Disorders of the Immune Response

Chapter19:DisordersoftheImmuneResponse 1

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I. AlterationsoftheImmuneSystemA. ImmunodeficiencystatesB. AllergicorhypersensitivityreactionsC. TransplantationrejectionD. Autoimmunedisorders

II. ImmunodeficiencyDisordersA. Abnormalityintheimmunesystemthatrendersapersonsusceptibleto

diseasesnormallypreventedbyanintactimmunesystemB. Classifications

1. Primarycongenitalorinherited2. Secondaryacquiredlaterinlife

a. Malnutritionb. InfectionHIV,AIDSc. Disseminatedcancersneoplasticdiseaseslymphomad. Immunosuppressivetherapycorticosteroidsortransplant

rejectionmedicationsC. WarningSignsofImmunodeficiencybyJeffreyModellFoundation/Immune

DeficiencyFoundation1. Eightormorenewearinfectionswithin1year2. Twoormoreserioussinusinfectionswithin1year3. Twoormoremonthsonantibioticswithlittleeffect4. Twoormorepneumoniaswithin1year5. Failureofaninfanttogainweightorgrownormally6. Recurrent,deepskinororganabscesses7. Persistentthrushinmouthorelsewhereonskin,after1yearofage8. Needforintravenousantibioticstoclearinfections9. Twoormoredeep‐seatedinfections10. Afamilyhistoryofprimaryimmunodeficiency

III. FourMajorCategoriesofImmuneMechanismsA. Humoralorantibody‐mediatedimmunityBlymphocytesB. Cell‐mediatedimmunityTlymphocytesC. ComplementsystemD. Phagocytosisneutrophilsandmacrophages

IV. HumoralImmunodeficienciesA. HumoralimmunodeficienciesinvolveB‐cellfunctionandimmunoglobulin

productionB. IncreasetheriskofrecurrentpyogenicinfectionsC. Humoralimmunityusuallyisnotasimportantindefendingagainst

intracellularbacteria(mycobacteria),fungi,andprotozoaD. Virusesusuallyarehandlednormally,exceptfortheenterovirusesthatcause

gastrointestinalinfectionsV. PrimaryHumoralImmunodeficiencyDisorders

A. GeneticdisorderofBlymphocytesB. Approximately70%ofprimaryimmunodeficiencies


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C. MaturationcycleinitiallyinvolvestheproductionofsurfaceIgM,migrationfromthebonemarrowtotheperipherallymphoidtissue,andswitchingtotheproductionofspecializedIgM‐,IgA‐,IgD‐,IgE‐,orIgG‐secretingplasmacellsafterantigenicstimulation

D. Immunoglobulinproductiondependson1. DifferentiationofstemcellsintomatureBlymphocytes2. Antigen‐dependentgenerationofimmunoglobulin‐producingplasma

cellsE. Caninterrupttheproductionofoneoralloftheimmunoglobulins

VI. CombineT‐CellandB‐CellImmunodeficienciesA. AffectallaspectsofimmunefunctionB. Severecombinedimmunodeficiencyrepresentsalife‐threateningabsenceof

immunefunction1. AbsenceofallT‐andB‐cellfunctionand,insomecases,alackofNKcells2. AffectedinfantshaveadiseasecoursethatresemblesAIDS,withfailureto

thrive,chronicdiarrhea,andopportunisticinfections3. X‐linkedSCID

a. Boys>girlsb. Causedbyageneticdefectinthecommongamma‐chainsubunit(γc)

ofcytokinereceptorsC. Combinedimmunodeficiency(CID)isdistinguishedfromSCIDbythe

presenceoflow,butnotabsent,T‐cellfunction1. Althoughantibody‐formingcapacityisimpairedinmostcases,itisnot

absent2. Autosomalpatternofinheritanceiscommon

a. Ataxia‐telangiectasiai. Complexsyndromeofneurologic,immunologic,endocrinologic,

hepatic,andcutaneousabnormalitiesii. Autosomalrecessivedisorderiii. Characterizations

o Cerebellarataxiapoormusclecoordinationo Appearanceoftelangiectaseslesionsconsistingofdilated

capillariesandarteriolesontheskinandconjunctivalsurfacesoftheeye

b. Wiskott‐Aldrichsyndromei. X‐linkedrecessivedisorderthatbecomessymptomaticduringthe

firstyearoflifeii. Plaguedbyeczema,lowplateletcounts,andsusceptibilityto

bacterialinfectionsiii. Bleedingepisodesorsymptomsduetoinfectionusuallybegin

withinthefirst6monthsoflifeiv. Pronetosepticemiaandmeningitis,lethalvaricellav. Management:treatmentofeczema,controlofinfections,and

managementofbleedingepisodes,antimicrobialtherapy,bonemarrowtransplantation,splenectomy


