Lecture 5

Effector Mechanisms

Host
Defense
Innate

Defense
Mechanisms

Inborn independent
of previous
experience

Naturally
acquired

Active

after natural
exposure to a foreign
agent

Passive

placental transfer

Adoptive

immune cells in
colostrum

Active

Specific
immunization

Passive

administration of
preformed antibodies

Adoptive

Bone marrow
transplant

Acquired

Artificially
acquired

Effector Mechanisms

Antibody-mediated
Neutralizing
Opsonization
Complement activation
Receptor-mediated

Antibody-dependent

cellular cytotoxicity

Cell-mediated
Direct cytotoxicity (induction of apoptosis)
Cytokines
Regulatory

T-cell Mediated Cytotoxicity

Necrosis
Programmedcelldeathorapoptosis

Cytokines

PolypeptidesproducedbyavarietyofcelltypesincludingT
lymphocytesusedforcommunicationsbetweencells.
Cytokineproductionistriggeredbyspecificreceptorbinding
andsubsequentsignaltransductionpathways
Cytokinerepertoireisdependentoncelltypetriggered,
receptorspresentonthatcelltype.
Cytokinesactoncellsthatpossessreceptorsforthem.

Playrolesimilartohormones(messengersoftheendocrinesystem)
Hormonesusuallyactatadistance
Cytokinesactlocally

Playanimportantroleinbothinnateandadaptiveimmunity

Properties of cytokines

Proteins
Lowmolecularweight
Bindtoreceptoroneithercellwhichproduceditor
anothercell
Receptorbindingtriggersasignal
Signalresultsinalteredpatternofgeneexpression
Arenotantibodies

Lymphocyte Migration, Activation, and Effector

Function Depends on Cell-Adhesion Molecules

A variety of cell surface polypeptides serve

as receptors to ensure appropriate cell-cell
interactions. These polypeptide include:

Selectins
Integrins
Immunoglobulin Superfamily
Mucin-like Vascular Addressins

Cytokine nomenclature
Interleukins(118)
Interferons()
Others(commonnames)

Cytokine -mediated effects

Cellgrowth
Celldifferentiation
Celldeath
Inducenonresponsivenesstoother
cytokines/cells
Induceresponsivenesstoothercytokines/cells
Inducesecretionofothercytokines

How can non-specific cytokines

act specifically?

Onlycellsexpressingreceptorsforspecificcytokines
canbeactivatedbythem
Manycytokineshaveveryshorthalflives

Onlycellsincloseproximitywillbeactivated

Highconcentrationsofcytokinesareneededfor
activation

Onlycellsincloseproximitywillbeactivated
Mayrequirecelltocellcontact

Cytokines in the immune response

Alertto
infection.tumor/etc.
Recruitcellstosite
Specifytypeofimmune
response
Immuneeffectorphase
Immunedownregulation
Immunememoryand
resettingthesystem

Earlymediators(IFN)
Chemokines(MIP1)
Early&latemediators
(IL2,IFN,IL4,IL5)
Downregulators(IL10,
TNF)
Maintenanceof
cytokines,etc.(GMCSF,
IL3,IL7,etc.)

Cytokine secretion and biological

activities of TH1 and TH2 Subsets
Cellmediated
Immuneresponse
(intracellular
Organisms)

Type 1

Type 2

Tcell
IL2
IFN
TNF

IL4
IL5

Humoral
response
(parasites)

Role of TH1/TH2 balance in determining

disease outcomes
Balanceoftwosubsetdeterminesresponse
todisease
Leprosy

Tuberculoid(TH1,CMIresponse,patientlives)
Lepromatous(TH2,humoralresponse,patient
dies)

Cytokine-related diseases

Bacterialsepticshock

Bloodpressuredrops,clotsform,hypoglycemiaensues,patientdies
LPStriggersresultsinTNFrelease
TNFinducesIL1whichinducesIL6andIL8

Bacterialtoxicshockandrelateddiseases

SuperantigenstriggerlargenumbersofTcellswhichreleasemassiveamounts
ofcytokines(SuperantigensarebacterialtoxinsthatbridgeCD4TcellreceptorsandtheMHCclassII
moleculesonAPCs,bypassingtheneedforantigen)

Lymphoidandmyeloidcancers

Somecancercellssecretecytokines

Chagasdisease

Trypanosomacruziinfectionresultsinseverimmunesuppression
DepressionofIL2receptorproduction

Infectious agents that target cytokines

EpsteinBarrvirusfosterthegenerationofThelpercells
thatdonotproduceIL2.
EBVproducesananalogofIL10thatfavorsT H2cells,
ratherthanTH1.
ParasitessuchastapewormsinducehighlevelsofIgE,
animmunoglobulininducedbyT H2cells.
SinceTH1cellsmediateinflammation,thismaybea
protectiveploytoavoiddestructiveinflammatory
processes.

Immunosuppressive effects of oral

bacteria on immune function

ImpairmentofBandTcellfunction(P.intermedia,P.
asaccharolytica,P.endodontalis,P.melaninogenica )
Productionofspecifictoxinsthatkillmonocytes(A.
actinomycetemcomitans)
Provokethereleaseofperoxide,prostaglandinsand
othermediatorscapableofinhibitinglymphocyte
function(T.denticola)
Modulateexpressionofcytokines

Cytokine-inducing components of
Gram-positive bacteria

Interferon Action

Viralreplicationstimulatestheinfectedhostcellto
produceinterferon.
Interferoninducesuninfectedcellsto

produceantiviralproteinsthatpreventtranslationofviral
mRNA
degradeviralnucleicacid

Viralreplicationisblockedinuninfectedcells

Interferon Action

Therapeutic uses of cytokines

ModulationofTHactivation
Interferewithreceptorfunction
Interferewithcytokine

Makeitunabletobindtoreceptor
Makeitunabletoact

Examples of therapeutic uses

SolubleTcellreceptor
AntiIL2R
Interleukinanalogswhichbindreceptor,butdonot
triggeractivation(tiesupreceptor)
ToxinsconjugatedtocytokineswhichkillactivatedT
cells
Administrationofcytokinestoenhanceimmunity(side
effects/shorthalflives)
Allergies

Summary
Effectorcellsandantibodiesplaycriticalrolesin
almostalladaptiveimmuneresponses
Antigenpresentingcellsplaycriticalrolein
processingandpresentingantigentoTcells
Cytokinesarereleasedbyavarietyofcelltypes
andregulateavarietyofbiologicaleffects
Tcellmediatedcelldeathislargelyviaapoptosis

Whats the bottom line?

Innate immunity is a function of anatomical, mechanical and biochemical

factors.

Adaptive immune system recognizes foreign agents via receptors and

develops memory.
Triggering the adaptive immune response results in activated T cells and
antibodies specific for the substance (antigen) that triggered it.
Antibodies react with antigen

No requirement for prior exposure/memory

Biochemical response may involve pattern recognition
Lacks the specificity of the adaptive immune system

Block or neutralize
Activate complement system
Bind to Fc receptors on cells providing specificity to the effector activity of those
cells

Activated T cells

Cytotoxic against foreign agent (tumor cell, transplant, virus-infected cell)

May influence other cells (Helper/Suppressor T cells, cytokines)