mhc class ii-dependent presentation€¦ · the mhc class ii-like molecule hla-docan subtly...
TRANSCRIPT
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MHC class II-dependent presentation
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Processazione e presentazione degli Ag extracellulari e citosolici
APC
Risposta CD4 Risposta CD8
Si No
No Si
No Si
Trasfezione
APC
Endocitosi
APC
Shock osmotico
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I linfociti CD4 riconoscono antigeni solubili presentati in associazione con le molecole di MHC classe II
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La processazione dell’antigene richiede la vitalità della cellula
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PROLIFERATION
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La processazione dell’antigene richiede tempo
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Antigen presentation through MHC class II molecules: antigen uptake
1^ fase
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Antigen presentation through MHC class II molecules: antigen uptake
Consente l’accesso di antigeni o patogeni allevie intracellulari di degradazione.I meccanismi di uptake:-Fagocitosi-Pinocitosi e micropinocitosi-Fagocitosi mediata dal recettore Fc delleIg-Fagocitosi mediata dal recettore per ilcomplemento-Fagocitosi del complesso Ig-antigene-Fagocitosi tramite recettore specificodirigono l’antigene nei compartimentiintracellulari deposti alla degradazione. 6
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Uptake dell’antigene
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Antigen presentation through MHC class II molecules
2^ fase
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Antigen presentation through MHC class II molecules
3^ fase
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The organelles of MCH class II
presentation
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Enzimi catalitici come le catepsine
sono presenti negli endosomi
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Enzimi catalitici come le catepsine
sono presenti negli endosomi
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La clorochina come farmaco che inibisce l’acidificazione degli endosomi
Infettività da Leishmania
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La processazione dell’antigene avviene nei lisosomi
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PROLIFERATION
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Antigen presentation through MHC class II molecules
4^ fase
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La presentazione dell’antigene non richiede cellule metabolicamente attive
60 min
PROLIFERATION
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La processazione e la presentazione dell’antigene sono processi diversi
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La processazione e la presentazione dell’antigene sono processi diversi
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PROCESSING 18
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PRESENTAZIONE
La processazione e la presentazione dell’antigene sono processi diversi
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Natura degli antigeni
Determinante antigenico od epitopo parte dell’antigene che èriconosciuto da un recettore specifico: BCR dei linfociti B (anticorpo) o dal TCR
(linfociti T)
Determinante lineare
Epitopi formati da una sequenza lineare di AA (epitopi T)
Determinante conformazionale
Epitopi formati da una sequenza di AA non vicini tra loro linearmente ma giustappposti nello spazio (epitopi B)
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MHC class II molecules need to be protected by random engagement
The cell surface form of the invariant chain
is known as CD74.
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Attività dell’invariant chain
The invariant chain (Ii) is a protein which binds the peptide bindinggroove of MHC II immediately following its assembly in the endoplasmicreticulum. This provides for the preservation of MHC until the vesiclefuses with MIIC and antigen peptides are introduced.
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Attività dell’invariant chain
1^ FASE
2^ FASE
CLIP
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Attività dell’invariant chain
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Attività dell’invariant chain
3^ FASE
CLIPclass II-associated
invariant chain peptide25
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MHC class II molecules need to be protected by random engagement
At this time, HLA-DM is free to begin functioning (Janeway et al., 2005)
2-4 hrs
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HLA-DM assists in the removal of CLIP
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HLA-DM is unable to allocate a peptide
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The function of HLA-DMHLA-DM has three
main functions: 1. dissociation of
CLIP from the peptide binding groove of MHC II,
2. stabilizes and prevents degradation of the empty MHC II,
3. facilitates the binding of antigen fragments to the open, stabilized binding groove (Janeway et al., 2005).
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HLA-DM deficiency
No known human immunodeficiency is related to the absence of HLA-DM.
Zarutskie et al. (2001) report that when HLA-DM is absent or rendered non-functional due to mutation, there is an observed increase in MHC
II:CLIP complex presented on the antigen presenting cell surface.
HLA-DM is a protein exchange molecule in MHC. Non-functional HLA-DM is unable to dissociate CLIP from MHC II which is therefore not give a chance to bind with antigen peptide and present it to
CD4 T cells to elicit an immune response.
