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!. !. LYMPHOID ORGANS. Prim a r y lymphoid organs : - B one marrow - T hymus. Secondary lymphoid organs: - S pleen - Lymphatic vessels - L ymph node s - Adenoids and t onsils - MALT (Mucosal Associated Lymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) - PowerPoint PPT Presentation
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Primary lymphoid organs:
- Bone marrow- Thymus
Secondary lymphoid organs:
- Spleen- Lymphatic vessels- Lymph nodes- Adenoids and tonsils- MALT (Mucosal Associated Lymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) BALT (Bronchus Associated Lymphoid Tissue) SALT (Skin Associated Lymphoid Tissue)
NALT (Nasal Associated Lymphoid Tissue)
LYMPHOID ORGANS!!
THE TWO ARMS OF THE IMMUNE SYSTEMTHE TWO ARMS OF THE IMMUNE SYSTEM
Monocytes, Macrophages, Dendritic cells, Granulocytes, NK cells and Complement components
B and T cellsMonocytes, Macrophages, Dendritic cells, Granulocytes, NK cells and Complement components
!!
Professional phagocytic cellsmacrophagesneutrophyl granulocytesdendrtitic cells
the phagocytosed cells or molecules may modify the functions of the cell
phagocytosis followed by enzymatic degradation
Professional antigen presenting cellsmacrophagesB lymphocytesdendrtitic cells
they express MHCII molecules
the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules
!!
!!
Cells of innate immune system:
Macrophages:Macrophages are constitutively present in tissues and recognize microbes that enter these tissues and respond rapidly to these microbes. Initiate the immune response•These cells are phagocytes (eliminate the pathogens)•Activate the innate immune response (by secreted proteins, called cytokines)•Activate the adaptive immune system. Macrophages serve as APCs that display antigens to and activate T lymphocytes
•Dendritic cellsare constitutively present in tissues and recognize rapidly microbes that enter these tissues. Initiate the immune response.•They have phagocytic capabilities migrate to lymph nodes, and display microbial antigens to T lymphocytes,professional antigen presentimg cells (APC)
Neutrophil granulocytes
are phagocytes, the main function to eliminate the pathogens
Appear only in the circulation under normal condition
Main actors In inflammatory processes
!!
Infection
Phagocyte activation
How do immunocytes communicate:Soluble mediators
CYTOKINES & CHEMOKINESSoluble proteinsproduced by cells. They have strong effect on the function of other cells. Bit similar to hormones.
How do immunocytes communicate:Cell-cell interaction
Cell-cell communication takes place commonly in all the phases of the immune response
T
CTL
T
BY
Antibody productionActivation of accessory cellsDendritic cell macrophage
Antigen presentation
Target cell
Cell killing
The most important mediators of indirect cell communication in the immune system („hormones” of the immune system).
Act in low concentrations.
Cytokines can affect in an autocrine way, in a paracrine way, or in an endocrine way
pleiotropic effect.
Cytokines can act by synergistic or antagonistic ways to each other. A given cell may by affected by many cytokines resulting in the same effect redundant effect.
- The responsiveness of the given cell is based on the expression of cytokine-specific receptors.
THE MOST IMPORTANT FEATURES OF CYTOKINESTHE MOST IMPORTANT FEATURES OF CYTOKINES
!
Cytokines can be devided into sub-groups by origin and functional properties.
Functional groups:
Inflammatory cytokinesDirect the development and maturation of immune cellsDirect activation and differentiation of immune cells
hormons
cytokines
chemokine
interleukins
interferons
Categories of cytokinesCategories of cytokines
General schema of receptor funtion
MOLECULES OF THE IMMUNE SYSTEM
Most important receptors of the imune system
•receptors (BCR, TCR, MHCI, MHCII, PRR, etc.)
