Robbins Essential Pathology - Diseases of the Immune System PDF

CHAPTER 4 Diseases of the Immune System 57 Table...

CHAPTER 4 Diseases of the Immune System 57 Table 4.7 The Major Primary Immunodeficiency Diseases Disease Functional Deficiencies Mechanism of Defect A. Defects in lymphocyte maturation Severe combined immunodeficiency (SCID) X-linked SCID Markedly decreased T cells; normal or increased B Cytokine receptor common ℽ-chain gene muta- cells; reduced serum Ig tions, defective T-cell maturation due to lack of IL-7 signals B cell immunodeficiencies X-linked agammaglobulinemia Decrease in all serum Ig isotypes; reduced B-cell Failure of maturation beyond pre-B cells, numbers because of mutation in Bruton tyrosine kinase Ig heavy-chain deficiencies Deficiency of IgG subclasses; sometimes associated Chromosomal deletion involving Ig heavy-chain with absent IgA or IgE locus Disorders of T-cell maturation DiGeorge syndrome Decreased T cells; normal B cells; normal or decreased Anomalous development of 3rd and 4th bran- serum Ig chial pouches, leading to thymic hypoplasia B. Defects in lymphocyte activation X-linked hyper-IgM syndrome Defects in helper T-cell–dependent B-cell and macro- Mutations in CD40 ligand phage activation Common variable immunodeficiency Reduced or no production of selective isotypes or Mutations in receptors for B-cell growth fac- subtypes of immunoglobulins; susceptibility to tors, costimulators bacterial infections or no clinical problems + Defective class II MHC expression: Lack of class II MHC expression and impaired CD4 Mutations in genes encoding transcription the bare lymphocyte syndrome T-cell activation; defective cell-mediated immunity factors required for class II MHC gene and T cell–dependent humoral immunity expressions X-linked lymphoproliferative disease Uncontrolled EBV-induced B-cell proliferation and Mutations in gene encoding SAP (an adaptor cytotoxic lymphocyte (CTL) activation; defective protein involved in signaling in lymphocytes) NK-cell and CTL function and antibody responses C. Defects in innate immunity Chronic granulomatous disease Defective production of reactive oxygen intermedi- Mutations in genes encoding components of ates by phagocytes the phagocyte oxidase enzyme Leukocyte adhesion deficiency-1 Absent or deficient expression of β2 integrins causing Mutations in gene encoding the β chain (CD defective leukocyte adhesion-dependent functions 18) of β2 integrins Leukocyte adhesion deficiency-2 Absent or deficient expression of leukocyte ligands Mutations in gene encoding a protein required for endothelial E- and P-selectins, causing failure of for synthesis of the sialyl-Lewis X compo- leukocyte migration into tissues nent of E- and P-selectin ligands Complement C3 deficiency Defect in complement cascade activation Mutations in C3 gene Complement C2, C4 deficiency Deficient activation of classical pathway of comple- Mutations in C2 or C4 gene ment, leading to failure to clear immune complexes and development of lupus-like disease EBV, Epstein-Barr disease; Ig, immunoglobulin; IL, interleukin; MHC, major histocompatibility complex. From Abbas AK, Lichtman AH, Pillai S: Basic Immunology: Function and Disorders of the Immune System, 5th ed., Philadelphia: Elsevier, 2016. a d e  e   on a e c   ng c  rom o s om a  re g  on 22q11 (see C  ap e r    D  G e or g e s y n drom e ( t y m c y p o p a s  a ) s c au s e d by a c on g e n - 6). Mo s  p a  e n s  mprov e w   age and do n o re q u  re  re a -  a  d e e c  n  e d e v e  opm e n o  e  y mu s , re s u   n g n de - m e n ( o  e r  an  or  n  e c   on s ). Un   k e mos o  e r pr  m a r y c  e n T- c e   m au r a  on. T ce s a re a b s e n n  e  y mp  no des,  m mu n o d e   c  e n c  e s , D  G e or g e s y n d rom e s a d e v e  opm e n a  spe en, and p e r p  e r a  bo o d, and  n  a n s w    s d e e c  a re d e e c  bu s n o  e r  a b  e. v u  ne r ab e o v ra ,  u ng a , and pro o z o a   n  e c   on s. Te ds-    D efects n nnate mmunty. Deecve producon o