Robbins Essential Pathology Diseases of the Immune System PDF

48 CHAPTER 4 Diseases of the Immune System Cytokine-mediated inflammation...

48 CHAPTER 4 Diseases of the Immune System Cytokine-mediated inflammation Cytokines Inflammation + CD4 T cell APC presenting tissue antigen Tissue injury Nor mal tissue A T cell–mediated cytolysis + Cell killing and CD8 tissue injury T cell APC presenting tissue antigen B Fig. 4.6 Mechanisms of T cell–mediated tissue injury (type IV hypersensitivity). T cells may cause tissue injury and disease by two mechanisms. (A) Inflammation may be triggered by cytokines produced mainly + by CD4 T cells in which tissue injury is caused by activated macrophages and inflammatory cells. (B) Direct + killing of target cells is mediated by CD8 cytotoxic T lymphocytes (CTLs). APC, Antigen-presenting cell. Pathogeness. Cyokne-medaed ypersensvy s a reacon o h1 efecor ces, bu h17 ces aso may conrbue o e reacon, espe- cay n cases were neurops are promnen n e nlammaor y nrae. h1 ces secree cyoknes, many nereron-γ (IFN-γ), wc are responsbe or many o e manesaons o deayed-ype yper- sensvy. IFN-γ–acvaed (casscay acvaed) macropages produce subsances a desroy mcrobes and damage ssues, and medaors a promoe nlammaon. Acvaed h17 ces secree cyoknes a recru neurops and monocyes. In ce-medaed cyooxcy, CD8+ T ces k angen-expressng arge ces. CD8+ T ces aso produce cyoknes, noaby IFN-γ, and are nvoved n nlammaor y reacons resembng deayed-ype ypersensvy, especay oowng vrus necons and exposure o some conac-senszng agens. Clncal Features. he ypca manesaon o s orm o ypersens- vy s cronc nlammaon (Fg. 4.7). I s caed deayed-ype yper- A B sensvy because  deveops over 1 o 2 days ater an angen caenge n a prevousy senszed ndvdua (n conras w mmedae yper- Fig. 4.7 Delayed-type hypersensitivity reaction in the skin. (A) Perivas- sensvy). hs me ag s due o e mupe seps nvoved n e cular accumulation (cuffing) of mononuclear inflammatory cells (lym- reacon, ncudng e capure, processng, and presenaon o e phocytes and macrophages), with associated dermal edema and fibrin angen, acvaon o T ces, mgraon o efecor T ces o e se o deposition. (B) Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with anti-CD4 anti- angen caenge, and producon o cyoknes. hs ype o reacon s bodies. (B, Courtesy Dr. Louis Picker, Department of Pathology, Oregon seen n many mmunoogc dseases (Tabe 4.5). he adven o cyokne Health Sciences University, Portland.) anagonss as erapeuc agens as revouonzed e reamen and prognoss or paens w ese dsorders. For exampe, neurazaon o TNF s gy efecve n e reamen o reumaod arrs.  CHAPTER 4 Diseases of the Immune System 49 Table 4.5 T Cell–Mediated Hypersensitivity Diseases Disease Specificity of Pathogenic T Cells Principal Mechanisms of Tissue Injury Clinicopathologic Manifestations Rheumatoid Collagen (postulated) Inflammation mediated by Th17 (and Th1?) Chronic arthritis with synovial arthritis Citrullinated self proteins cytokines; role of antibodies and immune inflammation, destruction of complexes articular cartilage Multiple sclerosis Protein antigens in myelin (e.g., Inflammation mediated by Th1 and Th17 Demyelination in central nervous myelin basic protein) cytokines, myelin destruction by activated system with perivascular inflam- macrophages mation; paralysis Type 1 diabetes Antigens of pancreatic islet β cells T cell–mediated inflammation, destruction of Insulitis (chronic inflammation in mellitus islet cells by cytotoxic lymphocytes islets), destruction of β cells; diabetes Inflammatory Enteric bacteria; self antigens Inflammation mediated by Th1 and Th17 Chronic intestinal inflammation, bowel disease (unknown) cytokines obstruction Psoriasis Self antigen (unknown) Inflammation mediated mainly by Th17 Cutaneous plaques cytokines Contact sensitivity Various environmental chemicals (e.g., Inflammation mediated by Th1 (and Th17?) Epidermal necrosis, dermal inflam- urushiol from poison ivy, therapeutic cytokines mation, causing skin rash and drugs) blisters Examples of human T cell–mediated diseases