Chapter 2 The innate immune response.pdf

,

1. WIDESCREEN PRESENTATION
Tips and tools for creating and presenting wide format slides
Chapter 2:
INNATEIMMUNE SYSTEM

2. Innate immunity
Presentfrombirth(limitedsetsofreceptorsandmechanisms
gainedthroughepochsofevolution)
Non-specific
Playaroleimmediatelyorwithinhoursofanantigen's
appearanceinthebody
Thetwomajortypesofresponsesoftheinnateimmune
systemthatprotectagainstmicrobesareinflammationand
antiviraldefense.

4. Main components of the innate immunity
Recognition system of microbes and damaged self
Cellular components of the innate immune system
Soluble recognition and effector molecules of innate
immunity
The inflammatory response
The antiviral response

5. Recognition system of microbes and damaged self
Theinnateimmunesystemrecognizesmolecularstructuresthatare
characteristicofmicrobialpathogensbutnotmammaliancells.
Therearetwoimportantmolecularstructures:
1.Pathogen-associatedmolecularpatterns(PAMPs).
2.Damageassociatedmolecular patterns (DAMPs).
PAMPs:microbialsubstancesthatstimulateinnateimmunityincludes:
nucleicacidsthatareuniquetomicrobes,suchasdouble-stranded
RNAfoundinreplicatingviruses,andunmethylatedCpGDNA
sequencesfoundinbacteria;featuresofproteinsthatarefoundin
microbes,andcomplexlipidsandcarbohydratesthataresynthesized
bymicrobesbutnotbymammaliancells,suchaslipopolysaccharide
(LPS)ingram-negativebacteriaandmannose-richoligosaccharides

6. Recognition system of microbes and damaged self
DAMPs:
endogenousmoleculesthatareproducedbyorreleasedfrom
damagedanddyingcells.
DAMPsmaybeproducedasaresultofcelldamagecausedby
infections.
Theymayalsoindicatesterileinjurytocellscausedbyanyof
myriadreasons,suchaschemicaltoxins,burns,trauma,or
decreasedbloodsupply.
Theinnateimmunesystemusesseveraltypesofcellularreceptors,
presentindifferentlocationsincells,andsolublemoleculesinthe
bloodandmucosalsecretionstorecognizePAMPsandDAMPs

8. Recognition system of microbes and damaged self
Thoserecognitionmoleculescanbedividedintotwo
groups
Cell-associated pattern recognition receptors
expressed on membranes or in the cytoplasm of cells
Soluble recognition molecules
found in the blood and extracellular fluids

9. Cell-associated pattern recognition
receptors of innate immunity
Innateimmunecellsare
providedwithreceptorsin
differentregionsand
compartments:cellsurface,
cytosolandendosome.

10. PatternRecognitionReceptors
(PRRs)arethosereceptors
bindtoPAMPs/DAMPsinitiate
manyresponsesandactivation
ofseveralsignalingpathways
andultimatelytranscription
factors,whichinducethe
expressionofgeneswhose
productsareimportantfor
inflammatoryandantiviral
responses
Pattern Recognition Receptors

11. Toll-likereceptors
ImmunecellshaveavarietyofToll-likereceptors
(whichrecognizebroadPAMPsoninfectiousagents.
BindingofinfectiousagentsviaToll-likereceptors
resultsinphagocytosisandthereleaseof
inflammatorycytokinesbytheimmunecells.
Pattern Recognition Receptors

13. Scavenger receptors
Scavenger receptors bind a wide variety of polyanionsand
low density lipoproteins on bacterial surfaces resulting in
phagocytosis of bacteria.
C-type lectin–like receptors
Such as mannose receptor that binds to microbial surface
carbohydrates with terminal mannose and fructose, and Dectin
receptor that binds to glucanspresent in fungal cell walls
Pattern Recognition Receptors

15. Complement receptors
Phagocytic cells have a receptor for the 3rd component of
complement, C3b. Binding of C3b-coated bacteria to this
receptor also results in enhanced phagocytosis and stimulation
of the respiratory burst. There are other complement receptors
such C3a and C5a receptors which are involved in…..?
Fc receptor: later (adaptive immunity)
Other types of receptors

16. Soluble recognition molecules
Thefollowingslideshowexamplesofdifferentsoluble
moleculeswhichfunctionasarecognitionsystemand
partoftheeffectormechanismoftheinnateimmunity.
Moreexplainedlaterinthischapter.