reacve oxygen ord e r s a c on s e qu e n c e o a d e v e  opm e n a  d e e c  a e c   ng  e speces n neurops s caused by muaons afecng e pago-    rd and  ou r   par y nge a  p ou c  e s , s  r u c  u re s   a g ve r s e cye oxdase enzyme (Caper 2). hs dsease s caed cronc gran- o  e  y mu s , p a r a y ro d g  ands , and p or   on s o  e ace and uomatous dsease (CGD) because srong macropage acvaon, a or   c a rc . T u s , n a d d   on o  e  y m  c and T- c e   d e e c  s , oten resung n granuoma ormaon, compensaes or e nab-   e re m ay be p a r a y ro d g  and y p op  a s  a , re s u   n g n y p o - y o neurops o desroy pagocyosed mcrobes. he eukocyte cacemc  e  a ny, as we  as a d d   on a  md ne d e v e  opm e n a  adeson deicences are caused by muaons afecng e uncons a bn or m a    e s. In 90% o cas es o D  G e or g e s y n d rom e ,   e re s 58 CHAPTER 4 Diseases of the Immune System o e adeson moecues negrns and seecns (Caper 2). Leu- conamnaed w HIV-neced bood. Transmsson by bood or kocye recrumen no ssues, and ence acue nlammaon, are bood producs can occur bu s now ver y uncommon because o mpared n ese dsorders. Decen recrumen and uncons o roune screenng. neurops resu n ncreased suscepby o bacera necons.    Moter-to-nfant transmsson s e major cause o pedarc AIDS. I can occur by ranspacena spread durng dever y and roug breas mk. Abou 2% o new cases are n babes born o neced ACQUIRED IMMUNODEFICIENCY SYNDROME moers. AIDS is caused by infection with human immunodeciency Human Immunodeficiency Virus: Structure and virus (HIV), which destroys CD4+ T cells and leads to profound immunodeciency. Life Cycle hs dsease was rs dened n e 1980s, and as become one o HIV is a retrovirus that infects cells via CD4 and coreceptors, inte- e grea scourges o e modern word. Recen successes o anvra grates into the host cell genome, and kills cells when it is activated drugs ave provded ope o paens, bu  remans a major medca to replicate. and socea probem, especay n deveopng counres. I s esmaed Lke oer rerovruses, HIV s an enveoped vrus wose core con- a ere are more an 35 mon HIV-neced ndvduas n e ans srucura capsd proens, enzymes nvoved n vra negraon, word, o wom 70% are n Arca and 20% n Asa, and amos 1 m- and wo srands o vra RNA, wc encode a ese proens, as we on de eac year rom e dsease. as numerous reguaors o vra gene expresson and repcaon (Fg. he dsease s ransmed by drec ranser o neced luds. he 4.15). here are wo genecay dferen bu reaed orms o HIV, ree man modes o ransmsson are: caed HIV-1 (e mos requen cause o AIDS) and HIV-2. To ener    S exua transmsson: hs s e domnan mode o necon, ces, e ouer capsd proen gp120 bnds o CD4 and subsequeny accounng or more an 75% o a cases. Abou 50% o e o e cemokne recepors CXCR4 or CCR5 (caed corecepors or repored cases are n omosexua or bsexua men, bu eero- e vrus). he vrus en uses w e os ce membrane and s sexua ransmsson as rapdy ncreased, especay n Arca nernazed. hereore, e ces a are neced are ose a express and Asa, were  accouns or a or more o new necons CD4 and e corecepors, many T ces and some macropages and n adus. he vrus s carred n e semen and eners e body dendrc ces. Poymorpsms n e gene encodng CCR5 aer e roug mucosa abrasons. suscepby o HIV necon, we ceran rare muaons n CCR5    Parentera transmsson: Anoer 20% o cases are n nravenous coner ressance. drug users. Transmsson occurs by sarng o needes and syrnges VIRUS gp120 Conformational gp120, CD4 gp41 membrane Fusion of HIV membrane CD4 binding change bind CCR-5 penetration with host cell membrane; entry of viral genome Membrane into cytoplasm fusion gp41 gp120 Cytokine VIRUS ENTRY gp41 p17 matrix Cytokine receptor gp120 p24 capsid CD4 Chemokine HIV RNA genome Lipid bilayer receptor Reverse transcriptase–mediated synthesis of proviral DNA Integrase Cytokine activation of cell; transcription Protease of HIV genome; RNA transport of viral RNAs to cytoplasm VIRUS Reverse Integration of provirus REPLICATION into host cell genome transcriptase Synthesis of HIV proteins; assembly of virion