantigen- specific + CD4 T cell Cytokines A Vascular smooth muscle cell B C D Fig. 4.14 Chronic rejection. (A) Graft arteriosclerosis caused by T-cell cytokines and antibody deposition. (B) Graft arteriosclerosis in a cardiac transplant. (C) Transplant glomerulopathy, the characteristic manifestation of chronic anti- body-mediated rejection in the kidney. The glomerulus shows inflammatory cells within the capillary loops (glom- eruliitis), accumulation of mesangial matrix, and duplication of the capillary basement membrane. (D) Interstitial fibrosis and tubular atrophy, resulting from vascular narrowing and ischemia. In this trichrome stain, the blue area (asterisk) shows fibrosis, contrasted with the normal kidney on the top right. At the bottom right is an artery show- ing prominent arteriosclerosis. (B, Courtesy Dr. Richard Mitchell, Department of Pathology, Brigham and Women’s Hospital, Boston; C, courtesy Dr. Zoltan Laszik, Department of Pathology, University of California San Francisco.) 56 CHAPTER 4 Diseases of the Immune System sem ces, and (n e case o eukema and oer magnances) k S evere combned mmunodeicency (SCID) presens n nanc y umor ces. he major probem w HSC ranspanaon s grat- w deecs n umora and ce-medaed mmuny and suscep- versus-os dsease (GVHD). Grats conan no ony HSCs bu aso by o a dverse range o necons. I s mos oten caused by maure T ces, and ese ces can aack os ssues and cause serous deecs n T-ce mauraon, and e absence o T-ce ep eads and even aa cnca probems. Even sma, non-MHC dferences o reduced anbody producon. Abou a e cases are X-nked beween donor and recpen can ec s response. he recpen, (X-SCID), caused by a muaon n e gene on e X cromosome beng mmunodecen, canno rejec e oregn, aackng ces. a encodes e common γ can (γc), one o e cans or e Acute GVHD s caracerzed by T ce–medaed kng o epea recepors or many c yoknes, ncudng nereukns IL-2 and IL-7. ces o e ver, gasronesna rac, and skn, producng ver aure B ecause IL-7 s requred or e proeraon o T-ce progenors, w jaundce, boody darrea, and rases. Cronc GVHD s a more e absence o IL-7 sgnang eads o a proound decenc y o ndoen condon n wc bross o e skn and oer ssues s maure T ces. As w a X-nked dseases, boys are afeced and promnen (probaby due o cronc nlammaon) and ere are var- grs are carrers. ous manesaons o auommuny (because o proonged acvaon he remanng cases o SCID are auosoma recessve. he o ympocyes). he cnca and soogc pcure may resembe sys- mos requen muaon n ese cases s n e gene encodng e emc sceross. enzyme adenosne deamnase, wc s expressed a g eves n Recpens o HSC ranspans aso may ave proound mmuno- deveopng T ces n e ymus. Adenosne deamnase decenc y decency beore e ranspaned ces produce adequae numbers o eads o e accumuaon o oxc purne meaboes, wc are granuocyes and T ympocyes. Recover y o mmune compeence especay damagng o rapdy proerang ces suc as mma- may ake severa mons. ure ympoc yes. Many oer genes ave been dened n rare cases o auosoma recessve SCID. Because bo T-ce and B-ce responses are mpared, paens IMMUNODEFICIENCY DISORDERS presen w recurren necons w a wde range o paogens, Immunodeciencies make individuals susceptible to infections and ncudng ung (Candda, Pneumocysts), bacera (Pseudomonas), and cancers. vruses (cyomegaovrus, varcea). HSC ranspanaon can repop- Aoug md decences o e mmune sysem seem o be que uae e paens w norma mmune ces and s e mansay o common, cncay sgncan deecs are reavey rare. he nec- reamen. X-SCID s e rs dsease a as been reaed w gene ous dseases ese paens ge may be e resu o new necons erapy, n wc a norma γc gene s nroduced no HSCs o paens w opporunsc and paogenc mcrobes or reacvaon o aen and e ces are ranspaned no e paens. necons. he cancers are mos oten vrus nduced bu can be que X-nked agammagobunema s due o a deec n B-ce maura- dverse. Paradoxcay, some paens w deecve mmune