1.

Overview of the Immune System

1) Immunityisthestateofprotectionagainstforeignorganisms/substances(antigens).Vertebrateshavetwotypesofimmunity,

innateandadaptive.
2) Innateimmunityisnotspecifictoanyonepathogenbutratherconstitutesafirstlineofdefense,whichincludesanatomic,
physiologic,endocyticandphagocytic&inflammatorybarriers.
3) Innateandadaptiveimmunityoperatein cooperative&interdepedentways.Theactivationofinnateimmuneresponses
producessignalsthatstimulate&directsubsequentadaptiveimmuneresponses.
4) Adaptiveimmuneresponsesexhibitfourimmunologicattributes:specificity,diversity,memory&self/nonselfrecognition.
5) Thehighdegreeofspecificityinadaptiveimmunityarisesfromtheactivitiesofmolecules(antibodies&Tcellreceptors)
thatrecognizeandbindspecificantigens.
6) Abrecognize&interactdirectlyw/Ag.TcellreceptorsrecognizeonlyAgthatiscombinedwitheitherclassIorclassII
majorhistocompatibilitycomplex(MHC)molecules.
7) 2majorsubpopulationsofTlymphocytesaretheCD4+Thelper(TH)cellsandCD8+Tcytotoxic(TC)cells.
THcellssecretecytokinesthatregulateimmuneresponseuponrecognizingAgcombinedw/classIIMHC.
TCcellsrecognizeAgcombinedwithclassIMHC&giverisetocytotoxicTcells(CTLs),whichdisplaycytotoxicability.
8) Exogenous(extracellular)Agareinternalized&degradedbyAPC(macrophages,Bcells&dendriticcells);theresulting
antigenicpeptidescomplexedwithclassIIMHCmoleculesarethendisplayedonthecellsurface.
9) Endogenous(intracellular)antigens(e.g.,viralandtumorproteinsproducedinalteredselfcells)aredegradedinthecytoplasm
andthendisplayedwithclassIMHCmoleculesonthecellsurface.
10) Theimmunesystemproducesbothhumoralandcellmediatedresponses.Thehumoralresponseisbestsuitedforelimination
ofexogenousantigens;thecellmediatedresponse,foreliminationofendogenousantigens.
11) Whilean adaptive immunesystemisfound onlyinvertebrates,innateimmunityhasbeendemonstratedinorganismsas
differentasinsects,earthworms,andhigherplants.
12) Dysfunctionsoftheimmunesystemincludecommonmaladiessuchasallergy/asthma.

13) Lossofimmunefunctionleaveshostsusceptibletoinfection;inautoimmunity,theimmunesystemattackshostcells/tissues.

2. Cells and Organs of the immune system

1) ThecellsthatparticipateintheimmuneresponseareWBC/leukocytes.The lymphocyte istheonlycelltopossessthe

immunologicattributesofspecificity,diversity,memory,andself/nonselfrecognition.
2) Manyofthebodyscells,tissues&organsarisefromtheprogenyofdifferentstemcellpopulations.Thedivisionofastem
cellcanresultintheproductionofanotherstemcellandadifferentiatedcellofaspecifictypeorgroup.
3) AllleukocytesdevelopfromacommonmultipotenthematopoieticSCduringhematopoiesis.Various hematopoieticgrowth
factors(cytokines)induceproliferation&differentiationofthedifferentbloodcells.ThedifferentiationofSCintodifferent
celltypesrequirestheexpressionofdifferentlineagedetermininggenes.AnumberofTFplayimportantrolesinthisregard.
4) Hematopoiesisiscloselyregulatedtoassuresteadystatelevelsofeachofthedifferenttypesofbloodcell.Celldivision&
differentiationofeachofthelineagesisbalancedbyprogrammedcelldeath.
5) Thereare3typesoflymphocytes:Bcells,Tcells&naturalkillercells(NKcells).NKcellsaremuchlessabundantthanB
andTcells&mostlackspecificreceptorforaparticularantigen.However,asubtypeofNKcells,NK1Tcells,havebothT
cellreceptorsandmanyofthemarkerscharacteristicofNKcells.Thethreetypesoflymphoidcellsarebestdistinguishedon
thebasisoffunction&thepresenceofvariousmembranemolecules.
6) NaiveB&Tlymphocytes(thosethathavenotencounteredantigen)aresmallrestingcellsintheG0phaseofthecellcycle.
Afterinteractingw/Ag,thesecellsenlargeintolymphoblasts,proliferate&differentiateintoeffectorcells&memorycells.
7) Macrophages&neutrophilsarespecializedforthephagocytosis&degradationofAg(F29).
8) PhagocytosisisfacilitatedbyopsoninssuchasAb,whichincreasetheattachmentofAgtothemembraneofthephagocyte.
9) Activatedmacrophages secretevariousfactorsthatregulatethedevelopmentofthe adaptive immuneresponse&mediate
inflammation (T 27). Macrophages also process & present Ag bound to class II MHC molecules, which can then be
recognizedbyTHcells.
10) Basophils&mastcellsarenonphagocyticcellsthatreleaseavarietyofpharmacologicallyactivesubstances&playimportant
rolesinallergicreactions.

