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Pathology:TheBigPicture>

Chapter3.PathologyoftheImmune
System
Overview
Diseasesoftheimmunesystemtakemanyforms,includinghypersensitivityreactions,autoimmune
disorders,andimmunodeficiencystates.Hypersensitivityreactionsoccurasoneoffourtypes(typesIIV).
Autoimmunediseasesaretheresultofafailureintheimmunesystemtorecognizeselfantigens,resultingin
productionofantibodiesthatreactagainstnormalcomponentsofcells.Mostoftheautoimmunediseasesare
associatedwithoneormorespecificantibodies,whichcanbeidentifiedbylaboratoryteststoaidindiagnosis.
Immunodeficiencystatescanbehereditaryoracquired.Amajorcauseofacquiredimmunodeficiencyishuman
immunodeficiencyvirus(HIV)infection.Theconceptsofimmunityarealsoimportantinregardtotransplantation
efforts.Thischapterwilldiscusshypersensitivityreactions,transplantationpathology,autoimmunediseases,
amyloidosis,andbothhereditaryandacquiredimmunodeficiency.

HypersensitivityReactions
Overview:Therearefourtypesofhypersensitivityreactions,eachofwhichhasadifferentmechanism.These
fourtypesofhypersensitivityreactionswillbediscussedbelow.

TypeIHypersensitivityReaction
Mechanism:ExposuretoanantigenresultsintheformationofIgE.TheantigenreactswithCD4+cells,which
differentiatetoT H2cells.T H2cellsreleaseinterleukin3(IL3),IL4,andIL5.IL5stimulateseosinophils,andIL
4activatesIgEproducingBcells.TheIgEbindstomastcells.Subsequentexposuretothesameantigenresults
inbindingoftheantigentoIgEboundtomastcells,withtheconsequenceofdegranulationofthemastcellsand
releaseofmediators(e.g.,histamine).Thereleaseofmediatorscausesincreasedvascularpermeability,leading
toedemaandincreasedsmoothmusclecontractionandeventuallytobronchoconstriction.
SequenceofeventsintypeIhypersensitivityreaction
1. Earlyphase(occurswithin530minutesofexposuretoantigen):Characterizedbyvasodilation,increased
vascularpermeability,andincreasedsmoothmusclecontraction.Theearlyphaseisduetobindingofantigen
toIgEboundtomastcells,withsubsequentdegranulationofthemastcellsandreleaseofmediators.
2. Latephase(occursafter224hoursandlastsfordays):Characterizedbyinfiltrationbyneutrophils,
eosinophils,basophils,andmonocytes,andresultsinmucosaldamageduetoreleaseofmediatorsbythese
recruitedinflammatorycells.
FormsoftypeIhypersensitivityreactions
Systemicanaphylaxis:Duetoparenteraladministrationofantigenforexample,abeestingorareactionto
penicillin.
Localreaction:Urticaria(hives).
Causes:Penicillin,angiotensinconvertingenzyme(ACE)inhibitors,intravenous(IV)contrastandotherdrugs,
proteins(e.g.,insectvenoms),andfood.
ClinicalpresentationoftypeIhypersensitivityreaction:Symptomsandsignsincludeabruptonset(within30
minutesofexposuretoantigen)ofrash,nauseaandvomitingandfacialswelling,wheezingandstridor,and
hypotensionandtachycardia.Serumtryptaseisamarkerofanaphylaxis.
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Complicationsofsystemicanaphylaxis:Deathduetoairwaycompromisefromlaryngealedema.

TypeIIHypersensitivityReaction
Overviewofgeneralmechanism:Antibodiesdirectedagainsttargetantigensoncellsorinextracellularmatrix.
Thetargetantigensmaybeendogenousorabsorbedexogenousantigens.
Specificmechanisms:TherearethreespecificmechanismsbywhichtypeIIhypersensitivityreactionsoccur.
Thethreemechanismsarecomplementdependentreactions,antibodydependentcellmediatedcytotoxicity,and
antibodymediatedcellulardysfunction.
Complementdependentreactions
Mechanism:Antibodyboundtoantigencanfixcomplementandcausedirectlysisofthecellthrough
productionofthemembraneattackcomplex(MAC),orthecomplementcancoatcellswithC3b(an
opsonin)andpromotephagocytosisoftheantigen.
Example:Glomerulonephritis.
Antibodydependentcellmediatedcytotoxicity
Mechanism:CelltypesthatbearreceptorsfortheFcportionofIgG,suchasneutrophils,eosinophils,
macrophages,andnaturalkiller(NK)cells,mediateremovalofantigen.
Examples:Transfusionreactions,erythroblastosisfetalis,andautoimmunehemolyticanemia.
Antibodymediatedcellulardysfunction
Mechanism:Antibodiesthemselvesaffectfunctionoftheantigen.
Examples:Gravesdiseaseisduetoanantibodythatactivatesthethyroidstimulatinghormone(TSH)
receptor,resultinginhyperthyroidism.Myastheniagravisisduetoantibodiesagainsttheacetylcholine
(ACh)receptor,impairingneuromusculartransmission.