18. Main components of the innate immunity
Recognition system of microbes and damaged self
Cellular components of the innate immune system
Soluble recognition and effector molecules of innate
immunity
The inflammatory response
The antiviral response

19. Cellular components of the innate immune system
Epithelialbarriers
Phagocytes
Dendriticcells
Naturalkillercells
Mastcells

20. Barriers against infection
The Epithelial barriers of the innate immune system are
as follows:
Mechanical Barriers
Chemical Barriers
Biological Barriers

21. Mechanical Barriers
Intact epithelial surfaces form physical barriers between microbes
in the external environment and host tissue.
The main interfaces between the environment and the host are the
skinand the mucosal surfaces of the gastrointestinal,
respiratory, and genitourinary tracts.

These interfaces are lined by continuous layers of specialized
epithelial cells that serve many physiologic functions, including
preventing the entry of microbes.

22. Loss of the integrity of these epithelial layers by trauma or
other reasons predisposes an individual to infections.
Mucus, a viscous secretion containing glycoproteinscalled
mucins
Mucus physically impairs microbial invasion and
facilitates microbe removalby ciliarymovement, coughing
or sneezing.
Other mechanical factors could be washing action of tears,
saliva and urine.

23. Chemical Barriers
Fatty acids in sweat inhibit the growth of bacteria.
Hydrolytic enzymes such as lysozymesfound in tears,
saliva and nasal secretions can breakdown the cell
wall of bacteria and destabilize bacterial
membranes.
The low pH of sweat and gastric secretions prevents
growth of bacteria.

24. Biological Barriers
The normal flora of the skin and in the
gastrointestinal tract can prevent the
colonization of pathogenic bacteria by
secreting toxic substances or by competing
with pathogenic bacteria for nutrients or
attachment to cell surfaces

26. •Phagocytes
Cellsthathavespecializedphagocyticfunctions
(primarilymacrophagesandneutrophils)
Thefirstlineofdefenseagainstmicrobesthatbreach
epithelialbarriers
Twogeneraltypesoffunctionsindefenseagainst
microbes:
Internalizeandkillmicrobes.
Producingvariouscytokinesthatpromoteinflammation
andalsoenhancetheantimicrobialfunctionofhostcellsat
thesiteofinfection.

27. •Dendritic cells and Mast cells (already we talked about in ch1)
TheyarelymphocytesdistinctfromTandBcellsthatplay
importantrolesininnateimmune
responsesmainlyagainstintracellularvirusesand
bacteria.
NKcellsdonotexpresshighlydiverse,clonallydistributed
antigenreceptors.
NKcellactivationisregulatedbyabalancebetween
signalsthataregeneratedfromactivatingreceptorsand
inhibitoryreceptors.
The effector functions of NK cells are to kill infected cells and
to activate macrophagesto destroy phagocytosedmicrobes.
•Natural killer cells:

29. Effector Functions
of NK Cells
Perforin
Granzymes>> apoptosis

30. Main components of the innate immunity
Recognition system of microbes and damaged self
Cellular components of the innate immune system
Soluble recognition and effector molecules of innate
immunity
The inflammatory response
The antiviral response

31. Soluble recognition and effector molecules of innate immunity
Moleculesthatrecognizemicrobesandpromoteinnateresponses
existinsolubleforminthebloodandextracellularfluids.
Provideearlydefenseagainstpathogensthatarepresentoutsidehost
cellsatsomepartoftheirlifecycle.
Thesolubleeffectormoleculesfunctionintwomajorways:
Byactingasopsoninsandenhancetheabilityofmacrophages,
neutrophils,anddendriticcellstophagocytosethemicrobes.
Promoteinflammatoryresponsesthatbringmorephagocytesto
sitesofinfections,andtheymayalsodirectlykillmicrobes.
Thereareseveralsystemsbutwewillstudytwo:naturalAbsand
thecomplementsystem

32. Normallyantibodiesareproducedinhumoralimmuneresponses
byBlymphocytesasanadaptiveresponsebut>>
NaturalantibodiesareproducedbyasubsetsofBcellsthat
produceantibodieswithonlyalimitednumberofspecificities
withoutovertexposuretoforeignantigens
Presentbeforeinfections,andtheyrecognizecommonmolecular
patternsonmicrobesorstressedanddyingcells
Usuallyspecificforcarbohydrateorlipidmoleculesbutnot
proteins,andmostareIgMantibodies
Theanti-ABOantibodiesareexampleofnaturalantibodies
NaturalAntibodies

