CHAPTER 2

Innate Immunity
The Immune System, Third Edition
2009 Garland Science Publishing

Questions
21
Explainwhythetypeofinnateimmuneresponseusedbythehostduringaninfectionis
dependentupontheparticularlocationinwhichthepathogenresides.
22
Explainthreemechanismsbywhichpathogensexertdamagingeffectsuponhostcells
duringthecourseofaninfection,andprovideanexampleofapathogenforeacheffect.
23
Whichofthefollowingdoesnotaccuratelydescribecomplementcomponents?
a.
solubleproteins
b.
madebythespleen
c.
locatedinextracellularspaces
d.
somefunctionasproteasesonceactivated
e.
activatedbyacascadeofenzymaticreactions.
24
ExplainwhyageneticdeficiencyofC3leadstoatypeofimmunodeficiency
characterizedbyrecurrentandsevereinfections.
25
Thelectinpathwayofcomplementactivationisinducedby:
a.
Creactiveprotein
b.
antibodiesboundtopathogens
c.
mannosebindinglectin
d.
C3Bb
e.
terminalcomponentsofthecomplementpathway.
26
WhichofthefollowingisthemembraneboundformofC3convertaseofthealternative
pathwayofcomplementactivation?
a.
iC3

2
b.
c.
d.
e.

C3a
C3b
iC3Bb
C3bBb.

27
ExplainhowthealternativeC3convertaseonpathogencellsurfacesis(A)formedand
(B)stabilized.
28
WhyisitimportanttoexposethehydrophobicsitesofC7andC8duringtheformationof
themembraneattackcomplex?
29
TheplasmaproteinsthatcounteracttheactivityoffactorPbyinactivatingC3convertase
throughthecleavageofC3bare:
a.
factorBandfactorH
b.
factorHandfactorI
c.
factorBandfactorI
d.
decayacceleratingfactorandfactorH
e.
decayacceleratingfactorandmembranecofactorprotein.
210
Themembraneboundproteinsonhumancellsthatdissociateandinactivatealternative
C3convertasetoavoidcomplementactivationare:
a.
factorBandfactorH
b.
factorHandfactorI
c.
factorBandfactorI
d.
decayacceleratingfactorandfactorH
e.
decayacceleratingfactorandmembranecofactorprotein.
211
ExplainthesimilaritiesbetweenMCP,factorH,andCR1intermsoftheircomplement
controlproperties.
212
ExplainhowtheanaphylatoxinsC3aandC5acontributephysiologicallytoinflammation
duringcomplementactivation.
213
Whichofthefollowingcomplementcomponentsisanopsoninthatbindstocomplement
receptor1(CR1)onmacrophages?
a.
C3b

3
b.
c.
d.
e.

C3a
Bb
Ba
C3bBb.

214
Whichofthefollowingpolymerizestoformatransmembranechannelthatcompromises
theintegrityofcellmembranes?
a.
C5
b.
C6
c.
C7
d.
C8
e.
C9.
215
Whichofthefollowingareimportantinanchoringthemembraneattackcomplextothe
membrane?
a.
C3andC5
b.
C5andC6
c.
C6andC7
d.
C7andC8
e.
C8andC9.
216
Whichofthefollowingdoesnotcontainaglycosylphosphatidylinositol(GPI)lipidtail?
a.
decayacceleratingfactor(DAF)
b.
homologousrestrictionfactor(HRF)
c.
membranecofactorprotein(MCP)
d.
protectin(CD59)
e.
alloftheabovecontainaGPItail.
217
TheligandforCR3andCR4formedbythecleavageofC3bbythecombinedactionof
factorsHandIiscalled:
a.
C3bBb
b.
C3a
c.
C3b2Bb
d.
iC3b
e.
C5b.
218
Whichofthefollowingdoesnotdescribetheactionsofthecoagulationsystem?

4
a.
b.
c.
d.
e.

bloodclotformation
enhancementofdisseminationofmicrobesintolymphaticsandbloodstream
decreaseinbloodlossandfluidintointerstitialspacesintissues
releaseofinflammatorymediatorsbyplatelets
woundhealing.