core structure HIV DNA HIV RNA provirus HIV core transcript structure Nucleus A VIRUS New HIV RELEASE virion Budding and release of mature virion B Fig. 4.15 The structure and life cycle of the human immunodeficiency virus (HIV). (A) The viral particle is covered by a lipid bilayer derived from the host cell and studded with viral glycoproteins gp41 and gp120. (B) The life cycle of HIV showing the steps from viral entry to the production of infectious virions. (Adapted with permission from Wain-Hobson S: HIV. One on one meets two. Nature 1996;384:117. Copyright 1996, Macmillan Magazines Limited.)  CHAPTER 4 Diseases of the Immune System 59 Ater enr y o HIV no e ce, vra RNA s reverse ranscrbed o neuropaes, and, mos commony, a progressve encepaopay produce provra DNA, wc persss n epsoma orm n e cyo- caed HIV-assocaed neurocognve dsorder. pasm or negraes no e genome o e neced ce. he vrus may B ecause e oss o mmune conanmen s assocaed w be sen n neced ces or years, esabsng a aen necon. I e decnng CD4+ T-ce couns, e C eners or Dsease C onro and neced ce s acvaed (e.g., by an necon or nlammaor y smu- Prevenon (CD C) casscaon o HIV necon sraes paens us), e provra DNA s ranscrbed, vra proens are produced, and no ree groups based on CD4+ ce couns: greaer an or equa compee vrons are reeased o connue e cyce o necon. o 500 ces/μL, 200 o 499 ces/μL, and ewer an 200 ces/μL. he exen o vrema, measured as HIV-1 RNA eves n e bood, s a Pathogeness. HIV depletes CD4+ cells, mainly as a consequence of useu marker o HIV dsease progresson and s o vaue n e man- viral replication in infected cells. agemen o HIV-neced ndvduas. Exacy ow e repcang vrus medaes s cyopac efec s Te dsease course descrbed prevousy s ypca o unreaed s uncear ; possbes ncude an ncrease n membrane permeab- paens. Curreny, ndvduas reaed w combnaons o anvra y caused by buddng vrons and compeve nererence w os drugs (gy acve anrerovra erapy [HAART]) do no deveop ce proen syness. he consequence s a progressve oss o T ces, mmune decenc y or AIDS w s aendan compcaons. How- prmary CD4+ ces. hs decne s nay mos promnen n muco- ever, e vrus s no eradcaed, so e reamen s no a cure, and sa ssues (e major se o vrus enr y), en s seen n dranng ymp ere are sgncan sde efecs o ese medcaons, ncudng ee- nodes, and ony aer s deeced n bood T ces. vaed pds, nsun ressance, perpera neuropay, and premaure In addon o e drec oss o neced T ces, oer mecansms cardovascuar, kdney, and ver dsease. Furermore, w ong- o mmune decency ave been posuaed o accoun or e requen erm erapy, paens are a ncreased rsk or dseases suc as cancer obser vaon a e severy o e mmune decs s muc greaer and cardovascuar dsease, or unknown reasons. an e numbers o neced ces (measured mosy n e bood). hese oer mecansms ncude e dea o unneced ces as a con- AMYLOIDOSIS sequence o er cronc acvaon, deecs n APCs, and e desruc- on o ympod ssue arcecure. Amyloid is an extracellular deposit of brillar protein that can Oer ce ypes a are afeced ncude B ces (wc are no affect many organs and tissues. neced bu sow excessve acvaon), macropages, and mcroga hese nsoube brs are produced by e aggregaon o var- n e CNS. Macropages and mcroga may be reser vors o nec- ous proens a are produced n excess amouns, are no ceared on; n ae sages o HIV necon, wen CD4+ T-ce numbers adequaey, or od mpropery. he proen deposs bnd carboy- decne greay, macropages may be an mporan se o connued drae-rc moecues, mparng sanng properes a resembe vra repcaon. sarc (ence, e name). Amyodoss, reerrng o amyod deposs and er paoogc efecs, s dscussed ere because some o e mos Clncal Course. HIV dsease may be dvded no ree sequena common orms are composed o anbody moecues. pases (Fg. 4.16).    