TypeIIIHypersensitivityReaction
Mechanism:Antibodiesbindtotheantigen,forminganimmunecomplex.Theantigenscanbeexogenous(e.g.,
viralproteins)orendogenous(e.g.,DNA).Theseimmunecomplexescanforminsitu,ortheycanforminthe
vasculatureandsubsequentlybedepositedinorgans,wheretheycausedamage.Theimmunecomplexcauses
activationofthecomplementcascade.Notethatimmunecomplexesarecommonlyformedforvariousreasons,
butonlyundercertaincircumstancesdotheyelicitanimmunereaction.
Examples:Immunecomplexmediatedvasculitisandformsofglomerulonephritis.

TypeIVHypersensitivityReaction
Generalmechanism:MediatedbysensitizedTcellsratherthanbyantibodies.
Specificmechanisms
DelayedformoftypeIVhypersensitivityreaction:CD4+helperTcells(T H1type)sensitizedfrom
previousexposuretoanantigensecreteinterferon,whichactivatesmacrophages.Activatedmacrophages
secreteIL12,whichcausesdifferentiationofT H1cells.
Microscopicmorphology:Stimulationofmacrophagesresultsingranulomas(i.e.,collectionsof
epithelioidhistiocytes).
Incitingagents:Mycobacteria,fungi,andparasites.
Examples:Tuberculinreactionandcontactdermatitis.
Cellmediatedcytotoxicity:SensitizedCD8+cellskillantigenbearingcells.Theantigensarepresentedby
classImajorhistocompatibilitycomplex(MHC)molecules.Therearetwomechanismsbywhichthisoccurs:
theperforingranzymesystemandtheFASFASligandsystem.
Perforingranzymesystem:Perforinproducesholesintheplasmamembraneofcells,allowing
granzymetoenterthecells.Granzymethenactivatesapoptosisthroughstimulationofcaspaseactivity.
FASFASligandsystem:ThesensitizedTlymphocyteshaveFASligand,whichbindstoFASontarget
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cells,leadingtoapoptosis.

TransplantationPathology
Overview:Rejectionoftransplantedorgansmaybecellularorhumoral,withcellularrejectionmediatedbyT
cells,andhumoralrejectionmediatedbyantibodies.Inaddition,rejectionmaybeclassifiedbaseduponitstiming
followingthetransplantprocedure.Therejectioncanbehyperacute,acute,orchronic.

CellularRejection
Mechanism:Cellularrejectionisduetohypersensitivityoftherecipient'sCD4+cells,whichresultsinkillingof
graftcellsbyCD8+cellsthathavematuredintocytotoxicTlymphocytes.ThecytotoxicTlymphocyteskillgraft
cellsthroughtheperforingranzymepathwayortheFASFASligandpathway.
Formsofcellularrejection
Direct:ThebodyrecognizesMHCmoleculesonthesurfaceoftheantigenpresentingcellsinthegraft.
Indirect:Antigensofthegraftarepresentedbytherecipient'scells.

HumoralRejection
Overview:Humoralrejectionisduetopreformedantibodiesorformationofantibodiesagainstgraftvasculature.