219
Whichofthefollowingisnotacharacteristicofmannosebindinglectin?Selectallthe
correctanswers.
a.
actsasanopsoninbybindingtomannosecontainingcarbohydratesofpathogens
b.
synthesizedbyhepatocytes
c.
inducedbyelevatedIL6
d.
amemberofthepentraxinfamily
e.
triggersthealternativepathwayofcomplementactivation.
220
WhichofthefollowingisnotacharacteristicofCreactiveprotein?
a.
actsasanopsoninbybindingtophosphocholineofpathogens
b.
synthesizedbyspleen
c.
inducedbyelevatedIL6
d.
amemberofthepentraxinfamily
e.
triggerstheclassicalpathwayofcomplementactivation.
221
Damagetotissuestriggersacascadeofplasmaproteinsinvolvingbradykininandis
knownas:
a.
thealternativepathwayofcomplement
b.
thecoagulationsystem
c.
thekininsystem
d.
receptormediatedendocytosis
e.
theacutephaseresponse.
222
Whichofthefollowingdoesnotdescribedefensins?
a.
highlyconservedwithfewvariants
b.
containalargeproportionofarginineresidues
c.
containthreeintrachaindisulfidebonds
d.
amphipathic,withhydrophobicandhydrophilicregions
e.
disruptpathogenmembranesbypenetratinganddisruptingtheirintegrity.
223
DescribethetwodifferentdomainsofTLRsandtheirrespectivefunctions.

5
224
ExplaintheconsequenceofengagementoftheTLR4,CD14,andMD2complexwith
LPSinmacrophages.
225
WhichofthefollowingTLRsdonotuseasignaltransductioncascadeinvolving
MyD88?
a.
TLR1:TLR2
b.
TLR3
c.
TLR4
d.
TLR2:TLR6
e.
TRL7.
226
WhichofthefollowingTLR3andTLR4adaptorproteinsparticipatesintheactivation
pathwaythatculminatesinthesynthesisoftypeIinterferons?
a.
Creactiveprotein
b.
MyD88
c.
LPSbindingprotein
d.
TRIFandTRAM
e.
NFB.
227
ExplainspecificallyhowthesystemicreleaseofTNFbymacrophagescauses(A)
septicshock,(B)disseminatedintravascularcoagulation,(C)organfailure,and(D)
hemorrhagingduringinfectionwithbloodbornepathogens.
228
Whichofthefollowingisnotacharacteristicofsepticshock?
a.
organfailure
b.
highmortalityrate
c.
compromisedbloodsupplytovitalorgans
d.
bloodvesselconstriction
e.
disseminatedintravascularcoagulation.
229
Whichofthefollowingpropertiesiscommontomacrophagesandneutrophils?
a.
lifespan
b.
anatomicallocation
c.
abilitytophagocytose
d.
morphology
e.
formationofpus.

6
230
Whichofthefollowingbestdescribesanendogenouspyrogen?
a.
cytokinesmadebypathogensthatdecreasebodytemperature
b.
pathogenproductsthatdecreasebodytemperature
c.
pathogenproductsthatincreasebodytemperature
d.
cytokinesmadebythehostthatdecreasebodytemperature
e.
cytokinesmadebythehostthatincreasebodytemperature.
231
Whichofthefollowingisanacutephaseproteinthatenhancescomplementfixation?
a.
TNF
b.
mannosebindinglectin
c.
fibrinogen
d.
LFA1
e.
CXCL8.
232
A.
Usingthetablebelow,matchthelocalandsystemiceffectsincolumnAwiththe
appropriatecytokineincolumnB.NotethatmorethanoneanswerincolumnBmaybe
used.
B.
(i)Whichofthesecytokinesareproducedbymacrophages?(ii)Whichcells
producetheother(s)?
a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
k.
l.
233

ColumnA
activationofbloodvessel
endothelium
fever
inductionofIL6synthesis
increaseinvascularpermeability
localizedtissuedestruction
productionofacutephaseproteins
byhepatocytes
inductionofresistancetoviral
replication
activationofNKcells
leukocytechemotaxis
activationofbindingby2integrins
(LFA1,CR3)
septicshock
mobilizationofmetabolites

ColumnB
1.