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D. RequiresbonemarroworstemcelltransplantationforsurvivalVII. DisordersofComplementSystem

A. Primary1. Mostlytransmittedasautosomalrecessivetraits2. Caninvolveoneormorecomplementcomponents3. Onlysupportivemeasuresareavailablefortreatmentofprimary

disordersofthecomplementsystema. Preventbacterialinfectionb. ImmunizedwithvaccinesforS.pneumoniae,H.influenzae,andN.

meningitidesB. Secondary

1. Occurinpersonswithfunctionallynormalcomplementsystemsbecauseofrapidactivationandturnoverofcomplementcomponentsasisseeninimmunecomplexdisease

2. Reducedsynthesisofcomponentschroniccirrhosisoftheliverormalnutrition

3. HereditaryangioneuroticedemaandlossofregulationVIII. PhagocyticSystems

A. Composedprimarilyofpolymorphonuclearleukocytes(neutrophilsandeosinophils)andmononuclearphagocytes(circulatingmonocytesandtissueandfixed[spleen]macrophages)

B. Actionofthesecells1. Migratetothesiteofinfectionchemo‐taxis2. Aggregatearoundtheaffectedtissueadherence3. Envelopeinvadingmicroorganismphagocytosis4. Generatemicrobicidalsubstancestokilltheingestedpathogens

C. DysfunctionofPhagocyticSystem1. Defectinanyofthesefunctionsorareductionintheabsolutenumberof

availablecellscandisruptthephagocyticsystem2. Pronetoinfections

a. BacteriaCandidaspeciesb. Filamentousfungi

3. Chronicgranulomatousdisease(CGD)a. Primarydisordersofphagocytosisb. Representsagroupofinheriteddisordersthatgreatlyreduceor

inactivatetheabilityofphagocyticcellstoproducetheso‐calledrespiratoryburstthatresultsinthegenerationoftoxicderivativesofoxygen(superoxideanionandhydrogenperoxide)createsanintracellularenvironmentthatkillsingestedmicroorganisms

c. Diagnosedbyexaminingtheabilityofaperson'sphagocytestoreduceayellowdyetoabluecompoundduringactiverespiration

d. Treatmenti. Bonemarrowtransplantationonlycureii. Supportivecarerecombinantinterferon‐gammaand

prophylacticantibiotictherapy


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D. StemCellTransplantation1. Manyoftheprimaryimmunodeficiencydisordersinwhichthedefecthas

beentracedtothestemcellcanbecuredwithallogeneicstemcelltransplantationfromanunaffecteddonora. SCIDb. Wiskott‐Aldrichsyndromec. Chronicgranulmatousdisease

2. Stemcellscanrepopulatethebonemarrowandreestablishhematopoiesisa. Tobeeffective,bonemarrowcellsofthehostaredestroyedby

myeloablativedosesofchemotherapyb. Chronicimmunoglobulintherapymaybenecessaryfortransplant

recipientswhoprimarilyretainBcellsofhostorigin3. Stemcellscanbecollectedfromthebonemarroworperipheralblood

a. HLA‐matchedsiblingsusuallyproducethebestresultsb. Stemcellaspirationfromthebonemarrowisthemostcommonform

ofallograftcollectionc. Umbilicalcordcollectedatthetimeofdeliverywithoutproducing

detrimentaleffectstothemotherandnewbornIX. AdaptiveImmunity

A. DevelopmentofresponsetoantigenB. SpecifichumoralandcellularrecognitionC. Memorycells

X. HypersensitivyDisordersA. ExcessiveorinappropriateactivationoftheimmunesystemB. Types

1. TypeI,IgE‐mediateddisorders2. TypeII,antibody‐mediateddisorders3. TypeIII,complement‐mediatedimmunedisorders4. TypeIV,T‐cell‐mediateddisorders