ClassificationofFormsofRejectionBasedUponTimingofRejectionafterTransplantation
Hyperacuterejection
Mechanism:Humoralreactionduetopreformedantibodiestograftendothelium.
Timecourse:Minutesfollowingtransplantation.
Morphology:Grossly,thereiscyanosisoftheorganandamottledparenchymamicroscopically,thereis
endothelialinjury,neutrophilsinarterioles,andinfarctsofparenchyma.
Acuterejection
Mechanism:Cellularorhumoralreaction.
Timecourse:Daystomonthstoyearsfollowingtransplantation.
Microscopicmorphologyofacutecellularrejection(Figure31):Interstitialmononuclearinfiltrate,edema,
interstitialhemorrhage,andendothelialitis(i.e.,swollenendothelialcells).
Microscopicmorphologyofacutehumoralrejection:Necrotizingvasculitis,neutrophilicinfiltrate,and
infarctsofparenchyma.
Importantpoint:Anacutecellularrejectionwillrespondtocyclosporine.
Chronicrejection
Mechanism:Possibly,theindirectformofcellularrejectionplaysanimportantrole.
Timecourse:46monthstoyearsfollowingthegraft.
Microscopicmorphology:Vascularchanges,interstitialfibrosis,interstitialmononuclearinfiltrate,and
ischemiawithsubsequenttissueloss.
FIGURE31.

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Acutecellularrejectioninthekidney.Inthislowpowerviewofarenaltransplant,notetheinfiltrateoflymphocytes
amongtheglomeruliandrenaltubules.Hematoxylinandeosin,100.

HematopoieticTransplantations
GraftversusHostDisease(GVHD)
Basicdescription:Immunecompetentcellsinthegraftrecognizeantigensinthehost.
Occurrence:Inbonemarrowtransplantsinsolidorgantransplantswhentheorganisrichinlymphocytes(e.g.,
liver)andinnonirradiatedblood.
FormsofGVHD
AcuteGVHD
Timecourse:Daystoweeks.
Organsaffected(andcomplications):Skin(rash),bileducts(jaundice),andgastrointestinalmucosa
(bloodydiarrhea).
Associatedfindings:AcuteGVHDresultsinimmunodeficiencyandthuspatientscanhavesecondary
infections,includingcytomegalovirus(CMV)pneumonia.
ChronicGVHD
Organsaffected(andcomplications):Dermisandskinappendages(fibrosis),bileducts(cholestatic
jaundice),andesophagus(strictures).
Associatedfindings:ChronicGVHDresultsinimmunodeficiencythuspatientscanhavesecondary
infections,includingCMVpneumonia.

AutoimmuneDiseases
Overview:Autoimmunediseaseresultsfromafailureofselftolerance.Inselftolerance,thebodyinactivatesits
immuneresponseagainstantigens,whicharepresentonandinitsowncells.Autoimmunediseasescanbe
organspecificorsystemic,andareoftenassociatedwithaspecificantibody(Table31).
Table31.AutoimmuneDiseasesandTheirAssociatedAntibodies
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Disease

AssociatedAntibodies

Systemiclupuserythematosus

AntidsDNA,antiSmith

Druginducedlupus

Antihistone

Rheumatoidarthritis

IgMversusFcportionofIg

Sjgrensyndrome

AntiSSAandantiSSB

CRESTsyndrome

Anticentromere

Diffusescleroderma

Antiscl70

CREST,calcinosis,Raynaudphenomenon,esophagealdysfunction,
sclerodactyly,telangiectasis.
Generalmechanism:Lossofselftolerance.Contributingfactorsincludesusceptibilitygenes(e.g.,certainHLA
typessuchasB27inankylosingspondylitis)andinfections.Infectionsmayupregulateexpressionof
costimulatoryproteinsonantigenpresentingcells,ormicrobescanhaveantigensthataresimilarinstructureto
selfantigens.Antibodiesagainsttheseforeignantigensthencrossreactwithselfantigens.