11) DendriticcellscaptureAg.Withthe exceptionoffolliculardendriticcells,thesecellsexpresshighlevelsofclass IIMHC

molecules.Alongwithmacrophages&Bcells,dendriticcellsplayanimportantroleinTHcellactivationbyprocessingand
presentingAgboundtoclassIIMHCmolecules&byprovidingtherequiredcostimulatorysignal.Folliculardendriticcells,
unliketheothers,facilitateBcellactivationbutplaynoroleinTcellactivation.
12) Primary lymphoid organs provide sites where lymphocytes mature & become antigenically committed. T lymphocytes
maturew/ithethymus,&Blymphocytesarise&maturew/itheBMofhumans,mice,otheranimals,butnotallvertebrates.
13) Primarylymphoidorgansarealsoplacesofselectionwheremanylymphocytesthatreactwithselfantigensareeliminated.
Furthermore,thethymuseliminatesthymocytesthatwouldmatureintouselessTcellsbecausetheirTcellreceptorsare
unabletorecognizeselfMHC.
14) The lymphatic systemcollects fluid that accumulates in tissue spaces &returns this fluid to the circulation via the left
subclavianvein.ItalsodeliversAgtothelymphnodes,whichinterruptthecourseoflymphaticvessels.
15) Secondary lymphoid organs capture Ag & provide sites where lymphocytes become activated by interaction w/ Ag.
Activatedlymphocytesundergoclonalproliferationdifferentiationintoeffectorcells.
16) Severaltypesof secondarylymphoidtissue:lymphnodes,spleen,thelooseclustersoffollicles,&Peyerspatchesofthe
intestine,&cutaneousassociatedlymphoidtissue.LymphnodestrapAgfromlymph,spleentrapsbloodborneAg,intestinal
associatedlymphoidtissues(aswellasothersecondarylymphoidtissues)interactw/AgthatenterthebodyfromtheGIT&
CALTprotectsepithelialtissues.
17) Aninfectionbeginsin1areaofthebodyeventuallyinvolvescells,organs,&tissuesthatmaybedistantfromthesiteof
pathogeninvasion.Agfromdistantsitescanarriveatlymphnodesvialymph&DC,therebyassuringactivationofTcells
&Bcells &releaseofthesecells&theirproductstothecirculation.Inflammatoryprocessesbringlymphocytes&other
leukocytes tothesiteofinfection.Thus,although dispersed throughoutthebody,thecomponentsoftheimmunesystem
communicate&collaboratetoproduceaneffectiveresponsetoinfection.
18) Vertebrateordersdiffergreatlyinthekindsoflymphoidorgans,tissues,&cellstheypossess.Themostprimitivevertebrates,
the jawlessfishes,haveonlyGALT,lackB&Tcells,&cannotmountadaptiveimmuneresponses.Jawedvertebrates
possessagreatervarietyoflymphoidtissues,haveB&Tcells,anddisplayadaptiveimmunity.

3. Antigens
1) Allimmunogensareantigensbutnotallantigensareimmunogens.
2) Immunogenicityisdeterminedbyforeignness,molecularsize,chemicalcomposition,complexity,dose,susceptibilitytoAg

3)

4)

5)