Soluble molecules:
• cytokines
• antibodies
• complement components
Receptors responsible for the recogniton of pathogens in the immune system
Caracteristics of innate immune system,macrophage, dendritic cells
PRR Pattern recognition receptors
Danger signal and Pathogen recognition mainly in the innate immun system
B cells BCR (B cell receptor) Antigen recognition of B cell
T cells TCR (T cell receptor) Antigen recognition of T cell
All nucleated cells in human
MHC (MHCI) Major Histocompatibility Complex
Do not recognise pathogens, but present intracellular peptides required for T cell receptor
professional antigen presenting cells:macrophages, DC, B cells
MHCII Do not recognise pathogens, but present extracellular peptides required for T cell receptor
INNATE IMMUNITY I
Physical and chemical barriers
pH of 3-4 Pepsin
Stomach
Skin
Tight junctions Keratin layer Antibacterial peptides; Defensins pH of 5.5 Fatty acids
Burns and susceptibility to infections!
pH of 3.8-4.5 Lactobacillus Lactic acid
Vagina
Eye Tear film (Oils, lactoferin, mucin and
lyzosyme)
Respiratory tract
Impaired cilia movement (CF)!
Cilliary movement Coughing, sneezing
Monocite / Monocite / macrofagmacrofag
e e DCDC Mast Mast
cellcellGranulo-Granulo-
citescites NK cellNK cell B cellB cell T cellT cell Comple-Comple-mentment
Recogni-tion
Cell-cel(APC)
Communication
Soluble
effector function
INNATE IMMUNITYPathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins,
NLRs and RIG-I helicases)
Phagocytosis, effector functions
Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins
Extracellular – on surface MHC II complex proteins
Recognition is inevitableRecognition is inevitable
Innate immunity as a first line of defence
Innate immune cells recognize frequently found structures of pathogens,
these are not found in human cells!
Examples: duple strain RNA bacterial cell wall components bacterial flagellin….
!!
Danger signal!The innate immune system also recognizes molecules that are released from damaged or necrotic cells. Such molecules are called damage-associated molecular patterns (DAMPs).
!!
Recognition is inevitableRecognition is inevitable
Innate immunity as a first line of defence
Innate immune cells recognize frequently found structures of pathogens,
these are not found in human cells!
Examples: duple strain RNA bacterial cell wall components bacterial flagellin….
!!
PAMPs- Pathogen associated molecular pattersStructures on pathogens recognized by the innate cells
PRR types
TOLLRIG like receptorsNOD
Scavanger receptors
C type lectin receptors
Mannose recognizing receptors
MaMaccrorophage/Dendritic cellphage/Dendritic cell
TLR5TLR5
FlageFlagelllinlin
VViirusrus
TLR3TLR3
ddssRNARNA
TLRs RECOGNIZE VARIOUS MICROBIAL STRUCTURES
TLR2TLR2
PeptidoglycanePeptidoglycane
Gram+
TLR4TLR4
LPSLPS
TLR6TLR6
Gram-
InterferonInterferonproducing cellproducing cellPC/DCPC/DC
IFN
BaBacctteeririaa
CpG DNACpG DNA
TLR9TLR9TLR7TLR7TLR8TLR8
ssRNSssRNS
TLR receptors:
• Intracellular and cell surface sensors.• Viral RNA, non-methylated DNA characteristic of bacteria, bacterial flagella, bacterial surface components (lipoproteins, peptidoglicans) and fungi structures.• Partial overlapping recognition between NOD and RIG like receptors.
TLRs Ligands: Microorganism recognized:
Cells carrying receptor:
Cellular location:
TLR1:TLR2Lypopotreins
lypoteichoic acid proteoglycan
zymosam
BacteriaParasites
DCs, mono, Eos/Baso, mast
cells
Plasma mem.
TLR2:TLR6 -”-G+ Bacteria
Fungi -”- Plasma mem.
TLR3 dsRNA Viruses NK cells Endosomes
TLR4:TLR4 LPS G- Bacteria Mϕ, DCs Plasma mem.
TLR5 Flagellin Motile Bacteria Intestinal Epi. Plasma mem.
TLR7 ssRNA VirusespDCsB cells
Eos/BasoEndosomes
TLR8 ssRNA Viruses NK cells Endosomes
TLR9Unmethylated
CpG-ODN (ssDNA)
BacteriaViruses
pDCsB cells
Endosomes
NOD like receptors
NOD-like receptors:• Intracellular receptors.• Recognizing intracellular pathogen and danger signals.• Partial overlapping recognition with TLRs.
RIG receptors:
•Intracellular sensors.
•Recognizing viral RNA, inducing an anti-viral response.