IL1

2.
3.
4.
5.
6.

IL6
CXCL8
IL12
TNF
typeIinterferons

7
Describeinchronologicalorderthefourstepsinvolvedintheextravasationofneutrophils
toinfectedtissuesitesduringaninnateimmuneresponse.Usethefollowingtermsin
yourdescription:rollingadhesion,tightbinding,diapedesis,migration,inflammatory
mediators,integrins,adhesionmolecules,chemokines,WeibelPaladebodies,Pselectin,
Eselectin,sialylLewisx,andbasementmembraneprotease.
234
Duringinflammation,hosttissuemaybedamagedowingtothereleaseoftoxicoxygen
derivativesproducedbyactivatedmacrophagesandneutrophils.Explainwhatcellular
mechanismslimitthesedamagingbystandereffects.
235
DescribethetwostructuraltypesofNKcellreceptor.

Answers
21
Theinnateimmuneresponsemustbeoftheappropriateformtoaccesstheparticular
compartmentofanongoinginfection.Ifapathogenexistsinextracellularspacesor
surfaces,thensolublemoleculessuchascomplementandantimicrobialpeptidesare
effectiveineradicatingthepathogen.Somepathogens,however,resideinintracellular
compartments,suchasthenucleus,cytosol,orvesicles.Ifthepathogensareenclosed
withinavesicle,theinnateimmuneresponseinstructstheinfectedcelltodirect
antimicrobialmechanismstotheinteriorofthevesicletoeradicateviablemicrobes.
Macrophagescarryoutthistypeofantimicrobialactivity.Ifthepathogensarereplicating
freeinthenucleusorcytosol,theninnatemechanismsaremoreaggressiveandareaimed
atkillingtheinfectedcell.Naturalkiller(NK)cellsmediatethistypeofactivity.
22
(i)Pathogenssecreteexotoxinsthatinteractwithaspecificreceptoronhostcellsurfaces
anddamageorkillthecell.Anexampleisthecholeraexotoxinproducedduringinfection
withVibriocholerae.(ii)Somepathogencomponentsactasendotoxins.Whenreleased
fromthepathogenandboundtomacrophages,endotoxinsinducetheproductionof
cytokinesthatactlocallyandsystemically.Anexampleistheendotoxinreleasedfrom
Yersiniapestis,theetiologicalagentoftheplague.(iii)Somepathogensgrowinsidehost
cellsanddamagethemdirectly.Anexampleistheinfluenzavirus,thecauseofinfluenza.
23:b
24
C3isakeyelementintheinitiationofthecomplementcascadeinallthreepathwaysof
complementactivation,namelythealternative,lectin,andclassicalpathways.Its
cleavageintoC3aandC3boccursearlyinthecomplementcascade.C3aactsasan
inflammatorymediatorandrecruitsinflammatorycellstothesiteofinfection.C3b
becomesfixedtothepathogensurfaceandfacilitatestheopsonizationofpathogensby
phagocytesandtheassemblyofcomplementcomponentsforperforationofthepathogen
membrane.IntheabsenceofC3,allthreepathwaysofcomplementactivationwouldbe
arrestedandextracellularpathogenswouldescapeimmunedetectionuntiladaptive
immunemechanismsdevelopfullymanydayslater.
25:c
26:e
27

