YL7

MOD14IMMUNOLOGY(INTERNALMEDICINE)

08December2011

INTRODUCTIONandREVIEWOFIMMUNOLOGYCONCEPTS

Dr.MichelleDeVera

OUTLINE I. TheImmuneSystem A. Function B. ComponentsoftheImmuneSystem C. TypesofAdaptiveImmuneSystem II. Approachtopatients:IMMUNODEFICIENCYDISEASES A. Diagnosis B. LaboratoryDiagnosis III. Approachtopatients:ALLERGICDISEASES A. HypersensitivityReactions B. Type1Hypersensitivity C. AllergicHistory D. PhysicalExamination I. THEIMMUNESYSTEM A. FUNCTIONOFTHEIMMUNESYSTEM Discriminateselffromnonself Protectagainstdifferentpathogens Intracellular(viruses,somebacteriaandparasites) Extracellular(mostbacteria,fungiandparasites) Eliminatealteredormodifiedself(e.g.malignantcells) Somecellsmaymutate.Butnoteveryonedevelopscancer becausetheimmunesystemactslikeasurveillance mechanism.Itrecognizesthemutatedcells,attackit,then killit. Failuresormalfunctionofimmunologicalmechanisms o Immunodeficiency o Autoimmunediseases o Autoinflammatorydiseasesincludingvasculitis o Malignanciesandotherproliferativediseases o Diseasesofimmunedysregulationincluding endocrinopathies o Geneticsyndromes o DefectsinDNArepairmechanisms o Allergiesandotherhypersensitivityreactions B. COMPONENTSOFTHEIMMUNESYSTEM 1.HallmarkofInnateImmuneSystem Older Madeupofmechanicalstuff Phagocytes Workswithinminutesorhours Infact,mostofthetime,theadaptiveimmunityisnolonger activatedbecausetheinnateimmunesystemtakescareofthe pathogens Thespecificityoftheimmunesystemisinheritedfromthe genome.Theyrecognizeitortheydontrecognizeit. Itisexpressedbyallofthecells,byallmacrophagesfor instance. Youtriggeranimmuneresponse.Theyrecognizeapathogen, buttheyarenotveryspecific,parasilangkillanddestroy,they justnowthatitisnonself. Bcellsdonotkillthepathogens;effectorcells(i.e.antibodies, helpercells,cytotoxicTcells)killthepathogens.

INNATEIMMUNITY(YL5LECTURE) AnatomicBarriers: o Skin(theprimarybarriersystem) Mechanicalbarriersretardsentryofmicrobes Outerepidermallayer=keratin(waterproofing) Dermis:connectivetissue,bloodvessels,hair follicles,sebaceousglands,sweatglands Sebummaintainsacidicenvironment(pH35) retardsgrowthofmicrobes o Mucousmembrane Conjunctive,alimentary,respiratory,urogenital tract Saliva,tears,mucoussecretionswashaway potentialinvaders Mucousentrapsforeignmicroorganisms Ciliapropelmicroorganismsoutofthebody Normalfloracompetewithothermicrobesfor attachmentandnutrients o Temperature Normalbodytemperatureinhibitsgrowthof pathogens Feverresponseinhibitsgrowthofsomepathogens LowpH o Acidityofstomachcontentskillsmostingestedmicro organism o Chemicalmediators o Lysozome(tears,mucous)cleavesbacterialcellwall o Interferoninducesantiviralresistanceand mechanisms PhagocytosisandEndocytosis: o Variouscellsendocytoseandbreakdownforeign macromolecules o Specializedcells,kill,anddigestwholemicroorganisms Inflammatorybarriers: o RomanMDCelsus:4cardinalsignsofinflammation (1stcentAD):Rubor(redness),Tumor(swelling),Calor (heat),Dolor(pain),Galen5thsign,Functiolaesa (lossoffunction) Skin Gut Lungs Eyes/nose Epithelialcellsjoinedbytightjunction Longitudinalflow Movement Tears Mechanical ofairorfluid ofmucus Nasalcilia bycilia Chemical Fatty Lowph Salivary acids Enzyme glands (pepsin) Antibacterialpeptides Microbiolo Normalflora gical a.CellularComponent:MACROPHAGE Themacrophageexpressesreceptorsformanybacterial constituents Amononuclearphagocyte