Lich et al. (2003) suggest that changing HLA-DM concentration levels within antigen presenting cells may
cause autoantigens to present on the cell surface, potentially leading to autoimmune disorders such as type I
diabetes. 30
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The peptide editing
High affinity peptides with high bindingenergy are more stable in the MHC bindinggroove while HLA-DM is present (Anderson
and Gorski, 2003).
Furthermore, HLA-DM binding to MHC IImolecules as well as catalytic peptideexchange are increased when the pH of theendosomal compartment is in the range of4.5-5.5 (Busch et al., 1998).
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The relevance of HLA-DO
The MHC class II-like molecule HLA-DO can subtly modulate the peptide repertoire loaded onto MHC class II molecules by
HLA-DM.
A new study shows that the in vivo effect of HLA-DO is to
decrease the presentation of self peptides by dendritic cells
(DCs) to T cells, which limits autoimmune responses without
affecting general immune competence.
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Altre modalità di riconoscimento dell’antigene
(presentazione non convenzionale)
1. Riconoscimento dei superantigeni
2. Presentazione MHC-indipendente
3. Presentazione attraverso la molecola CD1
4. Cross-presentazione
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Altre modalità di riconoscimento dell’antigene
(presentazione non convenzionale)
1. Riconoscimento dei superantigeni
2. Presentazione MHC-indipendente
3. Presentazione attraverso la molecola CD1
4. Cross-presentazione
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MHC-independent hapten presentation
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Altre modalità di riconoscimento dell’antigene
(presentazione non convenzionale)
1. Riconoscimento dei superantigeni
2. Presentazione MHC-indipendente
3. Presentazione attraverso la molecola CD1
4. Cross-presentazione
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CD1-mediated presentation
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CD1 presentation: how it works
• a CD1 heavy chains are assembled in the endoplasmicreticulum (ER), where they bind the chaperones calnexin,calreticulin and ERp57. They also bind b2-microglobulin (b
2m) non-covalently in the ER.
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CD1 presentation and effector activation
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Altre modalità di riconoscimento dell’antigene
(presentazione non convenzionale)
1. Riconoscimento dei superantigeni
2. Presentazione MHC-indipendente
3. Presentazione attraverso la molecola CD1
4. Cross-presentazione
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The meaning of cross-presentation
Until recently, MHC-I and MHC-II were thought to focus on thepresentation of peptides derived from distinct sources. MHC-I ligandswere derived from endogenous cytosolic proteins, whereas MHC-II ligandswere exogenous, encountering MHC-II molecules following endocytosis.Although this paradigm remains largely correct, we now know that bothboundaries can be crossed:-MHC-I can present peptides derived from exogenous antigens,-MHC-II can present intracellular antigens that do not come from theextracellular space.Although virtually all nucleated cells, not just professional or amateurAPCs, can present endogenous proteins on MHC-I, DCs (and to a far lesserextent MØ) can efficiently use exogenously obtained peptides for thispurpose: an event referred to as “cross-presentation.”Moreover, it is important to remember that only DCs can prime naive CD8+T cell responses, regardless of antigen source
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Pathways for cross-presenting antigen1. Particulate antigen is
internalizedinto phagosomes
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Pathways for cross-presenting antigen
2. phagosomes fuse with the ER
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Pathways for cross-presenting antigen
3 acquire the ER-resident antigen-presentation machinery (TAP, tapasin and MHC class I molecules)and Sec61 translocon. 46
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Pathways for cross-presenting antigen
B. Tapasin loads these peptides onto class I molecules, which are then transported to the cell surface.
A. internalized antigen is cleaved into peptides by proteases in the phagosome. 47
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Pathways for cross-presenting antigen
4. Internalized antigen is transferred
from the phagosome to the cytosol, possibly by
retro-translocation through Sec61
and ubiqitination by ubiquitin (Ub)-
conjugating enzymes(UBCs).