Acute pase. Vrus eners roug mucosa and necs and desroys There are several forms of the disease, each associated with a mor- CD4+ T ces a e se. Dendrc ces a mucosa ses carry e phologically identical but chemically distinct protein in the depos- vrus o regona ymp nodes, were e vrus repcaes and evenu- its (Fig. 4.17). ay spreads o oer ssues. he ndvdua mouns anvra umora    P rmar y amyodoss. he deposs are made o mmunogobu- and ce-medaed responses, resung n seroconverson (usuay n g cans (caed AL [amyod gt can]), wc are pro- wn 3 o 7 weeks o exposure) and e deveopmen o vrus-spe- duced n excessve amouns by a neopasm o pasma ces caed cc CD8+ CTLs. Around s me, paens deveop a se-med myeoma, or by cona proeraons o pasma ces wou over  acue HIV syndrome, w sysemc sympoms resembng ose n myeoma (see Caper 9). many oer acue necons. hs ypcay resoves n 2 o 4 weeks.    Reactve secondary amyodoss. he deposs are composed o e    C ronc pas e. he v r us repc aes man y n s e cond ar y y m- amyod A (AA) proen, wc s generaed by proeoyss o s pre- pod organs and des roys T ce s n  es e  ssues, bu ne c e d cursor serum amyod A (SAA) proen. SAA s an acue-pase pro- ce s are no numerous n  e bo o d. B e c aus e ne c e d p a ens en produced durng nlammaon. Proonged producon o arge do no ave s e vere sy mpoms,  s s oten c a  e d  e pas e o amouns o SAA s seen n cronc nlammaon, so s orm o cnc a   aenc y. Ly mp no des sow y mpo c ye depe on, and amyodoss s an nrequen compcaon o cronc nlammaory e venu a  y, over a p er o d o ye ars,  ere s a de cne n  e num- dsorders (ubercuoss n e pas; reumaod arrs more re- b er o CD4+ T ce s n  e bo o d. queny now, especay n deveoped counres).    AIDS. he progressve oss o CD4+ T ces umaey eads o pro-    O ter forms of amyodoss. Deposs o Aβ amyod are seen n e ound mmune decency. Paens w AIDS ave a g ncdence brans o paens w Azemer dsease and some oer orms o opporunsc necons (e.g., Pneumocysts jrovec, cyomeg- o demena. S evera ama orms o amyodoss are known, aovrus necons, cr ypococcoss, canddass, and mycobace- peraps e mos common o wc s assocaed w ama ra necons) and o ceran umors, many o wc are caused Mederranean ever, an nered “auonlammaor y” dsease n by oncogenc DNA vruses, ncudng Kapos sarcoma (Kapos wc paens sponaneousy deveop sysemc nlammaon, sarcoma erpesvrus), B-ce ympoma (Epsen-Barr vrus), and one consequence o wc s ncreased producon o e amyod cer vca and ana carcnoma (uman papomavrus). Invovemen precursor SAA. In oer ama orms, e amyod s made up o o e CNS s a common and mporan manesaon o AIDS. muan ransyren, a ransporer o yroxne. I s deposed n Lesons ncude an na se-med presumed vra menngoen- auonomc and perpera ner ves, gvng rse o poyneuropaes. cepas or asepc menngs, vacuoar myeopay, perpera In e pas, paens undergong emodayss deveoped amyod deposs composed o e β2-mcrogobun proen because  dd 60 CHAPTER 4 Diseases of the Immune System Infection of mucosal tissues + CD4 Dendritic T cell cell Death of mucosal + memory CD4 T cells Virus transported ACUTE CHRONIC AIDS to lymph nodes Primary infection 8 1200 10 Acute HIV syndrome Death 1100 Wide dissemination of virus Infection established )amsalp Seeding of lymphoid organs 7 in lymphoid tissues, 1000 10 Opportunistic e.g., lymph node 900 diseases 6 Lm/seipoc 800 Clinical latency 10 3 mm/sllec 700 Constitutional 5 600 10 symptoms Spread of infection ANR 500 Viremia T throughout the body 4 4DC 400 10 VIH( 300 aimeriV 3 200 10 Immune 100 response Anti-HIV HIV-specific 2 0 10 antibodies CTLs 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 Weeks Years Partial control of viral replication B Establishment of chronic Clinical infection; virus concentrated latency in lymphoid tissues; low-level virus production Other microbial infections; cytokines Increased viral replication Destruction of lymphoid tissues: AIDS depletion of CD4+ T cells A Fig. 4.16 Pathogenesis and clinical course of HIV infection. (A) The initial infection starts in mucosal tissues, involving mainly memory CD4+ T cells and dendritic cells, and spreads to lymph nodes. Viral replication leads to viremia and widespread seeding of lymphoid tissue. The viremia is controlled by the host immune response, and the patient then enters a phase of clinical latency. During this phase, viral replication in both T cells and mac- rophages continues unabated, but there is some immune containment of virus (not illustrated). There continues a gradual erosion of CD4+ cells, and ultimately, CD4+ T-cell numbers decline and the patient develops clinical symptoms of full-blown AIDS. (B) Clinical course of HIV infection. CTL, Cytotoxic T lymphocyte. (B, from Pantelo G, et al: N Engl J Med 328:327, 1993. Copyright 1993 Massachusetts Medical Society. All rights reserved.)  