4. physical and chemical barriersphysical and chemical barriers
The innate immunity (I.I) is based onThe innate immunity (I.I) is based on
physical and chemical barriers.physical and chemical barriers.
This defense mechanism are representedThis defense mechanism are represented
by :by :
epidermis,epidermis,
ciliated reapiratory epithelium,ciliated reapiratory epithelium,
vascular endothelium andvascular endothelium and
mucosed surface with antimicrobialmucosed surface with antimicrobial
secretionsecretion
5. physical and chemical barriersphysical and chemical barriers
1. Sweat secretion contains fatty acids1. Sweat secretion contains fatty acids
2. Lysozyme presents on the skin in tears,2. Lysozyme presents on the skin in tears,
in respirotary and cervical secretion, inin respirotary and cervical secretion, in
mucous membranesmucous membranes
3.Salive contains hydrolytic enzymes3.Salive contains hydrolytic enzymes
4. Acidity of stomach4. Acidity of stomach
5. normal flora5. normal flora
6. innate immune systeminnate immune system
The important ability of the innate systemThe important ability of the innate system
to recognize and limit microbes earlyto recognize and limit microbes early
during infection is based primerily onduring infection is based primerily on
-- Employment complement activationEmployment complement activation
- Phagocytosis- Phagocytosis
- Immune activation by different families- Immune activation by different families
of PRRof PRR
7. innate immune systeminnate immune system
The innate immune systemThe innate immune system
constitutes the first line of hostconstitutes the first line of host
defense and plays crucial roledefense and plays crucial role
in the early recognition andin the early recognition and
subsequent triggering ofsubsequent triggering of
proinflammatory response toproinflammatory response to
pathogenpathogen
8. Adoptive responseAdoptive response
Adoptive response isAdoptive response is
characterized by specifitycharacterized by specifity
developed by clonal genedeveloped by clonal gene
arragements from a broadarragements from a broad
repertour antigen specificrepertour antigen specific
receptors on lymphocytesreceptors on lymphocytes
9. innate immune systeminnate immune system
The innate immune response is mediatedThe innate immune response is mediated
by phagocytic cells andby phagocytic cells and
antigen presenting cells (APC) such asantigen presenting cells (APC) such as
macrophages and dendritic cells (DC)macrophages and dendritic cells (DC)
And has been regarded as relativelyAnd has been regarded as relatively
nonspecificnonspecific
10. innate immune systeminnate immune system
The innate immune response relies onThe innate immune response relies on
recognition of evolutionary conservedrecognition of evolutionary conserved
structures on pathogens termedstructures on pathogens termed
Pathogen-associated molecular patternsPathogen-associated molecular patterns
(PAMPs)(PAMPs) through a limited number ofthrough a limited number of
germ line encodedgerm line encoded pattern recognitionpattern recognition
receptors ( PRR)receptors ( PRR)
Toll –like receptors are some of themToll –like receptors are some of them
11. PRRPRR
PRR may present either on the cellPRR may present either on the cell
surface or intracellularlysurface or intracellularly
After interaction with PAMP, they triggerAfter interaction with PAMP, they trigger
proinflammatory and antimicrobialproinflammatory and antimicrobial
response by activating of intracellularresponse by activating of intracellular
signaling pathway including adaptorsignaling pathway including adaptor
molecules, kinases, and transcriptionmolecules, kinases, and transcription
factorsfactors
12. The family of TLR is the majorThe family of TLR is the major
class of PRRclass of PRR
The family of TLR can be devided intoThe family of TLR can be devided into
subfamilies:subfamilies:
TLR1 , TLR2, TLR4 , TLR6 recognizeTLR1 , TLR2, TLR4 , TLR6 recognize
lipidslipids
TLR3 , TLR7, TLR8 , TLR9 recognizeTLR3 , TLR7, TLR8 , TLR9 recognize
nuclear acidsnuclear acids
13. TLRTLR
Certain TLRs (TLR 1,2,4,5,6,10)Certain TLRs (TLR 1,2,4,5,6,10)
are expressed at membrane andare expressed at membrane and
mainly recognize bacterialmainly recognize bacterial
products unique to bacteria andproducts unique to bacteria and
not produced by the hostnot produced by the host
14. TLRTLR
TLR 3,7,8,9 are locatedTLR 3,7,8,9 are located
almost exclusively inalmost exclusively in
intracellular compartmentsintracellular compartments
including lysosomes and areincluding lysosomes and are
specialized in recognition ofspecialized in recognition of
nucleic acidsnucleic acids
15. TLR-independent recognitionTLR-independent recognition