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Pathways for cross-presenting antigen
5. antigen is cleaved by proteasomes that associate with the phagosome membrane
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Il sistema dei fagociti mononucleati
Le cellule dendritiche
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Concetti generali
Antigeni ed immunogeniI fagociti mononucleati e le cellule
dendriticheIl sistema maggiore di istocompatibilità
La presentazione dell’antigene
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La risposta immunitaria specifica si basa su :
•il riconoscimento di piccole porzionidegli antigeni (epitopi)
•l’esistenza di molecole diistocompatibilità
•la capacità delle APC di modificare(‘processare’) l’antigene 52
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La risposta immunitaria specifica si basa su :
•il riconoscimento di piccole porzionidegli antigeni (epitopi)
•l’esistenza di molecole diistocompatibilità
•la capacità delle APC di modificare(‘processare’) l’antigene 53
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Mechanisms of immunity
Humoral response
Antibodies
Mod from Burks AW et al, JACI 2008
B cell
Cellular response
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APCs antigen-presenting cells (cellule accessorie)
Cellule che non esprimono recettori clonali (ovvero
recettori per l’antigene clonalmente distribuiti) ma che
partecipano attivamente all’avvio delle risposte
immunitarie specifiche ( non sono cellule
immunocompetenti)
Sono rappresentate dai fagociti mononucleati e dalle
cellule dendritiche
Hanno precipua funzione di captare gli antigeni e di
presentarli in modo appropriato ai linfociti T
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Le cellule accessorie
Cellule che non esprimono recettori clonali (ovvero
recettori per l’antigene clonalmente distribuiti) ma che
partecipano attivamente all’avvio delle risposte
immunitarie specifiche ( non sono cellule
immunocompetenti)
Sono rappresentate dai fagociti mononucleati e dalle
cellule dendritiche
Hanno precipua funzione di captare gli antigeni e di
presentarli in modo appropriato ai linfociti T
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Le cellule accessorie
Cellule che non esprimono recettori clonali (ovvero
recettori per l’antigene clonalmente distribuiti) ma che
partecipano attivamente all’avvio delle risposte
immunitarie specifiche ( non sono cellule
immunocompetenti)
Sono rappresentate dai fagociti mononucleati e dalle
cellule dendritiche
Hanno precipua funzione di captare gli antigeni e di
presentarli in modo appropriato ai linfociti T
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Macrophages and dendritic cells: a bridge between innate and adaptive
immunity
The phagocyte‘eats’ a bacteria
The antigen is digestedand reaches the surface
The antigen is recognized by a T cell
The T cellactivates
The dogma of Antigen processing and association with MHC 58
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Macrophages and dendritic cells: a bridge between innate and adaptive
immunity
The phagocyte‘eats’ a bacteria
The antigen is digestedand reaches the surface
The antigen is recognized by a T cell
The T cellactivates
The dogma of Antigen processing and association with MHC
The immunological
synapsis
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Il sistema delle cellule presentanti l’antigene
M.O.
M.E.
M.A scansione
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Le cellule presentanti
captare gli antigeni
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Le cellule presentanti
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Le cellule presentanti
Esprimere particolari recettori63
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Le cellule presentanti
pattugliare l’organismo
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Le cellule presentanti
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Concetti generali
Antigeni ed immunogeniI fagociti mononucleati e le cellule
dendriticheIl sistema maggiore di istocompatibilità
La presentazione dell’antigene
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Mononuclear phagocyte system
circulating blood monocytes
macrophages (terminally differentiated cells)
committed myeloid progenitor cells in the bone marrow
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Le cellule circolanti del sistema immune
Globuli bianchi % Intervallo normale (/mmc)
Neutrofili 55-70 4,500-11,000
Eosinofili 0-4 0-450
Basofili O-1 0-200
Linfociti 25-30 1,000-4,800
Monociti 10-15 0-800
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The story comes from far
Paul EhrlichIlya Metchnikov
1908 Nobel Prize
‘….There is no need to be a doctor or ascientist to wonder why the human bodyis capable of resisting so many harmfulagents in the course of everyday life. Itis often seen that in households whereall members are exposed to the samedanger, or again in schools or troopswhere everyone lives the same life,disease does not strike everyoneindifferently. For some individuals whogo down at the attack, there are otherswho have immunity to a greater or lesserextent….’