•Partial overlapping recognition with TLRs.
Additional PRRs:
EEukarukaryotesyotes
GlucosamineGlucosamine
MannMannoseoseGalactoseGalactoseSiallic acidSiallic acid
MannMannózóz
ProkaryotesProkaryotes
Macrophage / Dendritic cellMacrophage / Dendritic cell
MannMannose receptorsose receptors
BaBacteriucteriumm
MannMannoseose
direct connetion between innate cells
and pathogen)(
Specificity of innate immunity
Few receptors (20-30) are responsible for the recognition of all the pathogens
!
OPSONIZATIONOPSONIZATION ! !
Main opsonins:antibodiesComplement fragmentsAcute-phase proteins
Opsonization facilitate and accelerate the recognition of the pathogen by phaogocytes,opsonins form a bridge between pathogen and a phagocyte connecting them.
Soluble mediators
Pathogen recognition by innate immune system 1. Directly via PRR
2. Indirectly via opsonization
INNATE IMMUNITYPathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins,
NLRs and RIG-I helicases)
Effector functions, elimination of pathogens
Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins
Extracellular – on surface MHC II complex proteins
INNATE IMMUNITY II
Effector functions, elimination of pathogens
1. Phagocytosis2. Killing with soluble mediators
3. Complement system4. NK cell activation
!!
DegradationACTIVATION
Uptake
PHAGOCYTOSIS
Phagocyte
PRR
0.5 - 1 hours
The amount of internalized particles is limited
Bacterium
Intracellular killing
Antigen presentationT cell
ACQUIRED IMMUNITY
THE PHTHE PHAGOCYTAGOCYTICIC SYSTEM SYSTEM
MACROPHAGMACROPHAGES ES DENDRITIC CELLDENDRITIC CELLS NEUTROPHILSS NEUTROPHILS
Phagocytic cellsPhagocytic cells
-MacrophagesMacrophages
-DendritiDendritic cellsc cells
-NeutroNeutrophilphil granuloc granulocytes ytes
(No presentation on MHC II)(No presentation on MHC II)
Professional Professional
antigen presenting cells antigen presenting cells
-MacrophagesMacrophages
-DendrDendritic cellsitic cells
- B lymphocytesB lymphocytes
(no killing action, only Ag presentation)(no killing action, only Ag presentation)
PHAGOCYTOSIS
Extracellular pathogen phagocytosis and killing
Extracellular pathogen phagocytosis and killing
Soluble mediators reeased from macrophages, granulocytes are responsible for kiliing of extracellular pathogens
ROS reactive oxigen speciesNO nitric oxide
Destructive enzymes, antimicrobial substances
2.
Intracellular bacterial evasion ofkilling in phagocytes
Defensins
Phagosome acidification
Phagosome–lysosome fusionLysosomal enzymes
Intraphagolysosomal killing
ROI
RNI
Iron starvation
Tryptophan starvation
Macrophage effector capacity
Lysis of bacteria
COMPLEMENT ACTIVATION
InflammationChemotaxis
Complement-dependent phagocytosis
Bacterium
COMPLEMENT
Lectin pathwayAlternative
pathway
Antigen + Antibody
ACQUIRED IMMUNITY
Complement-proteins
Few minutes – 1 hour
Enzymes get fragmented, complement activity can be exhausted
3.
NK cellsMajor differences between NK cells and B/T lymphocytes:
Contain large cytoplasmic granules.
Responds fast, circulate in a partly activated state.
Do not express surface receptors produced by rearranged genes.
Have a range of cell-surface receptors that deliver activating or inhibitory signals
Have two main types of receptors: Ig-like Rs and the Lectin-like Rs (inhibitory and activating) that recognize altered cell surface proteins as a result of a virus infection.
Overall balance of inhibitory or activating signals decides if the NK cell killing action will take place.
Individual NK cells express different combinations of receptors- heterogeneity repertoire of responses to pathogens.
Killing of the cells infected with intracellular pathogens
KAR KIR
KIR – Killer Inhibitory Receptor association to MHC I
KAR – Killer Activatory Receptor
NK
TargetMHC+
NK
KAR KIR
TargetMHC-
!