SpecificSystemicAutoimmuneDiseases
Overview:Therearemanydifferentautoimmunediseaseshowever,fivecommonsystemicautoimmune
disorders(systemiclupuserythematosus,rheumatoidarthritis,Sjgrensyndrome,systemicsclerosis,andmixed
connectivetissuedisorder)arediscussedbelow.
Systemiclupuserythematosus(SLE)
Epidemiology:Individualsaged2040years(i.e.,thoseofchildbearingage).Ofthegeneralpopulation,SLE
occursin1in2500individuals,witha9:1maletofemaleratio.Inchildrenandolderadults,themaletofemale
ratioismoreequal.SLEismorecommoninAfricanAmericans.
ClinicalpresentationofSLE
Skinrash(malar,photosensitivity,discoid).
Arthralgias:Arthralgia,myalgia,andarthritisareoftenthefirstcomplaintofpatientsdiagnosedwithSLE.
Pericarditis.
Renaldysfunction(proteinuria>0.5g/dLcellularcasts).
Neurologicdisorder(seizures,psychosis).
Hematologicdisorder(hemolyticanemia,leukopenia,lymphopenia,thrombocytopenia).
Immunologicdisorder(antidsDNAantibody,antiSmithantibody,orantiphospholipidantibodies):The
presenceofantiphospholipidantibodiesisdetectedbyapositivelupusanticoagulanttest,anabnormallevel
ofIgGorIgManticardiolipin,orafalsepositivetestforsyphilis.Cardiolipinisaconstituentofmaterialusedin
asyphilistest.
Antinuclearantibodies.
Associatedantibodies:AntidsDNA,antiSmith.
MechanismofinjuryofSLE:TypeIIIhypersensitivityreaction(i.e.,duetodepositionofimmunecomplexand
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subsequentactivationofthecomplementcascade).
RiskfactorsforSLE:Geneticsandenvironment.
Importantpoint:OpportunisticinfectionsarethemostcommoncauseofdeathofpatientswithSLE.Renaland
centralnervoussystem(CNS)diseasesarethesecondmostcommoncauseofdeath.
MorphologyofSLE
Gross:Somefindingsincludemalarrash,serositis,andLibmanSacksendocarditis(13mmnonbacterial
vegetationsoneithersurfaceoftheleafletthisisnowseenlessbecauseoftheadventofcorticosteroid
therapy).
Microscopic:AgeneralfeatureofSLEisthelupuserythematosus(LE)cellsintissue,whichareneutrophils
containingphagocytizednuclei.AspecificfeatureofSLEisrenaldisease,whichhasfiveclasses.
ClassI:Nodisease.
ClassII:Mesangialincreaseinmesangialmatrix,withdepositionofimmunecomplexes.
ClassIII:Focalproliferativeglomerulonephritisafewglomerulihaveproliferationofendothelialand
mesangialcellsassociatedwithanincreasednumberofneutrophilsandpossiblyfibrinoidnecrosis(Figure3
2).
ClassIV:Diffuseproliferativeglomerulonephritismostifnotallglomerulihavethechangesdescribedin
ClassIII.
ClassV:Membranousglomerulonephropathyglomerulihavethickenedbasementmembranes,producinga
wirelooppattern.
FIGURE32.

Focalproliferativeglomerulonephritisinapatientwithsystemiclupuserythematosus.Ofthethreeglomeruli
showninthephotomicrograph,onlytheoneonthefarrightshowsanypathologicchanges.Focally,thereisan
increasednumberofcellswithintheglomerulartuft(atthe3o'clockposition).Hematoxylinandeosin,200.
Associatedconditions:TwoconditionsoftenassociatedwithSLEareantiphospholipidantibodysyndromeand
druginducedlupus.
Antiphospholipidantibodysyndrome
Basicdescription:Thisconditionisduetoanantibodythatdelaysclottinginvitroinvivo,itinducesa
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hypercoagulablestate.
Complicationsofantiphospholipidantibodysyndrome:Arterialandvenousthrombi,spontaneous
abortions,andfocalcerebralandocularischemia.Theclassicclinicaltriadisthrombosis,thrombocytopenia,
andrecurrentabortions.
Formsofantiphospholipidantibodysyndrome
Primary:OccursasasoleentityandisnotassociatedwithSLE.
Secondary:OccursinpatientswithadiagnosisofSLE.
Druginducedlupus
Basicdescription:Diseaseassociatedwithcertaindrugs(e.g.,hydralazine,procainamide,orD
penicillamine)thatcancausesymptomssimilartoSLE,suchasarthralgia,fever,andserositis.Renaland
CNSmanifestationsarerare,however.
Associatedantibody:Antihistoneantibodies.
Importantpoint:Thediseaseremitswithremovalofthedrug.
Rheumatoidarthritis
Epidemiology:Rheumatoidarthritisismorecommoninwomenthaninmen.
Clinicalpresentationofrheumatoidarthritis:Arthritis(nonsuppurative,proliferativearthritis),sometimeswith
extraarticularsymptomsduetoinvolvementofskin,heart,bloodvessels,andlungs.Thearthritisischaracterized
bywarmth,swelling,andtendernessinthejoints,usuallybilaterallyandmostcommonlyinthehands.Theclassic
presentationismorningstiffness>1hourduration.Signsincludeaboutonniredeformityofthedistal
interphalangealjoint(DIP),aswanneckdeformityoftheproximalinterphalangealjoint(PIP),Bakercysts,and
rheumatoidnodules.
Associatedantibodies:Rheumatoidfactor(IgMantibodyagainsttheFcportionofIgG)in7080%ofthe
patients.
Mechanismofinjury:TypeIIIhypersensitivityreaction.
Microscopicmorphologyofrheumatoidarthritis:Inthejoint,apannusforms.Apannusisproliferating
synovialcellsmixedwithinflammatorycellsandgranulationtissue.Pannusformationcanleadtofibrosisand
calcificationofthejointspace(i.e.,ankylosis).Rheumatoidnoduleshaveacentralfibrinoidnecrosissurrounded
bypalisadingmacrophages,withanouterrimoflymphocytesandplasmacells(Figure33AandB).
FIGURE33.

