Innate immunity

iMMUNOLOGY

1. INNATE IMMUNITYINNATE IMMUNITY
Professor BoychenkoProfessor Boychenko

2. Innate immunityInnate immunity Adaptive Adaptive
immunityimmunity
specificityspecificitynonspecificnonspecific specificspecific
Immune Immune
memorymemory
Absence ofAbsence of
Immune memoryImmune memory
ImmuneImmune
memorymemory
SecondarySecondary
Immune Immune
responseresponse
Not improve byNot improve by
Repeated infectionRepeated infection
Improved byImproved by
RepeatedRepeated
infectioninfection
recognitionrecognitionPattern recognition Pattern recognition
receptorsreceptors
Antigen-specificAntigen-specific
Receptors on Receptors on
lymphocyteslymphocytes

3. Innate immunityInnate immunityAdaptive Adaptive
immunityimmunity
Sites of Sites of
recognitionrecognition
Patogen-assotiated Patogen-assotiated
molecular patterns molecular patterns
(PAMP)(PAMP)
Antigen’sAntigen’s
determinantsdeterminants
cellscells Phagocytes,NK,Phagocytes,NK,
APC-C,eosinophilsAPC-C,eosinophils
T,B cellsT,B cells
SolubleSoluble
factorsfactors
Complement, acute Complement, acute
phase proteins, phase proteins,
CRP, CRP,
lysozyme,interferonlysozyme,interferon
,collectins,collectins
antibodyantibody

4. physical and chemical barriersphysical and chemical barriers
The innate immunity (I.I) is based on The innate immunity (I.I) is based on
physical and chemical barriers.physical and chemical barriers.
This defense mechanism are represented This defense mechanism are represented
by :by :
epidermis, epidermis,
ciliated reapiratory epithelium, ciliated reapiratory epithelium,
vascular endothelium and vascular endothelium and
mucosed surface with antimicrobial mucosed 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, in in respirotary and cervical secretion, in
mucous membranes mucous membranes
3.Salive contains hydrolytic enzymes 3.Salive contains hydrolytic enzymes
4. Acidity of stomach4. Acidity of stomach
5. normal flora 5. normal flora

6. innate immune systeminnate immune system
The important ability of the innate system The important ability of the innate system
to recognize and limit microbes early to 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 PRR of PRR

7. innate immune systeminnate immune system
The innate immune system The innate immune system
constitutes the first line of host constitutes the first line of host
defense and plays crucial role defense and plays crucial role
in the early recognition and in the early recognition and
subsequent triggering of subsequent triggering of
proinflammatory response to proinflammatory response to
pathogenpathogen

8. Adoptive responseAdoptive response
Adoptive response is Adoptive response is
characterized by specifity characterized by specifity
developed by clonal gene developed by clonal gene
arragements from a broad arragements from a broad
repertour antigen specific repertour antigen specific
receptors on lymphocytesreceptors on lymphocytes

9. innate immune systeminnate immune system
The innate immune response is mediated The innate immune response is mediated
by phagocytic cells and by phagocytic cells and
antigen presenting cells (APC) such as antigen presenting cells (APC) such as
macrophages and dendritic cells (DC)macrophages and dendritic cells (DC)
And has been regarded as relatively And has been regarded as relatively
nonspecificnonspecific

10. innate immune systeminnate immune system
The innate immune response relies on The innate immune response relies on
recognition of evolutionary conserved recognition of evolutionary conserved
structures on pathogens termedstructures on pathogens termed
Pathogen-associated molecular patterns Pathogen-associated molecular patterns
(PAMPs)(PAMPs) through a limited number of through a limited number of
germ line encoded germ line encoded pattern recognition pattern 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 cell PRR may present either on the cell
surface or intracellularlysurface or intracellularly
After interaction with PAMP, they trigger After interaction with PAMP, they trigger
proinflammatory and antimicrobial proinflammatory and antimicrobial
response by activating of intracellular response by activating of intracellular
signaling pathway including adaptor signaling pathway including adaptor
molecules, kinases, and transcription molecules, kinases, and transcription
factorsfactors

12. The family of TLR is the major The family of TLR is the major
class of PRRclass of PRR
The family of TLR can be devided into The family of TLR can be devided into
subfamilies: subfamilies:
TLR1 , TLR2, TLR4 , TLR6 recognize TLR1 , TLR2, TLR4 , TLR6 recognize
lipidslipids
TLR3 , TLR7, TLR8 , TLR9 recognize TLR3 , 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 and are expressed at membrane and
mainly recognize bacterial mainly recognize bacterial
products unique to bacteria and products unique to bacteria and
not produced by the hostnot produced by the host

14. TLRTLR
TLR 3,7,8,9 are located TLR 3,7,8,9 are located
almost exclusively in almost exclusively in
intracellular compartments intracellular compartments
including lysosomes and are including lysosomes and are
specialized in recognition of specialized in recognition of
nucleic acidsnucleic acids