1. The activity of NK cells is enhanced by activatory receptors
2. Inhibitory receptors block NK cell activity. Self cells are protected by inhibitory receptors.
3. Infection or tumors may increase the amount of activation and/or decrease the efficacy of inhibition
Inhibition of lysis
lysis
Adaptive components are also able to activate NK cells
ADCC-Antibody Dependent Cell Cytotoxicity
Activating NK cells through FcR on NK cells recognizing pathogen-bound Antibodies
Lysis of infected cell
ACTIVATION OF NATURAL KILLER CELLS
Kinetics of the activity of the complement system and NK
cells in virus infection
IFNIL-12
2 4 6 8 101 3 5 7 9 1211 13
Complement system
NK-cells
days
Rel
atív
szi
nt/a
ktiv
itás
NK-CELLS
Virus-infectedcell
PRR
RECOGNITIONACTIVATION
RECOGNITION OF ALTERED HOST CELLS
RECOGNITION RECEPTORECOGNITION RECEPTORRS, SIGNAL TRANSDUCTION, S, SIGNAL TRANSDUCTION, PHAGOCYTOSISPHAGOCYTOSIS, , EFFECTOR MECHANISMEFFECTOR MECHANISM
Pattern recognitionReceptors (PRRs)
Engagement of PRRs triggers phagocytosis
and cytokine production
INNATE IMMUNITYPathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins,
NLRs and RIG-I helicases)
Phagocytosis, effector functions
Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins
Extracellular – on surface MHC II complex proteins
Recognition of PAMP or DAMP induce inflammation
NK-cellIL-12
macrophageIFNcytokines
neutrophilTNF-
INFLAMMATION – ACUTE PHASE RESPONSE
hrs
Pla
sma
leve
l
1 2 3 4 5
LPS (endotoxin) (Gram(-) bacteria)
TNF-
IL-1IL-6
Kinetics of the release of pro-inflammatory cytokines in
bacterial infection
TNF-IL-1IL-6
Few hours
ACUTE PHASE RESPONSE
Bacterium
LPS
DANGER SIGNAL
ACTIVATION
PRR
Reminder
INNATE IMMUNITYPathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins,
NLRs and RIG-I helicases)
Phagocytosis, effector functions
Communication/ Antigen presentation Intracellular – on surface MHC I complex proteins
Extracellular – on surface MHC II complex proteins
INTERFERON RESPONSEINTERFERON RESPONSE
Besides virus infected cells..
Plasmacytoid dendritic cells (pDCs) produce 1000x more type I interferon than other cells
NATURAL INTERFERON PRODUCING CELLS – IPC
After viral infection they are accumulated at the T cell zone of the lymph nodes
EFFECTS OF TYPE I INTERFERONS
vírus
Activate cellular genes that destroy viral mRNA and inhibit translation of
viral proteins
NK cells have a basal cytotoxicity level that is
increased up to x100 fold with the exposure to type I IFNs and produce IFN-γ when
exposed to IL-12
Helping the initiation of effector T cells- adaptive immune
response.