9
(A) Spontaneous hydrolysis of C3 without cleavage exposes its highly reactive thioester
bond, forming iC3. Factor B binds to iC3, is cleaved by factor D, and consequently
releases a small fragment called Ba. The larger fragment, Bb, remains associated with
iC3 to form iC3Bb, a soluble C3 convertase, which cleaves C3 into C3a and C3b. The
reactive thioester bond of C3b is attacked by R-OH and R-NH2 groups on the surface of
the pathogen, where it becomes anchored and binds to factor B. Factor D then cleaves
factor B, releasing fragment Ba and forming C3bBb on the pathogen surface.
(B) Factor P (properdin) binds to C3 convertase (C3bBb) bound to the pathogen surface,
and inhibits the proteolytic degradation of C3bBb. This stabilizes the C3 convertase and
enhances the rate of C3b deposition on the pathogen surface.
28
The hydrophobic sites of C7 and C8 enable anchoring of these two complement
components into the membrane of the pathogen. Once anchored in the membrane, the
hydrophobic site of C8 facilitates C9 polymerization, which completes the formation of
the membrane-attack complex.
29:b
210:e
211
MCP, factor H, and CR1 all bind to C3b and render it susceptible to proteolytic cleavage
by factor I. All three contain complement control protein (CCP) modules and are
therefore considered regulators of complement activation (RCA).
212
G-protein-coupled receptors for the anaphylatoxins C3a and C5a are found on
phagocytes, mast cells, and the endothelial cells of blood vessel walls. Anaphylatoxin
bound to mast cells causes them to degranulate, releasing inflammatory mediators such as
histamine and leading to increased vascular permeability. Through their action on
endothelial cells, anaphylatoxins exert vasoactive effects on blood vessels, contributing to
increased vascular permeability and increased blood flow, which facilitate the
extravasation of plasma proteins, such as complement proteins and antibodies, and the
recruitment of cells to infected tissues through increased adherence and chemotaxis.
Phagocytic activity is enhanced by anaphylatoxins, which bring about increased levels of
CR1 and CR3 and microbicidal activity. All these activities enhance inflammation.
213:a
214:e
215:d
216:c

10

217:d
218:b
219:d,e
220:b
221:c
222:a
223
ThefirstdomainoftheTLRisanextracellulardomain,alsoknownasthepathogen
recognitiondomain,whichcontainsahydrophobic,leucinerichrepeatregion(LRR)
whichformsahorseshoeshapedstructurethatbindsspecificallytoarraysonmicrobial
surfaces.TheseconddomainoftheTLRisthecytoplasmicsignalingdomain,also
knownastheTollinterleukinreceptor(TIR)domain,whichfacilitatesthetransmission
ofinformationtotheinteriorofthecell.
224
WhenTLR4onthesurfaceofmacrophagesisboundtoitsLPSligand,asignal
transductioncascadeisinitiatedthatmediatessignalingbetweenthecellsurfaceandthe
nucleus.Themacrophageinturnbeginstoexpressparticulargenesencoding
inflammatorycytokinesthatareimportantfortheinitiationofadaptiveimmune
responses.
225:b
226:d
227
A.

TNFinducestheactivationofendothelialcellsliningbloodvessels.Thisin
turnresultsinthedilationofbloodvessels,increasedvascularpermeability,and
thesubsequentleakageoffluidfromthebloodacrosstheendotheliumandinto
theinterstitialspacesoftissue.Thefluidconsistsofcomplementcomponentsand
antibodies,whicharereleasedinresponsetoTNFtohelpcombatinfectionin
tissues.ButwhenlargeamountsofTNFareproducedthroughoutthebodyas
theresultofasystemicinfection,bloodpressureiscompromised;bloodvolume
decreases,leadingtoshockassociatedwithlowbloodpressure(hypovolemic
shock).

11
B.

C.
D.

TNFalsotriggersthereleaseofplateletactivatingfactorfromactivated
endothelium.Plateletactivatingfactorinitiatesthebloodclottingcascade,
consumingbloodclottingfactorsandcausinglocalizedbloodvesselblockageat
sitesofTNFproductionbyresidentmacrophagesinvariousorgans,for
exampletheKupffercellsoftheliverandsplenicmacrophages.Whenthisoccurs
onalargescale,itisknownasdisseminatedintravascularcoagulation.
Thebloodsupplytoorgansischokedoffasaresultofdisseminatedintravascular
coagulation,leadingtoorganfailure.
Asbloodclottingfactorsareconsumedbydisseminatedintravascular
coagulation,theyarenotavailableelsewheretohelprepairbrokenbloodvessels.
Asaresult,hemorrhagingoccurs,causingpetechiaetodevelop,whichpresentas
smallpurplespotsundertheskin.