are listed. AUTOIMMUNE DISEASES Genetic Environmental triggers Autoimmune diseases are caused by adaptive immune responses susceptibility against self antigens. Infections, I s es mae d  a  es e d s e as e s a e c  1 % o 5 % o Weser n p op- inflammation, u  a ons, and  er  nc d ence s e ems o be  nc re as  ng , or un k now n tissue injur y re as ons. B as e d on  e  nvove d  ssue s and c n c a  man  es a ons , auommune ds e as es are bro ad y dv  de d  no organ -sp e c    c and sysemc d s e as es (summar  z e d n Tabe 4.6). In sysemc ds e as es Susceptibility  a are c aus e d by  mmu ne comp exe s and auo an b o d es,  e genes Tissue esons pr ncp a  y a e c   e con ne c  ve  ssues and b o o d ve ss es o nvove d organs. T ereore,  es e d s e as es are o en reer re d o as co  agen vas c u  ar d s e as es or con ne c  ve  ssue d s e as es, e ven Failure of Activation self-tolerance  oug   e mmunoog c re a c  ons are no sp e c    c a  y d  re c e d of tissue APCs agans cons uens o con ne c  ve  ssue or b o o d vess es. Mechanisms of Autoimmunity Influx of Self-tolerance in T and B lymphocytes prevents harmful reactions self-reactive against self tissues. lymphocytes into tissues he norma mmune sysem can reac o an enormous dversy o Self-reactive oregn angens bu does no recognze or respond o se angens. he lymphocytes ack o reacvy s caed toerance (mpyng a e ces “oerae” e presence o e angen); e absence o mmune responsveness agans one’s own ssues s caed sef-toerance. Because auommuny resus rom a breakdown o se-oerance, we rs dscuss e major Activation of self-reactive mecansms o oerance. lymphocytes    C entra toerance. S e-reacve ympoc yes are emnaed (deeed) beore ey compee er mauraon n e ymus (or T ces) and bone marrow (or B ces). Numerous se an- gens are presen n ese organs, and wen mmaure ympoc yes w g-ainy recepors or ese angens encouner em, e Tissue injury: ces de. C enra oerance emnaes many poenay dangerous autoimmune disease se-reacve ympoc yes bu s mperec, and some o ese ces maure and ener perpera ssues. Fig. 4.8 Postulated mechanisms of autoimmunity. In this proposed    Reguatory T ces. he response o se-reacve ympocyes a model of organ-specific T cell–mediated autoimmunity, various genetic loci may confer susceptibility to autoimmunity, probably by escape deeon s prevened by e acons o reguaor y T ces influencing the maintenance of self-tolerance. Environmental trig- (Tregs) n perpera ssues. he bes-dened Tregs are CD4+ ces gers, such as infections and other inflammatory stimuli, promote the a express e ranscrpon acor Foxp3. A severe auommune influx of lymphocytes into tissues and the activation of antigen-pre- dsease afecng many organs occurs n boys wo ner deeer- senting cells (APCs) and subsequently of self-reactive T cells, result- ous muaons n e X-nked FOXP3 gene. ing in tissue injury. 50 CHAPTER 4 Diseases of the Immune System Table 4.6 Organ-Specific and Systemic Autoimmune common y ncr mnae d s  e HL A o c us, w   sp e c c HL A a  ees Diseases sow ng “o dds ra  os” ( re a ve r sk o de veopng a d s e as e com - p are d o ndv du a s w o do no  n e r   a a  ee) o e ss  an 2 Organ-Specific Diseases Systemic Diseases o more  an 100 or d   eren d s e as es. I s re as onab e o p osu  ae  a a var  a on n HL A moe c u e s a e c  s  e pre s en a  on o s e Diseases Mediated by Antibodies an gens, bu ow a g ven HL A a  ee n uences  e r sk o d e veop - Autoimmune hemolytic anemia Systemic lupus erythema- tosus ng a p ar  c u  ar ds e as e rema ns u n k now n. Autoimmune thrombocytopenia Environmental Factors Autoimmune atrophic gastritis of Environmental factors participate in causing autoimmunity in a pernicious anemia genetically susceptible host. Myasthenia gravis A nk beween necons and auommuny as been posuaed Graves disease based on resus rom expermena modes and because o e ac Goodpasture syndrome a necous prodromes somemes precede auommune dseases a Diseases Mediated by T Cells n paens. I may be a mcroba paogens acvae mmune ces Type 1 diabetes Rheumatoid arthritis and overcome e norma mecansms o