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A,Alowpowerviewofarheumatoidnodule.B,Acloserviewshowingthecentralnecrosisontheleftsideofthe
photomicrograph,withsuccessivelayersofpalisadingmacrophagesandlymphocytes(totherightofthe
necrosis).Hematoxylinandeosin,A,40B,400.
Sjgrensyndrome
Epidemiology:Usuallyoccursinwomenbetweentheagesof50and60years.
ClinicalpresentationofSjgrensyndrome:Triadofdrymouth,dryeyes,andanautoimmunedisorder
(usuallyrheumatoidarthritis).
Associatedantibodies
AntiSSA(antiribonucleoprotein)patientswithahightiterofantiSSAaremorelikelytohavesystemic
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manifestations.
AntiSSB(antiribonucleoprotein).
Microscopicmorphology:Lymphocyticandplasmacyticinfiltrateofsalivaryandlacrimalglands,whichis
associatedwithductaldamage(Figure34).
FIGURE34.

SalivaryglandinapatientwithSjgrensyndrome.Thissectionofsubmandibularsalivaryglandhasalymphocytic
infiltrate(intheleftuppercornerofthephotomicrograph),associatedwithsomedisruptionoftheglandular
parenchyma.Withsuchdestructionofsalivaryglandtissue,theinabilitytoproducesalivaisimpairedhence,the
drymouthassociatedwithSjgrensyndrome.Hematoxylinandeosin,200.
ComplicationsofSjgrensyndrome:MALToma(neoplasmofmucosaassociatedlymphoidtissue)patients
canalsohaveextraglandularinvolvementproducingsynovitis,pulmonaryfibrosis,andneuropathy.
Systemicsclerosis(scleroderma)
Basicdescription:Autoimmuneconditionassociatedwithfibrosisoforgansinvolved.
Epidemiology:Usuallyoccursinindividuals50to60yearsofageandoldertheratioofoccurrenceis3:1female
tomale.
Clinicalpresentation
Limitedscleroderma(alsocalledCRESTsyndrome):Calcinosis,Raynaudphenomenon,Esophageal
dysfunction,Sclerodactyly,andTelangiectasia.
Diffusescleroderma:Widespreadskinandvisceralinvolvement,includingpulmonaryfibrosisresultingin
hypertensionandrenalinvolvementresultinginoliguricrenalcrises.
Associatedantibodies
CRESTsyndrome:Anticentromere.
Diffusescleroderma:AntiScl70(againstDNAtopoisomeraseI).
Microscopicmorphologyofsystemicsclerosis:Fibrosisinvolvingdermis,muscularisofgastrointestinaltract,
andalveolarseptaeinthelungandinterlobulararteriesinthekidneyandheart.
Mixedconnectivetissuedisorder
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Clinicalpresentation:FindingssuggestiveofSLE,polymyositis,rheumatoidarthritis,andsystemicsclerosis.
Associatedantibodies:Toribonucleoprotein(RNP)particlecontainingU1.
Importantpoints:Patientshavelittleornorenaldiseaseandrespondwelltotreatmentwithcorticosteroids.