Group01

Almajar,Alog,Buemio,DelosArcos,Manuel,Rabanal

Page1of9

INTROandREVIEWOFIMMUNOLOGYCONCEPTS Figure.Macrophagesare activatedbypathogens andbothengulfthemand initiateinflammatory responses.

INTERNALMEDICINE

b.CellularComponent:NEUTROPHILS Research[J]:Secondmajorfamilyofphagocytes AkaPolymorphonuclearneutrophilicleukocytes(PMN) Shortlivedcellsthatareabundantinthebloodbutarenot presentinnormal,healthytissues becauseofadhesionmoleculesofonthesurfaceofyour epitheliumandthereceptorsinthesurfaceofyourneutrophil, theyrollandbindtocytokines,theyinsertthemselvesthrough thetightjunction,andmigratethroughtheepithelium c.ComplementSystemCytokines Research[J]:anygeneralnameforanyproteinthatissecreted bycellsandaffectsthebehaviorofnearbycellsbearing appropriatereceptors. classicalandalternativepathway;theycausechemotaxisand opsonization(theyrecruitothercellsandsignalothercellsasto wheretogo)

2.HallmarkofAdaptiveImmuneSystem Self/nonselfdiscrimination MOSTIMPORTANT:Memory Subsequentencountersstimulateincreasinglyeffective defensemechanisms Specificity Responsetoaparticularantigenisspecificforthatantigen Amplifiesprotectivemechanismsofinnateimmunity,directsor focusesthesemechanismstothesiteofantigenentryand makesthembetterabletoeliminateforeignantigens a.ANTIGENPRESENTINGCELLS

Group01

PutyourmoneywhereyourmouthisDr.DeVera

Page2of9

 INTROandREVIEWOFIMMUNOLOGYCONCEPTS dendriticcellsubiquitous,majorAPC macrophagesfoundincertainpartsofthebody(body cavities) Bcellsfoundinperipheralblood b.ANTIBODIES Effectormechanismsforthehumoralimmunesystem Recognizespecificantigenonmicrobialpathogens Principaldefensivemechanism Eachantibody=antigenbindingregion,hingeregion,anda regionthatdeterminestheclassorsubclassoftheantibody Antigenspecificityandantigenbindingoccursprimarilyinthe hypervariableregionsofVHandVL(complementarity determiningregions) 5knownclasses:IgG,IgM,IgAgD,IgE Generalfunctionofantibodies Antigenbindingprimaryfunction o Canresultinprotection Effectorfunctionsusuallyrequireantigenbinding o Fixationofcomplement:lysisofcells,andrelease biologicallyactivemolecules o Bindingtovariouscells:activatephagocyticcells, lymphocytes,platelets,mastcells,andbasophils Antigenicstimulationandgenerationofdifferentisotypes producechangesinthebiologicaleffectorfunctionswithout changingthespecificityofIgmolecule Itsfoolproofifyoutakecareofit 3.CollaborationofInnateandAcquiredImmunity Research[J]:Innateimmuneresponsesoccurrapidlyon exposuretoaninfectiousorganism.Overlappingwiththe innateimmuneresponse,buttakingdaysratherthanhoursto develop,theadaptiveimmunesystemiscapableofeliminating infectionsmoreefficientlythantheinnateimmuneresponse. Maamsanalogy:innateimmunityislikethemarines.Adaptive immunityislikethesnipers.Theyhavetoworktogether otherwiseyouwouldntsurvive Macrophages,Dendriticcells,andBcellsantigenpresenting cells(APCs).Theybearpatternrecognitionsothattheycould triggeranimmuneresponse.Althoughtheyarepartofthe innateimmunesystemtheyhavetopresentthepathogensto theadaptiveimmunesystembecausewithoutthemthe adaptiveimmunesystemwontwork. CytokinesreleasedbyactivatedTcells.Alongwithchemokines, theyarethesignallingmolecules.Youdonthavetoknow specificcytokines,youhavetoknowwhattheyare.Butyou needtohavesomeideaofhowtheyworkorwhattheydo. Tcellstheynotonlyhelprecognitionbutalsoactivatethem. Antibodiesalthoughtheyarepartofthehumoraland adaptiveimmunesystem,theycanactasopsoninsforyour phagocytes.Theydontworkthatwellifthereareno complementalreceptors.
Group01