CHAPTER 4 Diseases of the Immune System 61 PRODUCTION OF ABNORMAL PRODUCTION OF NORMAL AMOUNTS OF PROTEIN AMOUNTS OF MUTANT PROTEIN (e.g., transthyretin) Native folded Acquired Chronic inflammation Inherited mutations protein mutations Macrophage Monoclonal activation B-lymphocyte proliferation Amyloidogenic intermediate IL-1, IL-6 (e.g., misfolded protein) Plasma Liver cells cells Monomers assemble to Immunoglobulin Mutant SAA Protein form β-sheet structure light chains transthyretin Limited Limited Aggregation proteolysis proteolysis FIBRIL AL PROTEIN AA PROTEIN ATTR PROTEIN A B C D Fig. 4.17 Pathogenesis of amyloidosis. (A) General mechanism of formation of amyloid fibrils. (B) Primary amyloidosis, in which unknown mutations cause monoclonal B cell or plasma cell proliferations, resulting in excessive production of one immunoglobulin, and the light chains form the AL (amyloid light chain) form of amyloid. (C) Reactive systemic amyloidosis, in which chronic inflammation leads to production of serum amyloid A (SAA), which is converted to the amyloid A (AA) protein. (D) Mutations in transthyretin (TTR) lead to deposition as amyloid fibrils (ATTR, amyloid TTR) in amyloid of aging, especially affecting the heart. no pass roug oder dayss membranes, bu newer ers ave Morphology. Exraceuar deposs o amyod may be presen n argey emnaed s probem. vruay any parencyma organ. In roune secons, ey appear as    L ocazed amyodoss. e prmar y and secondar y amyodoses pnk, gassy, aceuar maera, oten n vesse was. Deposs can be descrbed earer are sysemc n naure and afec many ssues dsngused rom oer subsances by e Congo red san, wc and ses. By conras, n some cases e amyod deposs are m- mpars a caracersc coor and yeow-green brerngence o e ed o a snge organ or se (e.g., skn, ung, ongue). A eas n deposs (Fg. 4.18). some ocazed orms, e amyod consss o AL amyod and may us be a manesaon o prmar y amyodoss.    Amyod of agng. Amyod assocaed w agng afecs edery paens (n er sevenes and eges) and n many cases ere Clncal Features. Amyod nereres w e norma uncon o e s domnan nvovemen o e ear, presenng as a resrcve organ were  s deposed. he mos requen cnca compcaons cardomyopay. Bocemcay, e amyod s comprsed o rans- resu rom deposon n e kdneys (neproc syndrome), ear yren. Unke n ama orms, ransyren s wd ype. (congesve ear aure), and gasronesna rac (maabsorpon). In a  es e yp es o amy  o d o s  s ,  e re sp ons  b e proe  n s he dagnoss o amyodoss depends on demonsraon o amyod pro du c e d n e xc e ss or as an u nu su a  s e qu e n c e. In  e cas e o AL n ssues. he prognoss o ndvduas w sysemc amyodoss s amy  o d, e x p e r  m e n a  d a a s u g ge s   a p ar   c u  ar   g  c a ns poor, parcuary ose w sysemc AL amyodoss. he course o are amy  o d o ge n  c an d o  e rs are n o ,  mpy  ng   a  e pr  m ar y reacve sysemc amyodoss depends on e conro o e underyng am  n o acd s e qu e n c e o  e   g  c a n d e e r m  n e s w e er amy - condon.  o d   br   s or m. Bu n any p ar   c u  ar c a s e, w y amy  o d or ms ( or n o ) s u n k n ow n. 62 CHAPTER 4 Diseases of the Immune System A B C Fig. 4.18 Amyloidosis. (A) A section of liver stained with Congo red reveals pink-red deposits of amyloid in the walls of blood vessels and along sinusoids. (B) Note the yellow-green birefringence of the deposits when observed by a polarizing microscope. (C) In the kidney, the glomerular architecture is almost totally obliterated by the massive accumulation of amyloid. The stain, called a PAS stain, reveals glycogen-rich deposits. (B, Courtesy Dr. Trace Worrell and Sandy Hinton, Department of Pathology, University of Texas Southwestern Medical School, Dallas.)