Amyloidosis
Overview:Amyloidosisisduetoabnormalproductionanddepositionofprotein.Withintissuesofthebody,there
areseveraltypesofamyloid,eachofwhichiscomposedofadifferentproteinandisassociatedwithcertain
diseases(Table32).
Table32.Amyloidosis:Types,ConstituentProtein,andAssociatedDiseases

Formsof
Amyloidosis

Typeof
Amyloid

Protein

AssociatedDisease

Systemic
amyloidosis

AL

Iglightchain

Multiplemyeloma

AA

Serumamyloid
associatedprotein

Chronicinflammatoryconditions
hereditaryamyloidosis

ATTR

Transthyretin

Systemicsenileamyloidosis

Amyloidprecursor
protein

Alzheimerdisease

ACal

Calcitonin

Medullarythyroidcarcinoma

Localized
amyloidosis

Microscopicmorphologyofamyloidosis
Lightmicroscope:Amorphous,hyalinedepositionthathasapplegreenbirefringenceuponpolarizationafter
Congoredstaining(Figure35).
Electronmicroscope:Mostformsofamyloidare7.5to10nanometerfibrilsinapleatedsheet
configuration.
FIGURE35.

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Amyloidosisoftheliver.Thislowpowerviewofthelivershowssinusoidsthataremarkedlyexpandedbyawaxy,
paleeosinophilic,acellularmaterial.Thismaterialisamyloidandwouldshowapplegreenbirefringenceupon
polarizationafterstainingwithCongored.Hematoxylinandeosin,100.
Someorgansaffectedbyamyloidosis:Kidney,spleen,liver,andheart.
Clinicalpresentation:Diastolicheartfailure,macroglossia,carpaltunnelsyndrome,andchronicrenaldisease.
Amyloidosisisoneoffourcausesofchronicrenaldiseaseassociatedwithenlargedkidneystheotherthree
causesarediabetesmellitus,polycystickidneydisease,andHIVnephropathy.

HereditaryImmunodeficiencyStates
Overview:Therearemanyhereditarycausesofimmunodeficiency.Majorpointsregardingsixofthemore
commonforms(XlinkedagammaglobulinemiaofBruton,commonvariableimmunodeficiency,isolatedIgA
deficiency,hyperIgMsyndrome,severecombinedimmunodeficiencydisease[SCID],andWiskottAldrich
syndrome)arediscussedbelow.

XLinkedAgammaglobulinemiaofBruton
Inheritancepattern:Xlinkedrecessive.
Mutatedgene:GeneforBcelltyrosinekinase.
Mechanism:FailureofmaturationofBcells.TheBcellsundergoheavychainrearrangementandthenstop
maturing.
Epidemiology:Manifestbytheageof6months.Thedelayinmanifestationsisbecauseofthepresenceof
maternalIgG.
ManifestationsofXlinkedagammaglobulinemiaofBruton:Recurrentinfectionsarebacterial(e.g.,
Haemophilusinfluenzae,Streptococcuspneumoniae,Staphylococcusaureus),someviral(e.g.,enteroviruses),
andsomeparasitic(e.g.,Giardialamblia).Patientshavehypoplasiaoftonsilsandadenoidsandverylow
immunoglobulinlevels.
Microscopicmorphology:Underdevelopedgerminalcentersinlymphoidorgans.
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CommonVariableImmunodeficiency
Inheritancepattern:Noonemodeofinheritance.
Mechanism:BcellsproliferateinresponsetoantigenbutcannotproduceIg.
Epidemiology:Affectsmalesandfemalesequallypresentsduringlaterchildhoodandadolescence.
Manifestationsofcommonvariableimmunodeficiency:SameasXlinkedagammaglobulinemiaofBruton.
Microscopicmorphology:Lymphoidfollicularhyperplasia.

IsolatedIgADeficiency
Mechanism:DefectindifferentiationofBlymphocytestoIgAproducingcells.Canbefamilialoracquireddueto
toxoplasmosisormeaslesinfections.
Epidemiology:1in600birthsmuchmorecommoninwhitesthaninAfricanAmericansandAsians.
ManifestationsofisolatedIgAdeficiency:Recurrentsinopulmonaryinfections,diarrhea,andincreased
incidenceofautoimmunediseases.Also,patientscandevelopananaphylacticreactiontobloodtransfusions.