INTERNALMEDICINE
SUMMARYofInnatevsAcquired(Adaptive)ImmuneSystem Innate Adaptive Receptorcharacteristic immunity Immunity Specificityinheritedinthe Yes No genome Expressedbyallcellsofa Yes No particulartype(iemacrophages) Triggersimmediateresponse Yes No Recognizesbroadclassesof Yes No pathogens Interactswitharangeof Yes No molecularstructureofagiven type Encodedinmultiplegene No Yes segments Requiresgenerearrangement No Yes Clonaldistribution No Yes Abletodiscriminateevenclosely No Yes relatedmolecularstructures Research(Janeway,p.39):Theresponsetoaninitialinfection occursinthreephases:
InnateImmunity (Immediate:04 hours) Recognitionby preformed, nonspecific andbroadly specific effectors Removalof infectionagent

Infection

EarlyInduced innateresponse (early:496 hours) Recognition ofmicrobial associated molecular patterns Inflammation recruitment and activationof effectorcells Removalof infectious agent

Infec tion

Adaptive Immune response (late:>96 hours) Infect ion Transportof antigento lymphoid organs Recogniti onby naveB andT cells Clonal expansi onand differen tiation to effector cells Removal

Tcellsproducecytokinesthatactivateimportanteffector pathwaysofinnateimmunity,forexamplemacrophagesand NKcells Cellsoftheinnateimmunesystem(forexample,macrophages) producecytokinessuchasIL12thatdirectTcellstobecome Th1Tcellsthatproduceinterferonalpha,andareimportant effectorpathwaysforintracellularmicrobialorganisms Antibodies(opsonins)enhancethephagocyticpathwayofthe innateimmunesystem Complementtype2receptorfunctionsasacoreceptorfor humoralimmuneresponses,andlinksthecomplement pathwayviaC3dwithantibodyproduction Innatehostdefensesagainstinfection
Page3of9

PutyourmoneywhereyourmouthisDr.DeVera

INTROandREVIEWOFIMMUNOLOGYCONCEPTS
IL6

INTERNALMEDICINE

ActivatedMacrophagessecretearangeofcytokines LocalEffects
IL1

Activates vascular endothelium Activates lymphocytes Localtissue destruction Increasesaccess ofeffectorcells

IL8

TNF

Chemotactic factorrecruits neutrophils, basophils,andT cellstositeof infection

Activatesvascular endotheliumand increasesvascular permeability,which leadstoincreased entryofIgG, complementand cellstotissuesand increasedfluid drainagetolymph nodes

Lymphocyte activation increased antibody production

IL12

ActivatesNK cellsinducesthe differentiation ofCD4Tcells intoTH1cells

SystemicEffects Fever Mobilizationof metabolites Shock Fever Inducesacute phaseprotein production 5knownclasses:IgG,IgM(heaviestantibody;tetravalent molecule),IgA,IgD,IgE Theybindtoantigens Effectorcomplementrequiresantigenbinding Whenyouhaveapathogenoranantigenthatisboundto yourantibodythecomplementrecognizesit Canactivatelymphocytes,platelets,etc ThereisafiniteamountofBcellsandTcellsinyourbody Theamazingthing:evenifitisanewpathogen,therewillbea BcellinyourentirerepertoireofBcellsthatwillrecognizeit! Theproblemishowfastwillitrecognizeit. RefertoabovenotesonAntibodies