se-oerance. In addon o necons, e dspay o ssue angens aso may be Multiple sclerosis Systemic sclerosis (sclero- b derma) aered by a varey o envronmena nsus. For nsance, uravoe b radaon causes ce dea and may ead o e exposure o nucear Sjögren syndrome angens a ec paoogc mmune responses (e.g., n SLE; see Diseases Postulated to Be Autoimmune aer). Smokng s a rsk acor or reumaod arrs, peraps Inflammatory bowel diseases (Crohn due o cemca modcaon o se angens. Loca ssue njur y or c disease, ulcerative colitis) any reason may ead o e reease o se angens, w subsequen b b Primary biliary cholangitis Polyarteritis nodosa auommune responses. Many auommune dseases are more com- b Autoimmune (chronic active) hepatitis Inflammatory myopathies mon n women an n men, suggesng a ormones nluence e a A role for T cells has been demonstrated in these disorders, but antibodies may deveopmen o auommuny, bu e underyng mecansms are also be involved in tissue injury. obscure. b An autoimmune basis of these disorders is suspected but not established. c In e oowng secons, we dscuss seeced auommune ds- These disorders may result from excessive immune responses to commensal enteric microbes, autoimmunity, or a combination of the two. eases a afec mupe organs and usrae mporan aspecs o The features of many of these diseases have been summarized in Tables 4.3, e paogeness and manesaons o s group o dsorders. Oer 4.4, and 4.5. organ-specc dseases are dscussed n reevan capers.    Inbtor y receptors. S e-re ac  ve y mpo c y es  a ave maure d Systemic Lupus Erythematosus (SLE) c an a s o be nac  vae d up on re c og n   on o s e an  gens n SLE is characterized by the production of autoantibodies and p er pera   ssues. O ne o  e me can s ms o nac  v a  on s immune complexes, which elicit inammation and damage many  a T y mpo c yes  a resp ond o s e an  gens express n  b- cells and tissues. or y re cepors (a s o caed conbtors), no aby  wo name d I s more common n women an n men (∼10:1 rao) and ends CTL A-4 and PD-1,  a su o   ur  e r y mpo c ye ac  v a  on , o occur n women o reproducve age. he paogeness o e dsease  us es absng “ce ckp o ns” n  mmu ne resp ons es. As we s bes undersood n erms o e anbodes a are produced. w ds c uss n C aper 5, umors a s o nduce  e ex press  on o  es e re cepors, and bo ck  ng  em s a s raeg y or s  mu  a  ng Pathogeness. The hallmark of SLE is autoantibodies produced mmune resp ons es aga ns c anc er c e s. Pre d  c  aby, p a  e n s against nuclear antigens, including double-stranded DNA (present  re ae d w   ce ckp o n b o ck ad e or c anc e r  m muno e r apy in about 50% of cases), nucleoproteins, and others. a s o de veop auom mun  y. he anbodes orm compexes w reeased angens, and e Numerous factors contribute to the breakdown of self-tolerance compexes depos n e kdneys and oer organs (ype III ypersen- and the development of autoimmunity, including susceptibility svy). Anbodes aso bnd o and opsonze bood ces, eadng o genes and environmental insults (Fig. 4.8). er desrucon by pagocyes (ype II ypersensvy). hese an- he suscepby genes may nluence ympocye oerance, and bodes and mmune compexes usuay acvae e compemen sys- envronmena acors, suc as necons or ssue njur y, may aer em, wc may ead o a a n serum compemen eves. e dspay o and responses o se angens. he compex neracons Aoug e eoog y and mecansms o SLE are no esabsed, beween ese dverse genec and envronmena acors n auom- a pausbe ypoess s e oowng: Exposure o uravoe g (a mune dseases are no compeey undersood. known rsk acor) eads o apoposs o varous ces; mproper cear- Genetic Susceptibility ance o nucear ragmens combned w aure o B and T ce oer- ance causes acvaon o ympocyes specc or se nucear angens. Autoimmune diseases are multigenic, meaning that polymor- Hg-ainy anbodes produced agans ese angens orm mmune phisms in many different genes are associated with an increased or compexes, wc are endocyosed by dendrc ces and B ympo- decreased risk of the disease. cyes. he nucear DNA and RNA smuae producon o ype I ner- E xcep or s ome rare mend e  an c aus es o auo mmune ds e as e, erons, wc acvae ympocyes and APCs, seng up a cyce o no auommune ds e as e c an be a r bue d o a s  ng  e gene. Among perssen auoanbody producon.  