HyperIgMSyndrome
Mutation:GeneatXq26proteinproductisCD40L.Thismutationisfoundin70%ofpatientsotherpatients
haveamutationofCD40.
Inheritancepattern:WiththemutationofCD40L,inheritanceisXlinkedrecessivewiththemutationofCD40,it
isautosomalrecessive.
Mechanism:TcellsfailtostimulateBcellstoproduceantibodyotherthanIgM.
ManifestationsofhyperIgMsyndrome:RecurrentpyogenicinfectionsandPneumocystispneumonia.

SevereCombinedImmunodeficiencyDisease(SCID)
Inheritancepatterns
Xlinkedrecessive(5060%ofcases)
Mutation:Geneforcommonchainsubunitofcytokinereceptors.
Mechanism:AdefectinthecytokinereceptorforIL7ismostimportantincausingtheeffectsofthe
disease,sinceIL7isrequiredforproliferationoflymphocytes.
Epidemiology:Malepredominance.
Autosomalrecessive
Mutation:Geneforadenosinedeaminase.
Mechanism:CausesaccumulationofdeoxyATP,whichistoxictolymphocytes.
ManifestationsofSCID:Recurrentinfectionsbeforetheageof6monthsbyawiderangeofpathogens,
includingCandida,variousbacteria(e.g.,Pseudomonas),andviruses(e.g.,CMV,varicella).

WiskottAldrichSyndrome
Inheritancepattern:Xlinkedrecessive.
Manifestations:Thrombocytopeniawithresultantbleedingatthecircumcisionsiteeczemaandrecurrent
infections.

AcquiredImmunodeficiencySyndrome(AIDS)
Cause:Infectionwithhumanimmunodeficiencyvirus(HIV),anRNAretrovirus.
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Mechanismoftransmission
Sexual:Virusisinsemen(extracellularandinmonocytes)andentersthepatientthroughtearsinthemucosa.
Parenteral(e.g.,IVdrugabuse).
Mothertoinfant:Transmissioncanoccurinutero,transplacental,orintrapartum(duringdelivery).
Types
HIV1:FoundinindividualsintheUnitedStates,Europe,andCentralAfrica.
HIV2:FoundinindividualsinWestAfrica.
Majorproteins,genes,andtheirfunctions
gp120andgp41.
p24majorcapsidprotein.
gaggeneencodesp24.
polgeneencodesreversetranscriptase.
MechanismofHIVinfection
gp120bindstoCD4,whichexposesthesiteforCXCR4onTcellsandforCCR5onmacrophages.Then,
gp41undergoesachange,whichallowsittoinsertintothetargetmembrane,allowingviralcellfusion.
Viralcoreentersthecelltheviralgenomethenundergoesreversetranscription.Individingcells,thecDNA
entersthenucleusandintegratesintotheviralgenome.
Whentheinfectedcellisactivated,proviraltranscriptionoccurs,whichresultsinlysisofcells.
HIVcolonizesthelymphoidorgans.
Importantpoint:HIVisinfectionwiththevirusAIDSisasyndromecharacterizedbycertainAIDSdefining
illnessesinotherwords,allpeopleinfectedwithHIVdonothaveAIDS.
Clinicalfeatures:PatientswithAIDSareatriskforopportunisticinfectionsandcertainneoplasms,andhave
characteristicCNSandrenalfindings.
1.Opportunisticinfections
Cryptosporidiosis(causesenteritis).
Pneumocystispneumonia(Figure36).
RiskfactorforPneumocystispneumonia:CD4+count<200cells/L.
Clinicalpresentation:Fever,nonproductivecough,dyspnea,increasedleveloflactatedehydrogenase
(LDH),anddiffuseinterstitial(groundglass)patternseenonachestradiograph.Hypoxemiaisusually
presentandmaybesevere.
FIGURE36.

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Pneumocystispneumoniaandcytomegalovirus(CMV)pneumonia.ThisHIVpositivepatienthadapneumonia
causedbybothPneumocystisandCMV.Pneumocystispneumoniaproducesafluffypinkexudateinthealveolar
spaces(arrow).ThearrowheadindicatesaCMVinfectedcell.Theinsetintherightuppercornerofthe
photomicrographbetterillustratesthecharacteristicintranuclearinclusionproducedinCMVinfectedcells.
Hematoxylinandeosin,400(mainimage)and1000(inset).
Toxoplasmosis(pneumoniaorinfectionofCNS).
Cryptococcosis(causesmeningitis).
Disseminatedhistoplasmosis.
Mycobacterium(infectionswithMtuberculosisorMaviumintracellulare).
CMV(seeFigure36).
Bacillaryangiomatosis(Bartonellahenselae).
Candidaesophagitis.
2.Neoplasms
Kaposisarcoma(relatedtoHHV8)(Figure37).
NonHodgkinlymphoma(Bcelllymphomasofthebrain)(Figure38).
FIGURE37.