Fever ProductionofIL 6

C. TYPESOFADAPTIVEIMMUNESYSTEM 1. HUMORAL Research:Antibodiesarefoundinthefluidcomponentof blood,orplasma,andinextracellularfluids.Becausebody fluidswereonceknownashumors,immunitymediatedby antibodiesisknownashumoralimmunity AntibodiesEffectorcells(haveanantigenbindingregion) Drawing: variableregion(Vpartatthetop):recognizesthepathogen stem:determineswhatkindofantibodyitis

2. CELLULAR a. TLYMPHOCYTES AriseinBMandmigrate Duringmaturation,expressTcellreceptor(forantigenbinding) CanonlyrecognizeantigenboundtoMHC Subpopulations:ThelperandTcytotoxiccells ThymiceducationdevelopmentofTcellswithinthymus CriticalfortheselectionofTcellsthathavetheabilityto respondtovariousexogenousantigenspresentedinthe contextofselfMHCmolecules ~95%ofenteringstemcellsareeliminatedw/inthethymus, nevertobecomecirculatingTcells Illustratesthetightregulationandextremeselectivityofthe process
Page4of9

Group01

PutyourmoneywhereyourmouthisDr.DeVera

INTROandREVIEWOFIMMUNOLOGYCONCEPTS c. MHCClassI

INTERNALMEDICINE

b. BCELLACTIVATION

Antigenpresentingcellsprocesstheantigenfirst Example,anendogenousantigen,likeavirus,wouldremain insidethecelltoreplicatetheviralDNA,makingthevirulentcell anantigen Antigenpresentingcellsrecognizethevirulentcellandthe othercellsgetpanicked CD8+cytotoxicTcellsonlyrecognizetheMHCclassIantigen presentingcells,thisisveryspecific OncethecytotoxicTcellsrecognizetheantigenpresentedby MHCI,theywillkilltheinfectedcellimmediately,theydonot discriminate

Bacteria,toxinsareantigensthatarerecognizedbyMHCclassII AntigengetsengulfedandareattackedbytheMHCclassII moleculesandtheyarepackagedthatway CD4+helperTcells2activatestheBcellstomakeantibodiesfor thatpathogen BcellsdontkilltheantigenimmediatelylikethecytotoxicT cells,insteadtheymaketheantibodies Antibodies:neutralizethetoxinsthattheyrecognizethrough theactivationofthecomplementcascadeandthrough activationofeffectorcellslikemacrophages,neutrophils, cytotoxiccells Antibodiesandantigenbindingactivatesthecomplement,and thisistheonlywayofactivationofthecomplementsystem
Group01

PutyourmoneywhereyourmouthisDr.DeVera

Page5of9

INTROandREVIEWOFIMMUNOLOGYCONCEPTS

INTERNALMEDICINE
CD4+helperTcell1tellsthemacrophagetorecognizethe pathogenandthenkillit.Sothereisrecognitionandastored memoryofthepathogenbeforeitiskilled. ADDITIONALINFO: TypesofEffectorTcell CD8CytotoxicTcells Killvirusinfectedcells CD4TH1cells Activateinfectedmacrophages ProvidehelptoBcellsforantibody production CD4TH2cells ProvidehelptoBcellsforantibody production,esp.switchingtoIgE CD4TH17cells Enhanceneutrophilresponse Cd4regulatoryTcells SuppressTcellresponse (various)

EffectorTcells:CytotoxicCD8Tcells Proteinlyticgranules Actionsontargetcells ofCytotoxicTcells Perforin Polymerizestoformaporein targetmembrane Granzymes Serineproteases,which activateapoptosisonceinthe cytoplasmofthetargetcell Granulysin Inducesapoptosis d. MHCClassII