XI. TypeIHypersensitivityReactionsA. IgE‐mediatedreactionsbeginrapidly5‐30minB. Allergicreactionstoallergens

1. Proteininpollen,housedustmites,animaldander,foods,andchemicalsliketheantibioticpenicillin

2. Exposurethroughinhalation,ingestion,injection,orskincontact3. Reactionscanbelocal(atopic)orsystemic

C. TwotypesofcellsarecentraltoatypeIhypersensitivityreaction1. Type2helperT(TH2)cellswithtwosubsetsofhelperTcellsTH1and

TH2a. DevelopfromprecursorCD4+Tlymphocyteb. TH1cells

i. Differentiateinresponsetomicrobesii. StimulatedifferentiationofBcellsintoIgM‐andIgG‐producing

plasmacells


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c. TH2celli. Differentiationinresponsetoallergensandhelminths(intestinal

parasites)ii. StimulatedifferentiationofBcellsintoIgE‐producingplasma

cells,actasgrowthfactorsformastcells,andrecruitandactivateeosinophils

2. Mastcellsorbasophilsa. Derivedfromhematopoieticprecursorcellsb. Containgranulesthatreleasemediatorsduringreactionsc. Mastcellsdistributedthroughoutconnectivetissue

i. Beneaththeskinandmucousmembranesoftherespiratory,gastrointestinal,andgenitourinarytracts,andadjacenttobloodandlymphvesselssurfacesthatareexposedtoenvironmentalantigensandparasites

d. TypeIhypersensitivityreactionsbeginwithmastcellorbasophilsensitizationi. Allergen‐specificIgEantibodiesattachtoreceptorsonthesurface

ofmastcellsandbasophilsii. Withsubsequentexposure,thesensitizingallergenbindstothe

cell‐associatedIgEandtriggersaseriesofeventsthatultimatelyleadtodegranulationofthesensitizedmastcellsorbasophils,causingreleaseoftheirpreformedmediators

iii. Mastcellsarealsothesourceoflipid‐derivedmembraneproducts(e.g.,prostaglandinsandleukotrienes)andcytokinesthatparticipateinthecontinuedresponsetotheallergen

D. TypeI,IgE‐mediatedhypersensitivityreactionprocess1. ThestimulationofB‐cell

differentiationbyanantigenstimulatedtype2helper(TH2)TcellleadstoplasmacellproductionofIgEandmastcellsensitization

2. Subsequentbindingoftheantigenproducesdegranulationofthesensitizedmastcellwithreleaseofpreformedmediatorsthatleadstoaprimary,orearly‐phaseresponse

3. TH2T‐cellrecruitmentofeosinophils,alongwiththereleaseofcytokinesandmembranephospholipidsfromthemastcell,leadstoasecondary,orlate‐phaseresponse


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E. ManyTypeIhypersensitivityreactionshave2phases1. Primaryorinitial‐phaseresponseoccurswithin5‐30minutesof

exposure,subsideswithin60mina. Vasodilationb. Vascularleakagec. Smoothmusclecontractiond. Mediatedbymastcelldegranulation

i. Releaseofhistamine,acetylcholine,adenosine,chemotacticmediators,enzymessuchaschymaseandtrypsinthatleadtogenerationofkinins

ii. Histaminepotentvasodilatorincreasespermeabilitysmoothmusclecontraction,bronchialconstrictionsystemicshock

iii. Acetylcholinebronchialsmoothmusclecontraction,dilationofsmallbloodvessels

iv. Kininspotentinflammatorypeptidesactivatedbyenzymesvasodilationandsmoothmusclecontraction

2. Secondaryorlate‐phaseresponsea. Occursabout2to8hourslaterandlastsforseveraldaysb. Moreintenseinfiltrationoftissueswitheosinophilsandotheracute

andchronicinflammatorycellsc. Tissuedestructionintheformofepithelialdamaged. Resultsfromtheactionoflipidmediatorsandcytokinesinvolvedin

theinflammatoryresponsei. Derivedfrommastcellmembranephospholipidsthatarebroken

downintoarachidonicacidsynthesizeintoleukotrienesandprostaglandinsthatactsimilartohistamineandacetylcholinebutwithdelayedandprolongedeffects

ii. Mastcellscytokines,chemotacticfactorsinfluxeosinophilsandleukocytesinflammatoryresponse

e. Playsaprotectiveroleinthecontrolofparasiticinfectionsi. IgEantibodiesdirectlydamagethelarvaeoftheseparasitesby

recruitinginflammatorycellsandcausingantibody‐dependentcell‐mediatedcytotoxicity

ii. Importantindevelopingcountrieswheremuchofthepopulationisinfectedwithintestinalparasites