6)
7)

processing&presentation,therecipientanimalsgenotype(inparticular,itsMHCgenes),routeofadministration&adjuvants.
Bcellepitopessizesrangewidely.Somearesmall(e.g.,smallpeptides/smallorganicmolecules)&oftenboundinnarrow
grooves/deeppocketsoftheAb.ProteinBcellepitopesarelarger&interactw/larger,flattercomplementarysurfaceonthe
Abmolecule.
TcellepitopesaregeneratedbyAgprocessing,whichfragmentsproteinintosmallpeptidesthatcombinew/classI/IIMHC
moleculestoformpeptideMHCcomplexesthataredisplayedonthesurfaceofcells.Tcellactivationrequirestheformation
ofaternarycomplexb/waTcellsTCR&peptideMHConantigenpresenting/alteredselfcells.
HaptensaresmallmoleculesthatcanbindtoAbbutcannotbythemselvesinduceanimmuneresponse.However,the
conjugateformedbycouplingahaptentoalargecarrierproteinisimmunogenic&elicitsproductionofantihaptenAb
wheninjectedintoananimal.Suchinjectionsalsoproduceanticarrier&antihapten/carrierAbaswell.
Inthebody,theformationofhaptencarrierconjugatesisthebasisofallergicresponsestodrugssuchaspenicillin.
Theinnateimmunesystemusespatternrecognitionreceptors(PRR)torecognize&respondtobroadstructuralmotifsthatare
highlyconservedw/imicrobialspeciesbutaregenerallyabsentfromthehost.

4. The Major Histocompatibility Complex

1) Themajorhistocompatibilitycomplex(MHC)comprisesastretchoftightlylinkedgenesthatencodeproteinsassociated
withintercellularrecognitionandantigenpresentationtoTlymphocytes.
2) sAgroupoflinkedMHCgenesisgenerallyinheritedasaunitfromparents;theselinkedgroupsarecalledhaplotypes.
3) sMHCgenesarepolymorphicinthattherearelargenumbersofallelesforeachgene,andtheyarepolygenicinthatthereare
anumberofdifferentMHCgenes.
4) sClassIMHCmoleculesconsistofalargeglycoproteinchainwith3extracellulardomainsandatransmembranesegment,and
?2microglobulin,aproteinwithasingledomain.
5) sClassIIMHCmoleculesarecomposedoftwononcovalentlyassociatedglycoproteins,the?and?chain,encodedby
separateMHCgenes.
6) sXraycrystallographicanalysesrevealpeptidebindingcleftsinthemembranedistalregionsofbothclassIandclassIIMHC
molecules.
7) sBothclassIandclassIIMHCmoleculespresentantigentoTcells.ClassImoleculespresentprocessedendogenousantigen
toCD8Tcells.ClassIImoleculespresentprocessedexogenousantigentoCD4Tcells.
8) sCertainconservedmotifsinpeptidesinfluencetheirabilitytointeractwiththemembranedistalregionsofclassIandclass
IIMHCmolecules.
9) sClassImoleculesareexpressedonmostnucleatedcells;classIIantigensarerestrictedtoBcells,macrophages,anddendritic
cells.
10) sTheclassIIIregionoftheMHCencodesmoleculesthatincludeadiversegroupofproteinsthatplaynoroleinantigen
presentation.

11) sDetailedmapsofthehumanandmouseMHCrevealthepresenceofgenesinvolvedinantigenprocessing,including
proteasomesandtransporters.
12) StudieswithmousestrainshaveshownthatMHChaplotypeinfluencesimmuneresponsivenessandtheabilitytopresent
antigen.
13) sIncreasedsusceptibilitytoanumberofdiseases,predominantly,butnotexclusively,ofanautoimmunenature,hasbeen
linkedtocertainMHCalleles.
5. Antigen Processing and Presentation
TcellsrecognizeantigendisplayedwithinthecleftofaselfMHCmoleculeonthemembraneofacell.
Ingeneral,CD4+THcellsrecognizeantigenwithclassIIMHCmoleculesonantigenprocessingcells.

CD8+TCcellsrecognizeantigenwithclassIMHCmoleculesontargetcells.

ComplexesbetweenantigenicpeptidesandMHCmoleculesareformedbydegradationofaproteinantigeninoneoftwodifferent
antigenprocessingpathways.
s

EndogenousantigensaredegradedintopeptideswithinthecytosolbyproteasomesandassemblewithclassImoleculesinthe
RER.
s

ExogenousantigensareinternalizedanddegradedwithintheacidicendocyticcompartmentsandsubsequentlypairwithclassII
molecules.
s

PeptidebindingtoclassIImoleculesinvolvesreplacingafragmentofinvariantchaininthebindingcleftbyaprocesscatalyzedby
nonclassicMHCmoleculeHLADM.
s

Presentationofnonpeptide(lipidandglycolipid)antigensderivedfrombacteriainvolvestheclassIlikeCD1molecules.