TLR-independent recognition ofTLR-independent recognition of
pathogens is accomplished by a largepathogens is accomplished by a large
group of cytosolic PRRs which can begroup of cytosolic PRRs which can be
broadly divided into retinoid acid-induciblebroadly divided into retinoid acid-inducible
gene I (Rig-I) like receptors andgene I (Rig-I) like receptors and
Nucleotide binding oligomerization domainNucleotide binding oligomerization domain
(NOD)-like receptors(NOD)-like receptors
16. TLRTLR
The most important cell types expressingThe most important cell types expressing
TLRs are APC, including:TLRs are APC, including:
MacrophagesMacrophages
DCDC
B-lymphocytesB-lymphocytes
17. TLRTLR PRRPRR
TLR4TLR4 Gramnegative bacteria via lipidAGramnegative bacteria via lipidA
TLR2TLR2 Grampositive bacteria via lipoteichoicGrampositive bacteria via lipoteichoic
acidsacids
TLR5TLR5 Flagellated bacteriaFlagellated bacteria
TLR3TLR3 Double stranded RNADouble stranded RNA
TLR7,8TLR7,8 Single stranded RNASingle stranded RNA
TLR9TLR9 Unmethylated CpG DNA present inUnmethylated CpG DNA present in
18. Principles in innate signalPrinciples in innate signal
transductiontransduction
Signal transduction is mediated by aSignal transduction is mediated by a
family of adaptor moleculesfamily of adaptor molecules
Recruitment of adaptive molecules to aRecruitment of adaptive molecules to a
given TLR is followed by activation ofgiven TLR is followed by activation of
downstream signal transduction pathwaydownstream signal transduction pathway
via activation of transcription factors whichvia activation of transcription factors which
regulate expression of genes involved inregulate expression of genes involved in
inflammation and antimicrobial defenseinflammation and antimicrobial defense
19. Principles in innate signalPrinciples in innate signal
transductiontransduction
NF-kbNF-kb plays central role in induction ofplays central role in induction of
proinflammatory response, causingproinflammatory response, causing
production of cytokines and IFNsproduction of cytokines and IFNs
20. Principles in innate signalPrinciples in innate signal
transductiontransduction
There is important link between innate andThere is important link between innate and
adaptive immunity provided by PRRadaptive immunity provided by PRR
particularly via TLR-mediated maturationparticularly via TLR-mediated maturation
of DC and activation of pathogen specificof DC and activation of pathogen specific
T-lymphocytesT-lymphocytes
21. Principles in innate signalPrinciples in innate signal
transductiontransduction
Following antigen uptake by DC, DC becomeFollowing antigen uptake by DC, DC become
activated and migrate to regional lymph nodes toactivated and migrate to regional lymph nodes to
present antigenic peptides in the context ofpresent antigenic peptides in the context of
revelant MHC molecules.revelant MHC molecules.
After having undergone maturation DC areAfter having undergone maturation DC are
endowed with the ability to stimulate naïve CD4endowed with the ability to stimulate naïve CD4
T lymphocytes into different T helper subsets,T lymphocytes into different T helper subsets,
the differentiation of which is controlled bythe differentiation of which is controlled by
variety of factors, including TLR-inducedvariety of factors, including TLR-induced
cytokinescytokines
22. PhagocytosisPhagocytosis
Process by which cellsProcess by which cells
engulf microbs and particlesengulf microbs and particles
Phagocytes act as barrier toPhagocytes act as barrier to
futher spreading of largefuther spreading of large
number of bacterianumber of bacteria
24. Function of phagocytic cellsFunction of phagocytic cells
MigrationMigration
ChemotaxisChemotaxis
IngestionIngestion
Microbial killingMicrobial killing
25. OpsoninsOpsonins
The phagocytosis is greatly enhanceThe phagocytosis is greatly enhance
by opsoninsby opsonins
OPSONINS are molecules whichOPSONINS are molecules which
create bridge between microbe andcreate bridge between microbe and
receptors on the membranes onreceptors on the membranes on
phagocytes (Fc- for Ig, C3b –forphagocytes (Fc- for Ig, C3b –for
complement)complement)
26. Ingestion of microbe has a followingIngestion of microbe has a following
effect in phagocytic granulocytes:effect in phagocytic granulocytes:
Oxigen consuption increases and thereOxigen consuption increases and there
increased generation of superoxide anionincreased generation of superoxide anion
O2- and increased releasing of H2O2O2- and increased releasing of H2O2
Glycolysis increases via hexoseGlycolysis increases via hexose
monophosphate shuntmonophosphate shunt