F. ExamplesofTypeI1. Anaphylactic(Systemic)Reactions

a. Systemiclife‐threateninghypersensitivityreactionb. Characterizedbywidespreadedema,vascularshocksecondaryto

vasodilation,anddifficultybreathingsystemicshockc. Exposureofantigenfrominjection,insectsting,skin,GImucosa

levelofseveritydependsonthelevelofsensitizationd. Initialmanagement:establishmentofastableairwayandintravenous

access,andadministrationofepinephrine


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2. Atopic(local)Reactionsa. Geneticallydeterminedhypersensitivity

i. Positivefamilyhistoryofallergyisfoundinabout50%ofatopicindividuals

ii. HavehighserumlevelsofIgEandincreasednumbersofbasophilsandmastcells.

b. EnvironmentalallergensmediatedbyanIgE‐mastcellreactionc. Mostcommonatopicdisordersurticaria(hives),allergicrhinitis

(hayfever),atopicdermatitis,foodallergies,andsomeformsofasthma

d. Treatmentforseasonalallergy/allergicrhinitisdesensitizationi. Frequent(usuallyweekly)injectionsoftheoffendingantigensii. Antigens,whicharegiveninincreasingdoses,stimulate

productionofhighlevelsofIgG,whichactsasablockingantibodybycombiningwiththeantigenbeforeitcancombinewiththecell‐boundIgEantibodies

XII. TypeII(Cytotoxic)HypersensitivityReactionsA. TypeII(antibody‐mediated)hypersensitivityreactionsaremediatedbyIgG

orIgMantibodiesdirectedagainsttargetantigensoncellsurfacesorinconnectivetissues1. Endogenousantigensthatarepresentonthemembranesofbodycells2. Exogenousantigensthatareadsorbedonthemembranesurface

B. Threedifferenttypesofantibody‐mediatedmechanisms1. Opsonizationandcomplement‐andantibodyreceptor‐mediated

phagocytosisa. Deletionofcellstargetedbyantibodycanoccurbywayofeitherthe

complementsystemorbyantibody‐dependentcell‐mediatedcytotoxicity(ADCC),whichdoesnotrequirecomplement

b. Occurbecausethecellsarecoated(opsonized)withmoleculesthatmakethemattractivetophagocytesorbecauseoftheformationofmembraneattackproteinsthatdisrupttheintegrityofthecellmembraneandcausecelllysis

c. WithADCCdestruction,cellsthatarecoatedwithlowlevelsofIgGantibodyarekilledbyavarietyofeffectorcellsthatbindtotheirtargetbytheirreceptorsforIgG,andcelllysisoccurswithoutphagocytosis

d. Examplesi. Mismatchedbloodtransfusionreactions,hemolyticdiseaseofthe

newbornduetoABOorRhincompatibilityii. Certaindrugreactions

o Bindingofcertaindrugsordrugmetabolitestothesurfaceofredorwhitebloodcellselicitsanantibodyresponsethatlysesthedrug‐coatedcell

o Causestransientanemia,leukopenia,orthrombocytopenia,o Correctedbytheremovaloftheoffendingdrug


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2. Complement‐andantibodyreceptor‐mediatedinflammationa. Whenantibodiesaredepositedintheextracellulartissues,suchas

basementmembranesandmatrix,theinjuryistheresultofinflammationratherthanphagocytosisorcelllysis

b. Depositedantibodiesactivatecomplement,generatingchemotacticbyproductsthatrecruitandactivateneutrophilsandmonocytesreleasedenzymescauseinflammationanddamagetissuesglomerulonephritis,vascularrejectioninorgangrafts,andotherdiseases

c. Goodpasturesyndromeantibodybindstoamajorstructuralcomponentofpulmonaryandglomerularbasementmembranes,causingpulmonaryhemorrhageandglomerulonephritis