6. Antibodies : Structure and Function

1) Anantibodymoleculeconsistsoftwoidenticallightchainsandtwoidenticalheavychains,whicharelinkedbydisulfide
bonds.Eachheavychainhasanaminoterminalvariableregionfollowedbyaconstantregion.
2) sInanygivenantibodymolecule,theconstantregioncontainsoneoffivebasicheavychainsequences(,,,,or)called
isotypesandoneoftwobasiclightchainsequences(or)calledtypes.
3) sTheheavychainisotypedeterminestheclassofanantibody(,IgM;,IgG;,IgD;,IgA;and,IgE).
4) sThefiveantibodyclasseshavedifferenteffectorfunctions,averageserumconcentrations,andhalflives.
5) sEachofthedomainsintheimmunoglobulinmoleculehasacharacteristictertiarystructurecalledtheimmunoglobulinfold.
Thepresenceofanimmunoglobulinfolddomainalsoidentifiesmanyothernonantibodyproteinsasmembersofthe
immunoglobulinsuperfamily.
6) sWithintheaminoterminalvariabledomainofeachheavyandlightchainarethreecomplementaritydeterminingregions
(CDRs).Thesepolypeptideregionscontributetheantigenbindingsiteofanantibody,determiningitsspecificity.
7) sImmunoglobulinsareexpressedintwoforms:secretedantibodythatisproducedbyplasmacells,andmembranebound
antibodythatassociateswithIg/IgheterodimerstoformtheBcellantigenreceptorpresent
8) onthesurfaceofBcells.
9) sThethreemajoreffectorfunctionsthatenableantibodiestoremoveantigensandkillpathogensare:opsonization,which
promotesantigenphagocytosisbymacrophagesandneutrophils;complementactivation,whichactivatesapathwaythatleads
tothegenerationofacollectionofproteinsthatcanperforatecellmembranes;andantibodydependentcellmediated

cytotoxicity(ADCC),whichcankillantibodyboundtargetcells.
10) sUnlikepolyclonalantibodiesthatarisefrommanyBcellclonesandhaveaheterogeneouscollectionofbindingsites,a
monoclonalantibodyisderivedfromasingleBcellcloneandisahomogeneouscollectionofbindingsites.

8.ANTIGENPROCESSING&PRESENTATION

SelfMHCRestrictionofTCells
RoleofAntigenPresentingCells

EvidenceforTwoProcessingandPresentationPathways

EndogenousAntigens:TheCytosolicPathwaysExogenousAntigens:TheEndocyticPathwaysPresentationofNonpeptide
Antigens

Tcellsrecognizeantigendisplayedwithinthecleftofa

selfMHCmoleculeonthemembraneofacell.

CD4+THcellsrecognizeantigenwithclassIIMHCmoleculesonantigenprocessingcells.

CD8+TCcellsrecognizeantigenwithclassIMHCmoleculesontargetcells.
Complexesbetweenantigenicpeptides&MHCmoleculesareformedbydegradationofaproteinantigeninoneoftwodifferent
antigenprocessingpathways.
s

EndogenousantigensaredegradedintopeptideswithinthecytosolbyproteasomesandassemblewithclassImoleculesinthe
RER.
s

ExogenousantigensareinternalizedanddegradedwithintheacidicendocyticcompartmentsandsubsequentlypairwithclassII
molecules.
s

PeptidebindingtoclassIImoleculesinvolvesreplacingafragmentofinvariantchaininthebindingcleftbyaprocesscatalyzedby
nonclassicMHCmoleculeHLADM.
s

Presentationofnonpeptide(lipid&glycolipid)antigensderivedfrombacteriainvolvestheclassIlikeCD1molecules.

7. Organization & Expression of IG Genes

8. T-Cell Receptor
9. B-Cell Generation, Activation and Differentiation
10. T-Cell Maturation, activation and differentiation
11. Antigen-Antibody Reactions

I.
II.
III.
IV.
V.
VI.

The Complement System

Leukocyte Activation and Migration
Cytokines and Chemokines
Cell-Mediated Effector Responses
Immunity to Infectious Disease
Vaccines

VII.
VIII.
IX.
X.
XI.
XII.

Hypersensitive Reactions
Tolerance and Autoimmunity
Immunodeficiency and AIDS
Cancer and the Immune System 501-523 (23)
Transplantation Immunology 481-499 (19)
Experimental Systems