e p oy mor pc genes  n ke d o auo mmun  y, by  ar  e mos  CHAPTER 4 Diseases of the Immune System 51 anbodes a bnd o pospopd–proen compexes nvoved Morphology. SLE can afec vruay any organ. he mos n cong, a orm o e anpospopd anbody syndrome (see caracersc esons resu rom mmune compex deposon n Caper 3). Neuropsycarc manesaons (ncudng sezures, bood vesses, kdneys, and skn: psycoss, and neuropay) and sysemc manesaons suc as    Bood vesses. An acue necrozng vascus nvovng capar- ever are common. Md arrs may occur secondar y o mmune es, sma areres, and areroes may be presen n any ssue. compex deposon. he arers eads o brnod necross o e vesse was. In cronc sages, vesses undergo brous ckenng w umna Systemic Sclerosis (Scleroderma) narrowng. Systemic sclerosis is characterized by brosis of the skin and walls    Kdney. Up o 50% o SLE paens ave cncay sgncan of the gastrointestinal tract and vascular abnormalities. rena nvovemen, and e kdney vruay aways sows ev- dence o abnormay  examned by eecron mcroscopy and Pathogenes s. e deveopmen o s puzzng dsease nvoves a mmunoluorescence (Suppemena eFg. 4.1). Rena nvove- poory dened nerpay o e mmune sysem, sma bood vesses, men akes a number o orms, a o wc are assocaed w and brobass. e presence o crcuang auoanbodes, especay e deposon o mmune compexes wn e gomeru. Pro- annucear anbodes, and T-ce nraes n afeced skn sugges erave gomeruoneprs s e mos common manesaon an auommune eoog y, bu neer e reevan se angen nor o rena paoog y (see Caper 11). e reason or e aure o se-oerance s known. he mmune    Skn. Caracersc er yema afecng e ace aong e brdge nraes oten conan CD4+ h2 ces and macropages a o e nose and ceeks (e buerly or maar ras) s seen n produce probroc c yoknes suc as ransormng grow acor-β. approxmaey 50% o paens, bu a smar ras aso may be Mcrovascuar dsease w evdence o endoea acvaon and seen on e exremes and runk. Exposure o sung nces paee aggregaon s a conssen eaure, bu s bass s aso no or accenuaes e er yema. Hsoogcay, e nvoved areas known. One ypoess saes a e vascuar dsease s e nang sow vacuoar degeneraon o e basa ayer o e epderms even, and a  causes e cronc scema a umaey resus (Suppemena eFg. 4.2). In e derms, ere s varabe edema n ssue njur y and bross. Aernavey, e prmar y deec may e and pervascuar nlammaon. Vascus w brnod necro- n brobass a are sponaneousy acvaed o produce excessve ss may be promnen. Immunoluorescence mcroscopy sows coagen. deposs o mmunogobun and compemen aong e der- moepderma juncon (Suppemena eFg. 4.3).    Cardovascuar system. here may be damage o any ayer o e Mor pholog y. Sysemc sceross s a mu-sysem dsease. he ear. Sympomac or asympomac percarda nvovemen s mos promnen canges occur n e skn, amenar y rac, mus- presen n up o 50% o paens and may be acue, subacue, or cuoskeea sysem, and kdney, bu esons aso are oten pres- cronc. Durng e acue pase, brnous exudae s seen on e en n e bood vesses, ear , ungs, and perpera ner ves. Mos percarda surace and an efuson may be presen. W me, paens ave dfuse bross o e skn and assocaed aropy organzaon o e exudae may ead o bross and a resrcve (Fg. 4.9), wc usuay begns n e ngers and dsa regons o percards. Myocards s ess common and may cause resng e upper exremes and exends proxmay o nvove e upper acycarda and eecrocardograpc abnormaes. Vavuar arms, souders, neck, and ace. Fbross oten s accompaned by (so-caed Lbman-Sacks) endocards (Suppemena eFg. 4.4) nnng o e epderms, oss o ree pegs, aropy o e derma was more common pror o e wdespread use o serods. hs appendages, and yane ckenng o e was o derma ar er- sere endocards akes e orm o snge or mupe, 1- o oes and capares. 3-mm verrucous deposs, wc may orm on eer surace o any ear vave, dsncvey on eer surace o e eales.    