3. Antibody‐mediatedcellulardysfunctiona. Antibodybindingtospecifictargetcellreceptorsdoesnotleadtocell

death,buttoachangeincellfunctionb. Gravesdiseaseautoantibodydirectedagainstthyroid‐stimulating

hormone(TSH)receptorsonthyroidcellsstimulatesthyroxineproduction,leadingtohyperthyroidism

c. Mmyastheniagravis,autoantibodiestoacetylcholinereceptorsontheneuromuscularendplateseitherblocktheactionofacetylcholineormediateinternalizationordestructionofreceptors,leadingtodecreasedneuromuscularfunction

C. TypeII,hypersensitivityreactionsresultfrombindingofantibodiestonormaloralteredsurfaceantigens1. Opsonizationandcomplement‐

orantibodyreceptor‐mediatedphagocytosisorcelllysisthroughmembraneattackcomplex(MAC)

2. Complement‐andantibodyreceptor‐mediatedinflammationresultingfromrecruitmentandactivationofinflammation‐producingleukocytes(neutrophilsandmonocytes)

3. Antibody‐mediatedcellulardysfunction,inwhichantibodyagainstthethyroid‐stimulatinghormone(TSH)receptorincreasesthyroidhormoneproduction

4. Antibodytoacetylcholinereceptorinhibitsreceptorbindingoftheneurotransmitterinmyastheniagravis


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XIII. TypeIIIImmuneComplexAllergicDisordersA. Mediatedbytheformationofinsolubleantigen‐antibodycomplexes,

complementfixation,andlocalizedinflammationB. Activationofcomplementbyimmunecomplexgenerateschemotacticand

vasoactivemediatorsthatcausetissuedamagebyalterationinbloodflow,increasedvascularpermeability,destructiveactionofinflammatorycells

C. Immunecomplexesformedinthecirculationproducedamagewhentheycomeincontactwiththevesselliningoraredepositedintissues,includingtherenalglomerulus,skinvenules,lung,andjointsynovium1. Vasculitisseenincertainautoimmunediseases2. Systemicimmunecomplexdisordersserumsickness

a. Triggeredbythedepositionofinsolubleantigen‐antibody(IgM,IgG,andoccasionallyIgA)complexesinbloodvessels,joints,andheartandkidneytissue

b. Mostcommoncauses:antibiotics(especiallypenicillin)andotherdrugs,variousfoods,andinsectvenom

c. S/S:urticaria,patchyorgeneralizedrash,extensiveedema(usuallyoftheface,neck,andjoints),andfever

d. Treatmentremovalofthesensitizingantigenandprovidingsymptomreliefi. Aspirinforjointpainandantihistaminesforpruritusii. Epinephrineorsystemiccorticosteroidsmaybeusedforsevere

reactions3. LocalizedimmunecomplexreactionsArthusreaction

a. Localizedtissuenecrosis(usuallyintheskin)causedbyimmunecomplexes

b. Producedbyinjectinganantigenpreparationintotheskinofanimmuneanimalwithhighlevelsofcirculatingantibody

c. Within4to10hours,ared,raisedlesionappearsontheskinatthesiteoftheinjectioni. Ulceroftenformsinthecenterofthelesionii. Injectedantigendiffusesintolocalbloodvessels,whereitcomes

incontactwithspecificantibody(IgG)toincitealocalizedvasculitis

D. TypeIII,immunecomplexreactionsinvolvingcomplement‐activatingIgGorIgMimmunoglobulinswith1. Formationofblood‐borneimmune

complexesthatare2. depositedintissues.Complement

activationatthesiteofimmunecomplexdeposition

3. leadstoattractionofleukocytesthatareresponsibleforvesselandtissueinjury


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XIV. TypeIVHypersensitivityReactionsA. Cell‐mediatedratherthanantibody‐mediatedimmuneresponse