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Kaposisarcoma.KaposisarcomaisamalignancyderivedfrombloodvesselsandisfoundinpatientswithAIDS.
ThehistologicappearanceofKaposisarcomaisaspindlecellneoplasmwithextravasatedredbloodcells.
Hematoxylinandeosin,200.
FIGURE38.

BcelllymphomaofthebraininapatientwithAIDS.ThenonHodgkinBcelllymphomainthispatientiscentered
ontheseptumpellucidumandfornix.NonHodgkinBcelllymphomasofthebrainoccurwithahigherfrequency
amongpatientswithAIDSwhencomparedwithacontrolpopulationofnonHIVinfectedindividuals.
3.CNSinvolvement:Encephalitischaracterizedbygiantcellsalso,vacuolarmyelopathyandAIDSdementia.
4.Renalinvolvement:HIVnephropathy,focalsegmentalglomerulosclerosis,andchronicrenaldisease
characterizedbyenlargedkidneys.
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Acutecellularrejectioninthekidney.Inthislowpowerviewofarenaltransplant,notetheinfiltrateoflymphocytes
amongtheglomeruliandrenaltubules.Hematoxylinandeosin,100.
Focalproliferativeglomerulonephritisinapatientwithsystemiclupuserythematosus.Ofthethreeglomeruli
showninthephotomicrograph,onlytheoneonthefarrightshowsanypathologicchanges.Focally,thereisan
increasednumberofcellswithintheglomerulartuft(atthe3o'clockposition).Hematoxylinandeosin,200.
A,Alowpowerviewofarheumatoidnodule.B,Acloserviewshowingthecentralnecrosisontheleftsideofthe
photomicrograph,withsuccessivelayersofpalisadingmacrophagesandlymphocytes(totherightofthe
necrosis).Hematoxylinandeosin,A,40B,400.
SalivaryglandinapatientwithSjgrensyndrome.Thissectionofsubmandibularsalivaryglandhasalymphocytic
infiltrate(intheleftuppercornerofthephotomicrograph),associatedwithsomedisruptionoftheglandular
parenchyma.Withsuchdestructionofsalivaryglandtissue,theinabilitytoproducesalivaisimpairedhence,the
drymouthassociatedwithSjgrensyndrome.Hematoxylinandeosin,200.
Amyloidosisoftheliver.Thislowpowerviewofthelivershowssinusoidsthataremarkedlyexpandedbyawaxy,
paleeosinophilic,acellularmaterial.Thismaterialisamyloidandwouldshowapplegreenbirefringenceupon
polarizationafterstainingwithCongored.Hematoxylinandeosin,100.
Pneumocystispneumoniaandcytomegalovirus(CMV)pneumonia.ThisHIVpositivepatienthadapneumonia
causedbybothPneumocystisandCMV.Pneumocystispneumoniaproducesafluffypinkexudateinthealveolar
spaces(arrow).ThearrowheadindicatesaCMVinfectedcell.Theinsetintherightuppercornerofthe
photomicrographbetterillustratesthecharacteristicintranuclearinclusionproducedinCMVinfectedcells.
Hematoxylinandeosin,400(mainimage)and1000(inset).
Kaposisarcoma.KaposisarcomaisamalignancyderivedfrombloodvesselsandisfoundinpatientswithAIDS.
ThehistologicappearanceofKaposisarcomaisaspindlecellneoplasmwithextravasatedredbloodcells.
Hematoxylinandeosin,200.
BcelllymphomaofthebraininapatientwithAIDS.ThenonHodgkinBcelllymphomainthispatientiscentered
ontheseptumpellucidumandfornix.NonHodgkinBcelllymphomasofthebrainoccurwithahigherfrequency
amongpatientswithAIDSwhencomparedwithacontrolpopulationofnonHIVinfectedindividuals.

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