Oter serosa cavty nvovement. Inlammaon smar o a Clncal Features. D    us e sk  n  bro s  s c aus e s  m mob   z a  on o  e seen n e percardum may nvove e peura, eadng o   nge rs and s    aca e au re s. Invove me n o  e e s op ag us e ads brnous exudaes, efusons, and bross. o dy spag  a and ob s r u c   on. Vas c u  ar n ar row  ng s re sp ons b e    Oter organs. he jons may be nvoved by a nonerosve syno- or s ce m  a o   nge rs and o e s , e sp e c  a  y n c o d we a e r, caed vs. Nonnlammaor y occuson o sma vesses by nma R ay nau d pe nome non. M  d proe  nu r  a s  re qu e n ,  nd  c a  ng proeraon may be seen n e CNS. re na   nvove me n. For u nc e ar re as ons , p a  e n s s ome   me s d e ve op pu  monar y or s y se m  c y p e r e ns  on. Mo s p a  e n s ave a s ow y pro g re ss ve c ou rs e, bu d e ve opme n o y p e r e ns  on s an om  nous Clncal Features. SLE s a gy varabe musysem dsease, and sgn. Two A NAs are s rong y ass o c  ae d w   s y se m  c s c e ro s s. s dagnoss rees on cnca, seroogc, and morpoogc ndngs. O ne, d  re c e d ag a ns DNA op o s ome r a s e I, s   g  y sp e c    c I may be acue or nsdous n onse. Many paens presen w and s ass o c  ae d w   a g re ae r   ke  o o d o pu  mon ar y  bro s  s vague and puzzng sympoms a requre an asue pyscan o and p e r pe r a  v as c u  ar d  s e as e. T e o e r, an an  c e n rome re dagnose. S o-caed generc annucear anbodes (ANAs) a bnd an b o dy, s ass o c  ae d w    e C R E ST s y nd rome, n w   c  e re o a varey o nucear angens are ound n vr uay 100% o paens are   m e d sk  n d s e as e, o e n c on   ne d o   nge rs , ore ar ms , and bu are no specc, wereas anbodes o doube-sranded DNA, ace; sub c u ane ous c a  c    c a  ons ; and  ae or no e s op age a   e s  ons deeced n 40% o 60% o cases, are gy specc or SLE, and ence and pu  monar y y p e r e ns  on. a useu dagnosc es. Rena nvovemen may produce a varey o ndngs, ncudng emaura, red ce cass, proenura, and neproc syndrome (see Caper 11). Anema or romboc yopena Sjögren Syndrome s a presenng manesaon n some paens and may be a domnan In this disease, chronic inammation and destruction of lacrimal cnca probem. romboemboc penomena are secondar y o and salivary glands lead to reduced production of tears and saliva.  CHAPTER 4 Diseases of the Immune System 51.e1 A B C D E Supplemental eFig. 4.1 Lupus nephritis. (A) Focal proliferative glomerulonephritis, with two focal necrotizing lesions at the 11 o’clock and 2 o’clock positions (H&E stain). Extracapillary proliferation is not prominent in this case. (B) Diffuse proliferative glomerulonephritis. Note the marked increase in cellularity throughout the glomerulus (H&E stain). (C) Lupus nephritis showing a glomerulus with several “wire-loop” lesions represent- ing extensive subendothelial deposits of immune complexes (periodic acid-Schiff stain). (D) Electron micrograph of a renal glomerular capillary loop from a patient with SLE nephritis. Subendothelial dense deposits (arrowheads) on basement membrane (arrow) correspond to “wire loops” seen by light microscopy. (E) Deposition of IgG antibody in a granular pattern, detected by immunofluorescence. (A to C, Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts. D, Courtesy of Dr. Edwin Eigenbrodt, Department of Pathology, University of Texas, Southwestern Medical School, Dallas, Texas. E, Courtesy of Dr. Jean Olson, Department of Pathology, University of California, San Francisco, California.) 51.e2 CHAPTER 4 Diseases of the Immune System Supplemental eFig. 4.3 Systemic lupus erythematosus involving the skin. An immunofluorescence micrograph stained for IgG reveals Supplemental eFig. 4.2 Systemic lupus erythematosus involving the deposits of Ig along the dermoepidermal junction. (Courtesy Dr. Richard skin. An H&E stained section shows liquefactive degeneration of the Sontheimer, Department of Dermatology, University of Texas South- basal layer of the epidermis and edema at the dermoepidermal junc- western Medical School, Dallas, Texas.) tion. (Courtesy Dr. Jag Bhawan, Boston University School of Medicine, Boston, MA.) Supplemental eFig. 4.4 Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows. (Courtesy of Dr. Fred Schoen, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.)