33. Consistsofseveralplasmaproteinsthatworktogetherto
opsonizemicrobes,topromotetherecruitmentofphagocytesto
thesiteofinfection,andinsomecasestodirectlykillthe
microbes.
Complementactivationinvolvesproteolyticcascades.
Recognitionofmicrobesbyanyofthethreecomplementpathways
resultsinsequentialrecruitmentandassemblyofadditional
complementproteinsintoproteasecomplexes
TheComplementSystem

34. Complement pathways
Alternative MBL or Lectin Classical
Activator C3b deposition on
pathogen surface
Terminal mannose
residues on many
microorganisms binds
to MBL
Ab-Ag complex
system innate Innate Adaptive
Examples of Agsthe
activator binds to
-LPS
-viruses
-necrotic cells
-GPbacteria (staph.
aureus)
-GN bacteria (E. coli)
-Fungi (Candida)
-HIV
-Necroticcells
-Streptococcus
pneumoniae

35. General overview

36. Detailed view

39. Main components of the innate immunity
Recognition system of microbes and damaged self
Cellular components of the innate immune system
Soluble recognition and effector molecules of innate
immunity
The inflammatory response
The antiviral response

40. The inflammatory response
Acuteinflammationisthemajorwaybywhichtheinnateimmune
systemdealswithinfectionsandtissueinjury.
Itistheaccumulationofleukocytes,plasmaproteins,andfluid
derivedfromthebloodatanextravasculartissuesiteofinfectionor
injury.
developinminutestohoursandlastfordays.
Chronicinflammationisaprocessthattakesoverfromacute
inflammationiftheinfectionisnoteliminatedorthetissueinjuryis
prolonged.
Duringinflammation,bloodcomponentsaredeliveredtothesiteof
infection.

41. Thedeliveryofthesebloodderivedcomponentstotheinflammatory
siteisdependentonreversiblechangesinbloodvesselsintheinfected
ordamagedtissue.
Thesechangesinclude:
increasedbloodflowintothetissueduetoarteriolardilation
increasedadhesivenessofcirculatingleukocytestotheendothelial
liningofvenules
increasedpermeabilityofthecapillariesandvenulestoplasma
proteinsandfluid
Allthesechangesareinducedbycytokinesandsmall-molecule
mediatorsinitiallyderivedfromresidentcellsinthetissue,suchasmast
cells,macrophages,andendothelialcells,inresponsetoPAMPorDAMP

42. opsonins

43. There are two different
mechanisms for killing:
Intracellular:
Oxygen-dependent (product
of respiratory burst Reactive
Nitrogen Intermediates (RNI)
and Reactive Oxygen
Species (ROS))
Oxygen-independent (low pH,
antimicrobial peptides,
damaging proteins and
proteases, as well as iron-
depriving mechanisms)
Extracellular: NK remember?

45. Stepsofthe
Inflammatory
Response:

47. The primary objective of inflammation is to localize and
eradicatethe irritant and repair the surrounding tissue.
BUT?
In severe infections, some cytokines may be produced in
large amounts and causes systemic clinical and
pathologic abnormalities such as
Inhibition of myocardial contractility
Thrombosis
wasting of muscle and fat cells
Fever…
There are many mechanisms to inhibit inflammatory
cytokines in order to regulate the inflammatory response.

49. Main components of the innate immunity
Recognition system of microbes and damaged self
Cellular components of the innate immune system
Soluble recognition and effector molecules of innate
immunity
The inflammatory response
The antiviral response

50. The antiviral response
Receptors,includingsomeTLRs,generatesignalsthatstimulateIFN-α
andIFN-βgeneexpressioninmanydifferentcelltypes.
ThetypeIinterferonsaresecretedfromthesecellsandactonother
cellstopreventspreadofviralinfection.
TypeIinterferons:
largefamilyofstructurallyrelatedcytokinesthatmediatetheearlyinnate
immuneresponsetoviralinfections
signalingthroughthetypeIinterferonreceptor,activatetranscriptionofseveral
genesthatconferonthecellsaresistancetoviralinfection,calledanantiviral
state.
upregulate expression of class I MHC molecules (what's the advantage?)
cause sequestration of lymphocytes in lymph nodes

52. Main components of the innate immunity
Recognition system of microbes and damaged self
Cellular components of the innate immune system
Soluble recognition and effector molecules of innate
immunity
The inflammatory response
The antiviral response