15. TLR-independent recognitionTLR-independent recognition
TLR-independent recognition of TLR-independent recognition of
pathogens is accomplished by a large pathogens is accomplished by a large
group of cytosolic PRRs which can be group of cytosolic PRRs which can be
broadly divided into retinoid acid-inducible broadly divided into retinoid acid-inducible
gene I (Rig-I) like receptors andgene I (Rig-I) like receptors and
Nucleotide binding oligomerization domain Nucleotide binding oligomerization domain
(NOD)-like receptors(NOD)-like receptors

16. TLRTLR
The most important cell types expressing The 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 lipoteichoic Grampositive 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 in Unmethylated CpG DNA present in
both virus and bacteria as opposed to both virus and bacteria as opposed to
methylated DNA present in mammalia methylated DNA present in mammalia
cellscells

18. Principles in innate signal Principles in innate signal
transductiontransduction
Signal transduction is mediated by a Signal transduction is mediated by a
family of adaptor moleculesfamily of adaptor molecules
Recruitment of adaptive molecules to a Recruitment of adaptive molecules to a
given TLR is followed by activation of given TLR is followed by activation of
downstream signal transduction pathway downstream signal transduction pathway
via activation of transcription factors which via activation of transcription factors which
regulate expression of genes involved in regulate expression of genes involved in
inflammation and antimicrobial defenseinflammation and antimicrobial defense


19. Principles in innate signal Principles in innate signal
transductiontransduction
NF-kbNF-kb plays central role in induction of plays central role in induction of
proinflammatory response, causing proinflammatory response, causing
production of cytokines and IFNs production of cytokines and IFNs

20. Principles in innate signal Principles in innate signal
transductiontransduction
There is important link between innate and There is important link between innate and
adaptive immunity provided by PRR adaptive immunity provided by PRR
particularly via TLR-mediated maturation particularly via TLR-mediated maturation
of DC and activation of pathogen specific of DC and activation of pathogen specific
T-lymphocytesT-lymphocytes


21. Principles in innate signal Principles in innate signal
transductiontransduction
Following antigen uptake by DC, DC become Following antigen uptake by DC, DC become
activated and migrate to regional lymph nodes to activated and migrate to regional lymph nodes to
present antigenic peptides in the context of present antigenic peptides in the context of
revelant MHC molecules.revelant MHC molecules.
After having undergone maturation DC are After having undergone maturation DC are
endowed with the ability to stimulate naïve CD4 endowed 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 by the differentiation of which is controlled by
variety of factors, including TLR-induced variety of factors, including TLR-induced
cytokinescytokines

22. PhagocytosisPhagocytosis
Process by which cells Process by which cells
engulf microbs and particlesengulf microbs and particles
Phagocytes act as barrier to Phagocytes act as barrier to
futher spreading of large futher spreading of large
number of bacterianumber of bacteria

23. PhagocytesPhagocytes
Polymorphonuclear Polymorphonuclear
phagocytes (PMN)phagocytes (PMN)
Phagocytic monocytes Phagocytic monocytes
(macrophages)(macrophages)
Fixed macrophages of Fixed macrophages of
reticuloendothelial systemreticuloendothelial system

24. Function of phagocytic cellsFunction of phagocytic cells
MigrationMigration
ChemotaxisChemotaxis
IngestionIngestion
Microbial killingMicrobial killing

25. OpsoninsOpsonins
The phagocytosis is greatly enhance The phagocytosis is greatly enhance
by opsoninsby opsonins
OPSONINS are molecules which OPSONINS are molecules which
create bridge between microbe and create bridge between microbe and
receptors on the membranes on receptors on the membranes on
phagocytes (Fc- for Ig, C3b –for phagocytes (Fc- for Ig, C3b –for
complement)complement)

26. Ingestion of microbe has a following Ingestion of microbe has a following
effect in phagocytic granulocytes:effect in phagocytic granulocytes:
Oxigen consuption increases and there Oxigen consuption increases and there
increased generation of superoxide anion increased generation of superoxide anion
O2- and increased releasing of H2O2O2- and increased releasing of H2O2
Glycolysis increases via hexose Glycolysis increases via hexose
monophosphate shuntmonophosphate shunt
Lysosomes rupture and their hydrolytic Lysosomes rupture and their hydrolytic
enzymes are discharged into the enzymes are discharged into the
phagolysosomephagolysosome

27. PhagocytosisPhagocytosis
Granulocytes`also contein Granulocytes`also contein
granules composed of granules composed of
lysozyme, other hydrolytic lysozyme, other hydrolytic
enzymes, cationic proteins, enzymes, cationic proteins,
defensinsdefensins
They take part in nonoxidative They 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 antiviral Plays a major role in innate antiviral
defensedefense
Consits of INF- Consits of INF- A A andand IN INF- F- bb
INF- INF- A A produced by leucocytesproduced by leucocytes
ININF- F- bb produced by fibroblasts produced by fibroblasts

29. INFINF
INF- INF- g g belongs to type IIbelongs to type II
It is produced by T lymphocytes and It is produced by T lymphocytes and
NK cellsNK cells
It plays a central role in activation of It plays a central role in activation of
macrophagesmacrophages

30. INFINF
Type III is represented by INF -Type III is represented by INF -ll
It shares many properties with INF-IIt shares many properties with INF-I