sysems on and a resuan aure o produce anbodes (gamma gobu- deveop auommuny, a relecon o a yperacve mmune sysem. ns s an od name or crcuang anbodes). he deec s caused he reason or s assocaon s uncear ; may be because oerance by muaons n e gene encodng a sgnang moecue, Bruon mecansms are os or because perssen necons nduce excessve yrosne knase. hs knase s assocaed w e B-ce recepor mmune acvaon. n maure B ces and e pre-B ce recepor n B ce progenors, and devers sgnas a are requred or B-ce proeraon and Immunodeciency diseases may be primary (resulting from muta- mauraon. Wou ese sgnas, B ces de a e pre-B sage, tions) or secondary to other disorders. resung n e absence o anbody-producng B ces and pasma Pr mar y mmunode f c e nc es are c aus e d by mu a ons a are ces. Afeced cdren are suscepbe o many bacera and vra usu a y n er e d, so e e r m congenta mmunode f c enc y s o en necons. us e d, bu s ome mes e mu a on s a ne w one n e a e c e d X -nked y per-IgM sy ndrome was orgnay dened by e p a en. Pa ens y p c a y pres en w re c ur re n n e c ons n absence o cass-swced IgG and IgA anbodes, and, ence, e nanc y or e ary c d o o d, bu n s ome d s e as es e rs sy mpoms domnance o IgM. I s usuay assocaed w a proound de- app e ar aer n e. cenc y o ce-medaed mmuny. he dsease s mos requeny Secondary mmunodeicences are muc more common an pr- caused by muaons n e gene or CD40-gand (CD40L), wc mar y ones. In ger-ncome counres, e mos requen cause o s expressed on eper T ces and s a mecansm by wc CD4+ mmunodecency s erapy a desroys e mmune sysem (e.g., T ces acvae (ep) B ces and macropages. CD40L bnds o cemoerapy and radaon or cancer) or a s used o nenonay CD40 on B ces and macropages, and devers sgnas a sm- suppress e mmune sysem (e.g., or grat rejecon and auommune uae B-ce responses as we as macropage acvaon (e cen- dseases). In ower-ncome counres, manuron s a major cause ra reacon o ce-medaed mmuny). Afeced cdren sufer o mmunodecency. he acqured mmunodecency syndrome rom necons by pyogenc and nraceuar bacera, vr uses, (AIDS) s an mporan cause o mmunodecency wordwde, and s and ung. dscussed aer. C ommon var abe mmunode f c e nc y s more re quen an e o er mmuno de c enc es d s c uss e d, bu s b ass s obs c ure. Primary (Congenital) Immunodeficiencies Pa ens ave de c ences o p as ma ce s and an b o d es, Primary immunodeciencies are caused by mutations that impact a oug e numb er o B c e s s v r u a y nor ma , sug ge s ng a one or more components of innate or adaptive immunity. bo ck n e d eren a on o maure B c e s. Te ge ne c b ass Because o e ncreasng use o DNA sequencng ecnoog y n s k now n n e wer an 10 % o c as e s ; mu a ons a e c ng re c e p - medcne, e genec bass o many prmar y mmunodecences s ors or g row ac ors and o e r y mpo c y e s g na ng p a ways now known. Tabe 4.7 and Suppemena eFg. 4.5 summarze e mos ave b e en rep or e d. Pa ens are sus c ep be o b ac e r a n e c- common o ese. Seeced dseases a usrae mporan prncpes ons. are dscussed beow. CHAPTER 4 Diseases of the Immune System 56.e1 BONE MARROW THYMUS Pluripotent stem cell ADA deficiency Pro-B cell Pro-T cell X-linked SCID Common γ (cytokine chain) myeloid-lymphoid progenitor Pre-B cell Immature T cell T-cell IgM Di George syndrome X-linked receptor heavy agammaglobulinemia chain (BTK) MHC class II deficiency CD40L IgM + CD4 T cell Mature T cells IgD Hyper-IgM syndrome Immature B cell (CD40L) + + CD8 CD4 CVID IgA deficiency IgM IgG IgA IgE Mature B cells Supplemental eFig. 4.5 Primary immune deficiency diseases. Shown are the principal pathways of lymphocyte development and the blocks in these pathways in selected primary immune deficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA, adenosine deaminase; CD40L, CD40 ligand (also known as CD154); CVID, common variable immunodeficiency; SCID, severe combined immunodeficiency.