1. Principalmechanismofresponsetoavarietyofmicroorganisms,includingintracellularandextracellularpathogens

2. Canleadtocelldeathandtissueinjuryinresponsetochemicalantigens(contactdermatitis)orself‐antigens(autoimmunity)

B. MediatedbyspecificallysensitizedTlymphocytesdividedintotwobasictypes1. Directcell‐mediatedcytotoxicity

a. CD8+cytotoxicTlymphocytes(CTLs)directlykilltargetcellsthatexpresspeptidesderivedfromcystosolicantigensthatarepresentedinassociationwithclassIMHCmolecules

b. ViralinfectionsCTLresponsescanleadtotissueinjurybykillinginfectedtargetcellsevenifthevirusitselfhasnocytotoxiceffects

c. CTLscannotdistinguishbetweencytopathicandnoncytopathicviruseskillvirtuallyallinfectedcellsregardlessofwhethertheinfectionisharmful

d. HepatitisthedestructionoflivercellsisduetothehostCTLresponseandnotthevirus

2. Delayed‐typehypersensitivitya. Occurinresponsetosolubleproteinantigensandprimarilyinvolve

antigen‐presentingcellssuchasmacrophagesandCD4+helperTcellsoftheTH1type

b. DuringthereactionTH1cellsareactivatedandsecreteanarrayofcytokinesthatrecruitandactivatemonocytes,lymphocytes,fibroblasts,andotherinflammatorycells

c. Requirethesynthesisofeffectormoleculesandtake24to72hourstodevelop,whichiswhytheyarecalled“delayed‐type”hypersensitivitydisordersi. Best‐knownDTHresponseisthereactiontothetuberculintest,in

whichinactivatedtuberculinorpurifiedproteinderivativeisinjectedundertheskinareaofrednessandindurationdevelopswithin8to12hours,reachingapeakin24to72hours

ii. Allergiccontactdermatitiso Inflammatoryresponseconfinedtotheskinthatisinitiatedby

reexposuretoanallergentowhichapersonhadpreviouslybecomesensitized

o Erythematous,papular,andvesicularlesionsassociatedwithintensepruritusandweeping

o Affectedareaoftenbecomesswollenandwarm,withexudation,crusting,anddevelopmentofasecondaryinfection

o Severityofthereactionassociatedwithcontactdermatitisrangesfrommildtointense


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o BecausethisconditionfollowsthemechanismofaDTHresponse,thereactiondoesnotbecomeapparentforatleast12hoursandusuallymorethan24hoursafterexposure

o Diagnosis:patchtesto Treatment

Removeirritant Topicalpreparationsointments,corticosteroidcreams

torelievesymptomaticskinlesionsandpreventsecondarybacterialinfections

Severereactionssystemiccorticosteroidsiii. Hypersensitivitypneumonitis

o Exposuretoinhaledorganicdustsorrelatedoccupationalantigens

o InvolveasusceptiblehostandactivationofpulmonaryTcells,followedbythereleaseofcytokinemediatorsofinflammation

o Produceslaboredbreathing,drycough,chillsandfever,headache,andmalaise

o “Farmer'slung,”aconditionresultingfromexposuretomoldyhay

o Diagnosis:obtainagoodhistory(occupationalandotherwise)ofexposuretopossibleantigens

o Treatmentconsistsofidentifyingandavoidingtheoffendingantigensorsystemiccorticosteroids

C.


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XV. HypersensitivityReactionsA. Exposuretolatexmayoccurbycutaneous,mucousmembrane,inhalation,

internaltissue,orintravascularroutes1. Mostseverereactionshaveresultedfromlatexproteinscomingin

contactwiththemucousmembranesofthemouth,vagina,urethra,orrectumcondoms

2. Allergicreactionstolatexproductscanbetriggeredbythelatexproteinsorbytheadditivesusedinthemanufacturingprocessa. Cornstarchglovepowderhasanimportantroleintheallergic

responselatexproteinsreadilyabsorbedbyglovepowderandbecomeairborneduringremovaloftheglove

b. High‐exposureareassuchasoperatingroomswherepowderedglovesareusedcontainsufficientlyhighlevelsofaerosolizedlatextoproducesymptomsinsensitizedpersons

B. TypeofLatexAllergies1. TypeI,IgE‐mediatedhypersensitivityreaction

a. Occurinresponsetothelatexproteinsb. Urticaria,rhinoconjunctivitis,asthma,oranaphylaxisc. Diagnosis:serumIgGlevels