Bacteria,toxinsareantigensthatarerecognizedbyMHCclassII Theantigenpresentingcellsforthesecaneitherbeyour dendriticcells,macrophages,andyourantibodies Antigengetsengulfedandareattackedby theMHCclassIImoleculesandtheyare packagedthatway Eithertheycanberecognizedasaplain pathogenoronlyaparticularpartofthe antigenispresentedorboundin macrophages Macrophagesmaynotrecognizethatthey engulfedpathogenimmediately
Group01

Page6of9

PutyourmoneywhereyourmouthisDr.DeVera

 INTROandREVIEWOFIMMUNOLOGYCONCEPTS II. APPROACHTOPATIENTwithIMMUNOLOGICDISEASES A. DIAGNOSISOFIMMUNODEFICIENCY Whentosuspectimmunodeficiency? Unusual,chronic,recurrentinfections >1bacterialsystemic >2seriousrespiratoryordocumentedbacterialinfections within1year(cellulitis,drainingotitismedia,pneumonia, lymphadenitis) IntakinghistoryandPE,makesurethatthepastmedical historyisdocumented.Ifthepatientmentionsthathehad pneumonialastmonth,makesurethatitisdocumented,not justbecausehewastoldsobyhisneighbors Seriousinfectionsoccurringatunusualsites(liverorbrain abscess) Infectionswithunusualpathogens Infectionswithcommonpathogensbutunusualseverity CluesinHistory:Respiratoryinfections AlthoughrecurrentURTIiscommoninchildren(610x/year) thereareotherdistinguishingfeaturessuggestiveofabnormal hostresistance Chronicandcanleadtocomplications:otitismediawith mastoiditis,bronchiectasis Donotcompletelyclearorrespondinadequatelytotreatment Bacterialinfectionsaresevere:pneumonia,meningitis,sepsis Althoughcanoccurinimmunocompetentchildren Infectionwithopportunisticorganisms:Pneumocystis,Candida, Aspergillus,Pseudomonas. IfyouhaveapatientwithPneumocystis,alwayssuspecta concomitantHIVinfectionbecausetheimmunocompromised arepronetothispathogen CluesintheHistory:PastMedicalHistory MaternalillnessesduringpregnancyHIV,rubella Diseasesthatcancauseimmunodeficiencies:diabetes,renal failure,cancer/malignancies Failuretothrive, Prolongedorchronicdiarrhea,malabsorptionorvomiting Adversereactionstopreviousbloodorplasmatransfusions GVHDtobloodtransfusionlikelyinTcellimmunodeficiencies IncreasedriskforHIVfrombloodproductsduring19781985 Adversereactionstolivevaccines Gestationalageandbirthweight=prematureinfantsaremore vulnerabletoinfections AbsenceofmaternalIgGtransferbefore32weeksAOG Relativelackofmaturityofsecondarylymphoidorgans o Innateimmunityaffected Priortreatmentsofinfections,needforrepeatedantibiotic, responsetoantibiotics,treatmentwithgammaglobulin CluesintheHistory:FamilyHistory ManyprimaryimmunodeficienciesareinheritedasXlinkedor autosomalrecessiveinheritedtraits Earlyinfantsdeaths,recurrentorchronicinfections, lymphoreticularmalignanciesorautoimmunedisorders Racialbackground Hemoglobinopathies(egSicklecelldiseas)infamilymembers suggestcauseforrepeatedinfections
Group01

INTERNALMEDICINE
III. LABORATORYTESTING CBCgoodtest,itsnotjustsomethingforinfection,checkfor percentagesoflymphocytecount,etc. ScreeningforquantityandfunctionofBandTcells,phagocytic cellsandcomplement E.g.Serumimmunoglobulins,specificantibodyproduction,B/T cellsubsets,respiratoryburstassay,delayedhypersensitivity testing,responsetomitogens HowdoyouknowifmyIgGisspecifictopneumoniagetIgG titersfor(i.e.)Pneumococcal.Yourenotjustinterestedwith genericantibodiesbutwithitsspecificantigen Culturesandimagingstudies IV. APPROACHTOPATIENTSwithALLERGICDISEASES A. HYPERSENSITIVITYREACTIONS Fourtypesofreactionsmediatedbyimmunological mechanismsthatcausetissuedamage FromRobbins(research)seeAppendix WhenyousayallergythatsanothernameforType1 B. IMMEDIATETYPE/IgEMediated(TYPE1)