31. INFINF
The classical function of type I INF The classical function of type I INF
comprise antiviral activity mediated by comprise antiviral activity mediated by
several enzymes and proteins which several enzymes and proteins which
together inhibit protein synthesis, induce together 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 INF DC maturation is induced by INF
A/b A/b following stimulation with viral following stimulation with viral
infectioninfection

32. The complement systemThe complement system
The complement system includes serum The complement system includes serum
and membrane-bound poteins that and membrane-bound poteins that
function in both innate and adaptive host function 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 participate 2.Production of mediators that participate
in inflammation and attract phagocytosisin inflammation and attract phagocytosis
3. Opsonisation of organisms and immune 3. Opsonisation of organisms and immune
complex for clearance by phagocytosiscomplex for clearance by phagocytosis
4. Enhancement of antibody-mediated 4. Enhancement of antibody-mediated
immune responseimmune response

34. The complement systemThe complement system
Complement proteins are synthesized Complement 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 activates Ag-ab complex bound to C1 activates
C1s, which cleaves C4 and C2 to form C1s, which cleaves C4 and C2 to form
C4bC2bC4bC2b
C4bC2b is an active C3 convertase,which C4bC2b 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 which C3b forms`a complex with C4bC2b which
cleaves C5 into C5a and C5bcleaves C5 into C5a and C5b
C5a is anaphylotoxin and chemotactic C5a is anaphylotoxin and chemotactic
factorfactor
C5b binds to C8 and C7 to form a complex C5b 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 followed C8 then binds to the C5b/C6/C7 followed
by polymerization of up to C9 to produce by polymerization of up to C9 to produce
membrane attack complexmembrane attack complex

37. Classic pathwayClassic pathway
The membrane attack complex forms a The membrane attack complex forms a
chenal or pore in the membrane and chenal or pore in the membrane and
causes cytolysis by allowing free passage causes 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 and C3 is cleaved via action of factors B,D and
properdinproperdin
the alternative C3convertase the alternative C3convertase
(C3bBb)generates more C3b.(C3bBb)generates more C3b.
The additional C3b binds to C3convertase The additional C3b binds to C3convertase
to form to form C3bBb C3b which is alternative C5 C3bBb C3b which is alternative C5
convertase, that generatesconvertase, that generates C5b,C5b, leading to leading to
production of the membrane attack production of the membrane attack
complex complex

39. The alternative pathwayThe alternative pathway
The alternative pathway is very important The alternative pathway is very important
as a first line of defense against infection as a first line of defense against infection
of microbsof microbs
The alternative pathway can be activated The alternative pathway can be activated
by microbial surface and proceeds in the by microbial surface and proceeds in the
absence of antibodiesabsence of antibodies

40. Mannan-binding lectine pathwayMannan-binding lectine pathway
Mannan-binding lectine (Mbl) is Mannan-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 surface mannose found in microbial surface
polysaccharides such LPSpolysaccharides such LPS
The (Mbl) when bound to microbial The (Mbl) when bound to microbial
surface can activate C4 and C2surface can activate C4 and C2
The rest of this pathway is the same as The rest of this pathway is the same as
the classic pathway the classic pathway

41. Biological effects of complementBiological effects of complement
1. 1. Opsonizatiion Opsonizatiion Cells, ag-ab Cells, ag-ab
complexes`are phagocytosed more complexes`are phagocytosed more
efficiently in the presence of C3b, because efficiently in the presence of C3b, because
of the presence C3b receptors on the of the presence C3b receptors on the
surface of phagocytessurface of phagocytes
2.2.ChemotaxusChemotaxus C5a stimulates movement C5a stimulates movement
of neutrophils and monocytes towards of neutrophils and monocytes towards
sites of antigen deposition sites of antigen deposition

43. Biological effects of complementBiological effects of complement
3. 3. Anaphylotoxins C3a and C5aAnaphylotoxins C3a and C5a can can
produse increased vascular permeability produse increased vascular permeability
and smooth muscle contraction. They also and smooth muscle contraction. They also
stimulate mast cells to realize histaminestimulate mast cells to realize histamine
4. 4. Cytolysis Cytolysis Insertion of the C5b6789 Insertion of the C5b6789
complex into cell surface leads to killing or complex into cell surface leads to killing or
lysis of many tipes of cells including lysis of many tipes of cells including
erythrocytes, bacteria and tumor cells erythrocytes, 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 to The level of which rises in response to
inflammationinflammation
Its role is to bind to phosphocholine expressed Its role is to bind to phosphocholine expressed
on the surface of dead or dying cells and some on the surface of dead or dying cells and some
types of bacteria in order to activate the types of bacteria in order to activate the
complement systemcomplement system
CRP ia synthesized by liver in response to factor CRP 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 to Their function is to
bind to oligosaccharide structure or lipids, which bind to oligosaccharide structure or lipids, which
are on the surface of microbesare on the surface of microbes
Like other PRR they bind PAMP of Like other PRR they bind PAMP of
oligosaccharide originoligosaccharide origin
Binding may trigger elimination of microbs by Binding 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 type are collagen-containing C type
lectineslectines