2. TypeIV,Tcellmediatedresponsea. Mostcommontypeofreactionb. Contactdermatitisusuallydevelops48to96hoursafterdirect

contactwithlatexadditivesaffectsthedorsumofthehandsandischaracterizedbyavesicularrashglovecontactiscontinued,theareabecomescrustedandthickened

c. Diagnosis:serumTH1C. Treatment

1. Avoidinglatexexposure,medicalbracelet,skinmoisturizer2. Useofpowder‐freeglovescanreducetheamountofairbornelatex

particles3. Healthcareworkerswithsevereandlife‐threateningallergymaybe

forcedtochangeemployment4. Allsurgicalorotherproceduresonpersonswithlatexallergyshouldbe

doneinalatex‐freeenvironmentinwhichnolatexglovesareusedintheroomorsurgicalsuiteandnolatexaccessories(e.g.,catheters,adhesives,tourniquets,andanesthesiaequipment)comeincontactwiththepatient


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D. XVI. TransplantationImmunopathologies

A. Processoftakingcells,tissues,ororgans,calledagraft,fromoneindividual,andplacingthemintoanotherindividual

B. Theindividualwhoprovidedthetissueiscalledthedonor,andtheindividualwhoreceivesthegraftiscalledeithertherecipientorthehost

C. Rejection:processinwhichtherecipient'simmunesystemrecognizesthegraftasforeignandattacksit

D. Typesoftransplants1. Allogenicdonorandrecipientarerelatedorunrelatedbusharesimilar

HLAtypes2. Sygeneicdonorandrecipientareidenticaltwins3. Autologousdonorandrecipientarethesameperson

E. CellsurfaceantigensthatdeterminewhetherthetissueoftransplantedorgansisrecognizedasforeignaretheMHCorhumanleukocyteantigensMajorHistocompatibilityComplex1. Lymphocyterecognition2. Antigenpresentation3. Controltheimmuneresponsethroughrecognitionofselfandnonself4. Themoredifferenttheyare,thehigherchancethebodywillrejectthe

donor


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F. Rejectionisacomplexprocessthatinvolvescell‐mediatedimmunityandcirculatingantibodies

G. BasicPatternsofTransplantRejection1. Hyperacutereaction

a. Occursalmostimmediatelyaftertransplantationb. Producedbyexistingrecipientantibodiestograftantigensthat

initiateatypeIII,Arthus‐typehypersensitivityreactioninthebloodvesselsofthegraft

c. Antibodiesusuallyhavedevelopedinresponsetopreviousbloodtransfusions,pregnanciesinwhichthemothermakesantibodiestofetalantigens,orinfectionswithbacteriaorvirusespossessingantigensthatmimicMHCantigen

d. Veryveryraremismatch,seriouscomplicationproblemwithsamplehandling(humanerror)

2. Acuterejectiona. Occurswithinthefirstfewmonthsaftertransplantationandis

evidencedbysignsoforganfailureb. Mayoccursuddenlymonthsorevenyearslater,after

immunosuppressionhasbeenusedandterminatedc. Tlymphocytesplayacentralroleinacuterejection,respondingto

antigensinthegrafttissueactivatedTcellscausedirectlysisofgraftcellsandrecruitandactivateinflammatorycellsthatinjurethegraft

d. Canbecontrolledbyimmunosuppressanttherapye. TypeIVreaction

3. Chronicrejectiona. Occursoveraprolongedperiodb. Manifestswithdenseintimalfibrosisofbloodvesselsofthe

transplantedorganc. Renaltransplantcharacterizedbyagradualriseinserum

creatinineoveraperiodof4to6monthsd. Common

XVII. Graft‐Versus‐HostDiseaseA. Occurswhenimmunologicallycompetentcellsorprecursorsare

transplantedintorecipientswhoareimmunologicallycompromisedB. InvolvesactivatedCD4+andCD8+Tcellswithultimategenerationofatype

IV,cell‐mediatedDTHandCTLreactionsC. ThreebasicrequirementsarenecessaryforGVHDtodevelop

1. Transplantmusthaveafunctionalcellularimmunecomponent2. Recipienttissuemustbearantigensforeigntothedonortissue3. Recipientimmunitymustbecompromisedtothepointthatitcannot

destroythetransplantedcellsD. AcuteGVHD

1. Developswithindaystoweeksaftertransplantation2. Involvestheepithelialcellsoftheskin,liver,andgastrointestinaltract


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a. Skindevelopmentofapruritic,maculopapularrash,whichbeginsonthepalmsandsolesandfrequentlyextendsovertheentirebody,withsubsequentdesquamation

b. Gastrointestinalsymptomsincludenausea,bloodydiarrhea,andabdominalpain

c. Liverpainlessjaundice,hyperbilirubinemia,andabnormalliverfunctiontestresultsi. Progresstodevelopmentofveno‐occlusivedisease,drugtoxicity,

viralinfection,ironoverload,extrahepaticbiliaryobstruction,sepsis,andcoma

ii. Veno‐occlusivediseaseobliterationofthesmallhepaticveinsandvenulescentrilobularcongestionandhepatocellularnecrosis