Lysosomes rupture and their hydrolyticLysosomes rupture and their hydrolytic
enzymes are discharged into theenzymes are discharged into the
phagolysosomephagolysosome
27. PhagocytosisPhagocytosis
Granulocytes`also conteinGranulocytes`also contein
granules composed ofgranules composed of
lysozyme, other hydrolyticlysozyme, other hydrolytic
enzymes, cationic proteins,enzymes, cationic proteins,
defensinsdefensins
They take part in nonoxidativeThey take part in nonoxidative
mechanism of killingmechanism of killing
28. There are 3 types of INFThere are 3 types of INF
Type I is` induced by PRR signalingType I is` induced by PRR signaling
Plays a major role in innate antiviralPlays a major role in innate antiviral
defensedefense
Consits of INF-Consits of INF- ΑΑ andand ΙΝΙΝF-F- ββ
INF-INF- ΑΑ produced by leucocytesproduced by leucocytes
ΙΝΙΝF-F- ββ produced by fibroblastsproduced by fibroblasts
29. INFINF
INF-INF- γγ belongs to type IIbelongs to type II
It is produced by T lymphocytes andIt is produced by T lymphocytes and
NK cellsNK cells
It plays a central role in activation ofIt plays a central role in activation of
macrophagesmacrophages
30. INFINF
Type III is represented by INF -Type III is represented by INF -λλ
It shares many properties with INF-IIt shares many properties with INF-I
31. INFINF
The classical function of type I INFThe classical function of type I INF
comprise antiviral activity mediated bycomprise antiviral activity mediated by
several enzymes and proteins whichseveral enzymes and proteins which
together inhibit protein synthesis, inducetogether inhibit protein synthesis, induce
RNA cleavage and interfere replicationRNA cleavage and interfere replication
I-INF also takes part in adaptive immunity:I-INF also takes part in adaptive immunity:
DC maturation is induced by INFDC maturation is induced by INF
Α/βΑ/β following stimulation with viralfollowing stimulation with viral
infectioninfection
32. The complement systemThe complement system
The complement system includes serumThe complement system includes serum
and membrane-bound poteins thatand membrane-bound poteins that
function in both innate and adaptive hostfunction in both innate and adaptive host
defense system.defense system.
Complement has several main effects:Complement has several main effects:
33. The complement systemThe complement system
1. Lysis of cells1. Lysis of cells
2.Production of mediators that participate2.Production of mediators that participate
in inflammation and attract phagocytosisin inflammation and attract phagocytosis
3. Opsonisation of organisms and immune3. Opsonisation of organisms and immune
complex for clearance by phagocytosiscomplex for clearance by phagocytosis
4. Enhancement of antibody-mediated4. Enhancement of antibody-mediated
immune responseimmune response
34. The complement systemThe complement system
Complement proteins are synthesizedComplement proteins are synthesized
mainly by the liver and by phagocytic cellsmainly by the liver and by phagocytic cells
35. Classic pathwayClassic pathway
The formation immune complex antigen-The formation immune complex antigen-
antibody is needed for activationantibody is needed for activation
Ag-ab complex bound to C1 activatesAg-ab complex bound to C1 activates
C1s, which cleaves C4 and C2 to formC1s, which cleaves C4 and C2 to form
C4bC2bC4bC2b
C4bC2b is an active C3 convertase,whichC4bC2b is an active C3 convertase,which
cleaves C3 unto 2 fragment: C3a and C3bcleaves C3 unto 2 fragment: C3a and C3b
C3a is anaphylotoxinC3a is anaphylotoxin
36. Classic pathwayClassic pathway
C3b forms`a complex with C4bC2b whichC3b forms`a complex with C4bC2b which
cleaves C5 into C5a and C5bcleaves C5 into C5a and C5b
C5a is anaphylotoxin and chemotacticC5a is anaphylotoxin and chemotactic
factorfactor
C5b binds to C8 and C7 to form a complexC5b binds to C8 and C7 to form a complex
that insert into membrane belayerthat insert into membrane belayer
C8 then binds to the C5b/C6/C7 followedC8 then binds to the C5b/C6/C7 followed
by polymerization of up to C9 to produceby polymerization of up to C9 to produce
membrane attack complexmembrane attack complex
37. Classic pathwayClassic pathway
The membrane attack complex forms aThe membrane attack complex forms a
chenal or pore in the membrane andchenal or pore in the membrane and
causes cytolysis by allowing free passagecauses cytolysis by allowing free passage
of water across the cell membraneof water across the cell membrane
38. The alternative pathwayThe alternative pathway
C3 is cleaved via action of factors B,D andC3 is cleaved via action of factors B,D and
properdinproperdin
the alternative C3convertasethe alternative C3convertase
(C3bBb)generates more C3b.(C3bBb)generates more C3b.