paracrine
autocrine
Infected cell
subtypes
IFN-
IFN-
IFN response
IRF-3
IRF-7
Virus
IFN-
IFN-
NFBAP-1
Type I IFN receptor
IFN response
VIRUS INDUCED TYPE I INTERFERON PRODUCTION
IRF: interferon regulatory factor
IRF-3
TRIF
TANK
IKKε TBK1
IRF-3
TRIF
TRAM
TLR3
TLR4
MyD88
IRF-5
TLR7TLR8TLR9
IFN-β, IFN-α1
RIG-1
Stimulation of Ig-productionby B-cells
Type I interferon receptor
IRF-7
Increased cytotoxicity and proliferation of NK-cells
Activation of - and γδ T-cells
Increased antigen presentationin myeloid dendritic cells
IRAK-1
TRAF-6
IRF-7
MULTIPLE EFFECTS OF TYPE I INTERFERONS
on immune cells
INTERFERON EFFECTOR PATHWAYSinduction of the „antiviral state”
1. Mx GTPase pathway– block viral transcription
2. 2',5'-oligoadenylate-synthetase (OAS) -directed Ribonuclease L pathway
– degrade viral RNA
3. Protein kinase R (PKR) pathway (Ser/Thr kinase, dsRNA-dependent)
– inhibit translation, preventing viral protein synthesis
4. ISG15 ubiquitin-like pathway– modify protein function
CELLULAR GENES THAT CONTROL ALL STEPS OF VIRAL REPLICATION
Plasma membrane
Cytoplasm
Type I. IFN receptor Type II. IFN receptorType III. IFN receptor (IFNλ)
TYK2 JAK1TYK2 JAK1
JAK2
JAK1JAK1
JAK2
STAT1STAT1
STAT2
Nucleus
STAT1 STAT2P
P
STAT1 STAT2P
P
STAT1STAT1 PP
STAT1STAT1 PP
IRF9
ISREISRE GAS – promoter elementsGAS – promoter elements
Antiviral immunity Antimycobacterial immunity
ISG15, Mx,OAS and
PKR
IL-10R2IFNLR1IFNAR1/2 IFNG1/2
Interferon-stimulated genes
Interferon-stimulated Regulatory elements
ISGF-3
GAS: Gamma Activating sequence
Signal Transducers and Activators of Transcription
Oligomer accumulationin cytoplasmic
membranes(e.g. ER)
(Nucleus)
(Cytoplasm)
ISRE MxA
MxA monomer
MxA oligomer
Trapped viralcomponents
(Nucleus)
(Cytoplasm)
ISRE OAS1
Inactive OAS1 monomer
Induction byviral dsRNA
Active OAS1 tetramer
synthetized pppA(2’p5’A)ninactive
RNaseLmonomer
active RNaseLdimer
cleaved RNA
(Nucleus)
(Cytoplasm)
ISRE PKR
Inactive PKR monomer
Active PKR dimer
Induction byviral RNAs
EIF2 EIF2P Inhibition of
translation
Mechanism of action of Mechanism of action of MxA, OAS1 and PKRMxA, OAS1 and PKR
NK-cellIL-12
macrophageIFNcytokines
neutrophilTNF-
INFLAMMATION – ACUTE PHASE RESPONSE
hrs
Pla
sma
leve
l
1 2 3 4 5
LPS (endotoxin) (Gram(-) bacteria)
TNF-
IL-1IL-6
Kinetics of the release of pro-inflammatory cytokines in
bacterial infection
TNF-IL-1IL-6
Few hours
ACUTE PHASE RESPONSE
Bacterium
LPS
DANGER SIGNAL
ACTIVATION
PRR
Reminder
RECEPTORS ON MACROPHAGES
TLR4 + CD14
MHCI
MHCII
TLR – pathogen pattern
CR1 (CD35)
CR3 (CD11b/CD18)
LFA1 (CD11a/CD18)
FcRIII (CD16)
FcRII (CD32)
FcRI (CD64)
Ag + IgG complex
Mannose receptor
Scavanger receptor
FcRs
RECEPTOR LIGAND FUNCTION
FcR IgG, IgE Opsonized phagocytosis, ADCC, release of inflammatory mediators
CR3 iC3B, ICAM-1 Opsonized phagocytosis
Macrophage Mannose Receptor
Lectin Endocytosis, phagocytosis, antigen capture and transport
SR-A LPS, polianions, lipoteikolic acid
Endocytosis, phagocytosis, adhesion
CD14 LPS Transduces LPS activation , TNFa release
CCR1 MIP1a, MCP-3 Recruitment, migration of monocytes
CCR3 Eotaxin Haematopoiesis, HIV-1 coreceptor
CCR5 MIP1 Haematopoiesis, HIV-1 coreceptor
CXCR4 SDF-1a Haematopoiesis, HIV-1 coreceptor
Receptors and molecules of macrophages
INNATE IMMUNITYPathogen recognition PRRs (TLRs, C type lectins, Mannose and Glucan binding lectins,
NLRs and RIG-I helicases)
Cell activation Increase in MHC, co-stimulation, killing efficiency (ROI, NO, lysosomal enzymes) and cytokine secretion
Phagocytosis and Antigen processing Intracellular – degradation in Proteosomes
Extracellular – Endiocytosis then degradation in Phagolysosomes
Antigen presentation Intracellular – on surface MHC I complex proteins
Extracellular – on surface MHC II complex proteins