E. ChronicGVHD1. Whensymptomspersistorbegin100daysormoreaftertransplantation2. MayfollowacuteGVHDoritmaydevelopinsidiously3. Developskinlesionsresemblingsystemicsclerosisandmanifestations

mimickingotherautoimmunediseasesF. Treatmentblockanyofthe3stepsofpathogenesisTcellactivationand

actionofcytokines1. Immunosuppressivedrugscyclosporine,tacrolimus2. Anti‐inflammatorydrugsorglucocorticoids

XVIII. AutoimmuneDiseaseA. Self‐toleranceabilityoftheimmunesystemtodifferentiateselffrom

nonself1. HLAantigensencodedbyMHCgenesthatserveasrecognitionmarkersof

selfandnonselffortheimmunesystem2. Autoimmunityresultsfromlossofself‐tolerance

B. Systemic1. Mixedconnectivetissuedisease2. Polymyositis‐dermatomyositis3. Rhematoidarthritis4. Scleroderma5. Sjögrensyndrome6. Systemiclupuserythematosus

C. Blood1. Autoimmunehemolyticanemia2. Autoimmuneneutropeniaandlymphopenia3. Idiopathicthrombocytopenicpurpura

D. Otherorgans1. Acuteidiopathicpolyneuritis2. Atrophicgastritisandperniciousanemia3. Autoimmuneadrenalitis4. Goodpasturesyndrome5. Hashimotothyroiditis


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6. Type1DM7. Myastheniagravis8. Prematuregonadal(ovarian)9. Primarybiliarycirrhosis10. Sympatheticopthalmia11. Temporalarteritis12. Thyrotoxicosis(Gravesdisease)13. Crohndisease,ulcerativecolitis

E. Mechanismsofautoimmunedisease1. Inheritanceofsusceptibilitygenesthatcontributetothemaintenanceof

self‐tolerance2. Gender

a. SLEoccurmorecommonlyinwomenthanmen,suggestingthatestrogensmayplayaroleinthedevelopmentofautoimmunedisease

b. Estrogensstimulateandandrogenssuppresstheimmuneresponse3. Environmentalfactorsthatpromotetheactivationofself‐reactive

lymphocytesa. Infectiousagentsb. BreakdownofT‐cellanergy(stateofunresponsivenesstoantigen)

prolongedorirreversibleinactivationoflymphocytes,suchasthatinducedbyanencounterwithself‐antigens

4. FailuresofSelftolerancea. DisordersinMHC‐antigencomplex‐receptorinteractionsb. Molecularmimicrymicrobesharesanimmunologicepitopewith

thehostc. Superantigensfamilyofsubstancesabletoshort‐circuitthe

normalsequenceofeventsinanimmuneresponse,leadingtoinappropriateactivationofCD4+helperTcells

F. Summary Autoimmune diseases represent a disruption in self-tolerance that results in damage to body tissues by the immune system. Autoimmune diseases can affect almost any cell or tissue of the body. The ability of the immune system to differentiate self from nonself is called self-tolerance. Normally, self-tolerance is maintained through central and peripheral mechanisms that delete autoreactive B or T cells or otherwise suppress or inactivate immune responses that would be destructive to host tissues. Defects in any of these mechanisms could impair self-tolerance and predispose to development of autoimmune disease. The ability of the immune system to differentiate foreign from self-antigens is the responsibility of HLA encoded by MHC genes. Antigen is presented to receptors of T cells in combination with MHC molecules. Among the possible mechanisms responsible for development of autoimmune disease are failure of T-cell-mediated immune suppression; aberrations in MHC-antigen-TCR interactions; molecular mimicry; and superantigens. The suggested criteria for determining that a disorder results from an autoimmune disorder are evidence of an autoimmune reaction, determination that the immunologic findings are not secondary to another condition, and the lack of other identifiable causes for the disorder.

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Disorders of the Immune Response