228:d
229:c
230:e
231:b
232
A.

B.

a.
Activationofbloodvesselendothelium1,5
b.
Fever1,2,5
c.
InductionofIL6synthesis1
d.
Increaseinvascularpermeability5
e.
Localizedtissuedestruction1
f.
Productionofacutephaseproteinsbyhepatocytes2
g.
Inductionofresistancetoviralreplication6
h.
ActivationofNKcells4,6
i.
Leukocytechemotaxis3
j.
Activationofbindingby2integrins(LFA1,CR3) 3
k.
Septicshock5
l.
Mobilizationofmetabolites5
(i)ThecytokinesIL1,IL6,CXCL8,IL12,andTNFareproducedby
macrophages.(ii)TypeIinterferonscanbeproducedbymanydifferenttypesof
cellwheninfectedwithavirus.Specializedcellscalledinterferonproducingcells
(IPCs)ornaturalinterferonproducingcells(NIPCs)producelargeamountsof
interferon.

233
Step1:dilationofbloodcapillaries,combinedwiththebindingofneutrophilsialyl
Lewisxcarbohydratetoselectins,atypeofadhesionmolecule,expressedonactivated
endothelium,slowsdownneutrophilsastheyrollalongtheendothelium,binding

12
reversiblytotheendothelialselectins,aprocesscalledrollingadhesion.Twotypesof
selectinareexpressedonactivatedendotheliuminresponsetoinflammatorymediators.
Thefirst,Pselectin,isstoredinpreformedgranulescalledWeibelPaladebodiesandis
expressedsoonafterendothelialactivation.Later,Eselectinwillappearonthesurfaceof
activatedendotheliuminresponsetoTNForLPS.Step2:inresponsetothe
chemokineCXCL8,neutrophilintegrinsLFA1andCR3increasetheiraffinityforthe
endothelialadhesionmoleculeICAM1throughconformationalchanges.Leukocytesare
nowengagedintightbindingtotheendotheliumandtherollingstops.Step3:the
neutrophilsqueezesbetweentheendothelialcells.Whenthebasementmembraneis
encountered,proteasesaresecretedbytheneutrophil,thebasementmembraneis
degraded,andtheprocessofdiapedesisiscomplete.Step4:migrationtothefocusof
infectionismediatedthroughachemokine(CXCL8)gradient.NeutrophilsbearingIL8
receptorswilltraveltowardthehighestconcentrationofIL8untiltheyarriveatthefocus
ofinfection.
234
Toxicoxygenspeciesincludingsuperoxide,hydrogenperoxide,singletoxygen,hydroxyl
radical,hypohalite,andnitricoxideareproducedduringtherespiratoryburstin
macrophagesandneutrophils.Simultaneousextraphagosomalproductionofenzymesthat
neutralizethesecompoundsoccurs.Specifically,superoxidedismutasemetabolizes
superoxidetohydrogenperoxide,whichisfurthermetabolizedbycatalasetoinnocuous
waterandmolecularoxygen.
235
NKcellshavetwomainstructuraltypesofextracellularreceptor.TheNKcell
immunoglobulinlikereceptorcontainsimmunoglobulindomainsthatinteractwith
proteinligandsontargetcells.TheNKcelllectinlikereceptorresemblesthemannose
bindinglectinstructurally,butcaninteractwithproteinandcarbohydrateligandson
targetcells.Activatingreceptorscontainchargedaminoacidresiduesspanningthe
transmembraneregion,whichassociatewithintracellularsignalingproteinsthatwill
initiatetheactivationofNKcells.Inhibitoryreceptorscontainlongcytoplasmictails
bearinganimmunoreceptortyrosinebasedinhibitorymotif(ITIM),whichinhibitsNK
cellactivation.