Page7of9

PutyourmoneywhereyourmouthisDr.DeVera

INTROandREVIEWOFIMMUNOLOGYCONCEPTS

INTERNALMEDICINE

C.ALLERGICHISTORY PresentIllness Natureofillness Worseningofsymptomsonexposuretoallergens Ageofonset Frequencyofattacks Durationofattacks Changesinnature,frequencyandtreatment Present/currenttreatment Environmentalreactions Timeofyearanddayofsymptoms Whatproducessymptoms Whatrelievessymptoms Doessymptomsoccurathome,workorvacation Reactionstodifferentpossibletriggersdustyormoldy environmentpets,odors,foods,medicines,insects,colds changesinweather,smoke,exercise,emotion,outdoor activitiesorsports D.PHYSICALEXAMINATION CompletePEwithspecificattentiontocertainareaswhere atopicdiseasemanifested(skin,eyes,ears,etc) Conjunctivaeforhyperemiaandedema+fundoscopy Middleearandsinusesforsecondarycomplications Nosefornasalcrease,mucosalchanges,nasalsecretions, polyps,patency Mouthandoropharynxforedema,mucous,cobblestone appearance Chest Entireskinexaminedforimportantphysicalchanges (lichenification,chronicalteration) MODULEREMINDERS Nolecturepowerpointswillbegiven Somelecturersmightgiveaquiz ClinicalEncounterWriteupdueonDec16(thatsthelastday ofschool,youdontwanttodoitduringthebreak) ClinicalcasesweregivenwiththeModuleGuide Wehave1SGD,1CasePaneland1Patientencounter Exam:Friday,100itemsMultipleChoice

Group01

PutyourmoneywhereyourmouthisDr.DeVera

Page8of9

INTROandREVIEWOFIMMUNOLOGYCONCEPTS

INTERNALMEDICINE

Reaction Immediate (typeI) hypersensitivity

Antibody mediated(type II) hypersensitivity Immune complex mediated(type III) hypersensitivity Cellmediated (typeIV) hypersensitivity

APPENDIX:MechanismsofImmunologicallyMediatedHypersensitivityReactions th (Robbins,8 ed) PrototypicDisorder ImmuneMechanisms PathologicLesions Anaphylaxis;allergies; Vasculardilation,edema, ProductionofIgEantibody bronchialasthma(atopic immediatereleaseofvasoactive smoothmusclecontraction, forms) aminesandothermediatorsfrommast mucusproduction,tissue injury,inflammation cells;laterrecruitmentof inflammatorycells Autoimmunehemolytic Phagocytosisandlysisofcells; ProductionofIgG,IgMbindsto anemia;Goodpasture inflammation;insome antigenontargetcellortissue syndrome diseases,functional phagocytosisorlysisoftargetcellby activatedcomplementorFcreceptors; derangementswithoutcellor tissueinjury recruitmentofleukocytes Systemiclupus Depositionofantigenantibody Inflammation,necrotizing erythematosus;some vasculitis(fibrinoidnecrosis) complexescomplementactivation formsofglomer recruitmentofleukocytesby ulonephritis;serum complementproductsandFcreceptors sickness;Arthusreaction releaseofenzymesandothertoxic molecules Contactdermatitis; Perivascularcellular ActivatedTlymphocytes multiplesclerosis;typeI infiltrates;edema;granuloma (i)releaseofcytokines diabetes;rheumatoid formation;celldestruction inflammationandmacrophage arthritis;inflammatory activation; boweldisease; (ii)Tcellmediatedcytotoxicity tuberculosis

Group01

PutyourmoneywhereyourmouthisDr.DeVera

Page9of9