Struggle to survive Magic bullets69
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Fagociti mononucleati
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CLP: precursore linfoide comuneCMP: precursore mieloide comuneGMP: precursore macrofagi/polimorfo nucleatiMEP: precursore eritrociti/megacariociti
Cellule di derivazione mieloide
Cellule di derivazione linfoide
Origine dei monociti/macrofagi
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Evolutionary origin of neutrophils and monocytes
(precursore macrofagi/polimorfo nucleati)
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Fagociti mononucleati: i monociti
Origine: cellula staminale emopoieticaCellula circolanteDiametro: 10-18 micronNucleo: grande, reniformeCitoplasma: abbondanteEmivita: 2-3 gg (midollo osseo), 2-3 gg (sangue)Funzione: immunità innatafagocitosi, attivazione dei meccanismi battericidi, produzione di citochine della flogosi;Immunità adattiva presentazione dell’antigene nel linfonodo, direzionamento delle risposte immuni
sangue
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The monocyte/macrophage system
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Fagociti mononucleati: i macrofagi
Origine: cellula staminale emopoieticaCellula stanzialeEmivita: molti mesiFunzione: immunità innatafagocitosi, attivazione dei meccanismi battericidi, produzione di citochine della flogosi;Immunità adattiva presentazione dell’antigene nel linfonodo, direzionamento delle risposte immuni
sangue
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Fagociti mononucleati: i macrofagi
(10-18 micron)
sangue SNC
microglia
Cellule del Kuppfer
Fegato Milza
Macrofagi splenici
Cute
Cellule di Langerhans
Rene
Cellule mesangiali
Osso
Osteoclasto
Connettivo
Istiocita
….macrofagi alveolari, macrofagi intestinali, siti in infiammazione/infezione…….altro76
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Fagociti mononucleati nei tessuti di flogosi
Cellule giganti di Langhans
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Recettori dei monociti/macrofagi
CD marker FunzioneCD11b/CD18 Legame con particelle rivestite con C3bi
CD68 Lipoproteine a bassa densità
CD40 Costimolazione dei linfociti T
CD14Co-riconoscimento di LPS
(insieme a TLR4)
CD1 Riconoscimento di Atg lipidici
CD80 Costimolazione dei linfociti T
CD86 Costimolazione dei linfociti T
MHC classe II Presentazione dell’Atg ai linfociti T CD4+
CD16, CD32, CD64 FcgR
TLR2, TLR4, TLR8 Toll-like receptors 78
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Funzioni dei monociti/macrofagi
- fagocitosi,- attivazione dei meccanismi battericidi,- produzione di citochine della flogosi e di direzionamento delle risposte immuni.
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Innate immunity in the war against pathogens
Remove cellular debris and pathogens Stimulate repair Activate specific immunity
increase capillary permeability
Neutrophils (1h-3d)Macrophages (8h-mo)
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Phagocytosis and diapedesis are main features of innate cells
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Phagocytosis and diapedesis are main features of innate cells
Circulating monocyte eating malaria parasite
Neutrophil attacking bacteria
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Fagociti mononucleati
patogeno
internalizzazione
1
2
3
4
5
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Recettori dei monociti/macrofagi coinvolti nella fagocitosi
(uptake)
Receptor family Example Function
Scavenger SR-A Phagocytosis of bacteria and apoptotic (dying) cells
Toll-like receptors TLR4
TLR2
Response to LPS (Gram negative bacteria)
Response to peptidoglycan (bacteria)
C-type lectin –like receptors
Dectin-1 B-glucan receptor, fungal particle ingestion
Integrin CR3 Complement receptor-mediated phagocytosis
Adhesion to endothelium
Ig Superfamily FcR Antibody dependent binding/killing
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Malattie da aumentata funzione fagocitaria
Sindrome da attivazione macrofagica (MAS)
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Funzioni dei monociti/macrofagi
- fagocitosi, - attivazione dei meccanismi battericidi,- produzione di citochine della flogosi e di direzionamento delle risposte immuni.
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Prodotti dei monociti/macrofagi
Prodotto Ruolo
Citochine pro-infiammatorie
(TNF-alfa, IL-1, IL-6, IL-8)
Reclutamento dei linfociti, reclutamento di neutrofili
febbre
Citochine modulatorie
(IL-12, IFNs tipo I)
Differenziamento delle cellule T in senso TH1
Prodotti intermedi
dell’ossigeno, ossido nitrico,
enzimi lisosomiali
Uccisione dei batteri all’interno dei fagolisosomi
Chemochine
(IP-10/CXCL10, RANTES/CCL5,
MIP/CCL3)
Reclutamento delle cellule della flogosi
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Agenti battericidi rilasciati dai monociti/macrofagi
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Il ‘respiratory burst’
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Immunodeficienze da alterazione della funzione monocito-macrofagicaLa Malattia Granulomatosa Cronica come esempio di alterato meccanismo
di fagocitosiGenetic deficiency of NADPH oxidase (phagocytes do notproduce the toxic oxygen derivatives of the respiratory burstand so are less able to kill ingested microorganisms and clearan infection).The most common form of CGD is an X-linked disease(inactivating mutations in the gene encoding the gp91 subunitof cytochrome b558, located on the X chromosome)unusuallysusceptible to bacterial and fungal infections, especially ininfancy. Autosomal mutations in other subunits of the NADPHoxidase can also cause chronic granulomatous disease, but canbe milder and have a later onset.