The additional C3b binds to C3convertaseThe additional C3b binds to C3convertase
to formto form C3bBb C3b which is alternative C5C3bBb C3b which is alternative C5
convertase, that generatesconvertase, that generates C5b,C5b, leading toleading to
production of the membrane attackproduction of the membrane attack
complexcomplex
39. The alternative pathwayThe alternative pathway
The alternative pathway is very importantThe alternative pathway is very important
as a first line of defense against infectionas a first line of defense against infection
of microbsof microbs
The alternative pathway can be activatedThe alternative pathway can be activated
by microbial surface and proceeds in theby microbial surface and proceeds in the
absence of antibodiesabsence of antibodies
40. Mannan-binding lectine pathwayMannan-binding lectine pathway
Mannan-binding lectine (Mbl) isMannan-binding lectine (Mbl) is
component of plasmacomponent of plasma
(Mbl) binds to sugar residues like(Mbl) binds to sugar residues like
mannose found in microbial surfacemannose found in microbial surface
polysaccharides such LPSpolysaccharides such LPS
The (Mbl) when bound to microbialThe (Mbl) when bound to microbial
surface can activate C4 and C2surface can activate C4 and C2
The rest of this pathway is the same asThe rest of this pathway is the same as
the classic pathwaythe classic pathway
41. Biological effects of complementBiological effects of complement
1.1. OpsonizatiionOpsonizatiion Cells, ag-abCells, ag-ab
complexes`are phagocytosed morecomplexes`are phagocytosed more
efficiently in the presence of C3b, becauseefficiently in the presence of C3b, because
of the presence C3b receptors on theof the presence C3b receptors on the
surface of phagocytessurface of phagocytes
2.2.ChemotaxusChemotaxus C5a stimulates movementC5a stimulates movement
of neutrophils and monocytes towardsof neutrophils and monocytes towards
sites of antigen depositionsites of antigen deposition
42.
43. Biological effects of complementBiological effects of complement
3.3. Anaphylotoxins C3a and C5aAnaphylotoxins C3a and C5a cancan
produse increased vascular permeabilityproduse increased vascular permeability
and smooth muscle contraction. They alsoand smooth muscle contraction. They also
stimulate mast cells to realize histaminestimulate mast cells to realize histamine
4.4. CytolysisCytolysis Insertion of the C5b6789Insertion of the C5b6789
complex into cell surface leads to killing orcomplex into cell surface leads to killing or
lysis of many tipes of cells includinglysis of many tipes of cells including
erythrocytes, bacteria and tumor cellserythrocytes, bacteria and tumor cells
44. Active phase proteinsActive phase proteins
C-reactive protein (CRP)C-reactive protein (CRP) is found in blood.is found in blood.
The level of which rises in response toThe level of which rises in response to
inflammationinflammation
Its role is to bind to phosphocholine expressedIts role is to bind to phosphocholine expressed
on the surface of dead or dying cells and someon the surface of dead or dying cells and some
types of bacteria in order to activate thetypes of bacteria in order to activate the
complement systemcomplement system
CRP ia synthesized by liver in response to factorCRP ia synthesized by liver in response to factor
released by macrophages and mast cellsreleased by macrophages and mast cells
CRP was the first PRRCRP was the first PRR
45. Active phase proteinsActive phase proteins
Collectins are soluble PRRCollectins are soluble PRR.. Their function is toTheir function is to
bind to oligosaccharide structure or lipids, whichbind to oligosaccharide structure or lipids, which
are on the surface of microbesare on the surface of microbes
Like other PRR they bind PAMP ofLike other PRR they bind PAMP of
oligosaccharide originoligosaccharide origin
Binding may trigger elimination of microbs byBinding may trigger elimination of microbs by
aggregation, complement activation,aggregation, complement activation,
opsonization or ingibition of microbial growthopsonization or ingibition of microbial growth
CollectinsCollectins are collagen-containing C typeare collagen-containing C type
lectineslectines