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Funzioni dei monociti/macrofagi
- fagocitosi, - attivazione dei meccanismi battericidi,- produzione di citochine della flogosi e di direzionamento delle risposte immuni.
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Attivazione dei monociti/macrofagi
Macrofago non stimolato
Fattori umoraliAderenza alla plasticaGlicaniPMACitochineMicroorganismiLigandi di TLR
Macrofago stimolato
secrezionekillingendocitosimetabolismodimensioniVelocità di diffusioneEspressione di recettori
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Prodotti dei monociti/macrofagi
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Citochine prodotte dai macrofagi e dalle DCs
MacrofagiCheratinociti
MacrofagiDCs
MacrofagiDCs
MacrofagiDCs
MacrofagiDCs
Linfociti
Linfociti
Fegato
Fegato
Fagociti
Cellule T indifferenziate
EndotelioVascolare
Aumenta la risposta
Induce la produzione di proteine di fase acuta
Aumenta la risposta
Induce la produzione di proteine di fase acuta
Chemoattrattante per neutrofili
Devia la risposta immunitaria in senso Th1, secrezione di citochine
Induce modificazioni nell’endotelio vascolare (espressione di selettine, tight junctions) con edema locale, aumento della permeabilità, coagulazione
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Prodotti dei monociti/macrofagi
Prodotto Ruolo
Citochine pro-infiammatorie
(TNF-alfa, IL-1, IL-6, IL-8)
Reclutamento dei linfociti, reclutamento di neutrofili
febbre
Citochine modulatorie
(IL-12, IFNs tipo I)
Differenziamento delle cellule T in senso TH1
Prodotti intermedi
dell’ossigeno, ossido nitrico,
enzimi lisosomiali
Uccisione dei batteri all’interno dei fagolisosomi
Chemochine
(IP-10/CXCL10, RANTES/CCL5,
MIP/CCL3)
Reclutamento delle cellule della flogosi
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Modificazioni del monocita/macrofago dopo attivazione
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Classificazione dei monociti/macrofagi
i) On the basis of their tissue distribution
ii) On the basis of their functional polarization
M1 (proinflammatory)M2 (alternatively activated) Regulatory cells in response to both
exogenous infectionsand solid tumors
Monociti/macrofagi come cellule ‘plastiche’99
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Polarizzazione funzionale dei monociti/macrofagi
M1 (proinflammatory) “Classical Activation”
i) secreted molecules (IFN-γ, TNF-α) of activated T helper 1 (Th1) CD4+ lymphocytes or natural killer
(NK) cells, or ii) bacterial lipopolysaccharide (LPS) give rise to a population of macrophages with enhanced microbicidal capacity and increased
secretion of proinflammatory cytokines to further strengthen the cell-mediated adaptive immunity
CD14High CD16neg
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Polarizzazione funzionale dei monociti/macrofagi
M2 “Alternative Activation”
interleukin-4 (IL-4) and IL-13, signature cytokines of the CD4+ Th2 response
induce the activation of macrophages playing an important role not only in the immune
response to parasites, but also in allergy, wound healing, and tissue remodeling
• M2a (elicited by IL-4 or IL-13), • M2b (following stimulation by immune complexes in the presence of a Toll-like
receptor ligand), • M2c (when exposed to anti-inflammatory stimuli such as glucocorticoid
hormones, IL-10, or Transforming Growth Factor-β,TGF-β)
CD14low/negCD16+ 101
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Regulatory monocytes/macrophages
Cells playing a pivotal role in limiting inflammation duringinnate and adaptive immune responses and producing highlevels of IL-10; unlike M2 cells, they do not contribute tothe production of extracellular matrix and express highlevels of the costimulatory molecules CD80/B7-1 andCD86/B7-2.
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Functional differentiation processes of macrophages
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Polarizzazione funzionale dei monociti/macrofagi
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Concetti generali
Antigeni ed immunogeniI fagociti mononucleati e le cellule
dendriticheIl sistema maggiore di istocompatibilità
La presentazione dell’antigene
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Origine dei monociti/macrofagi
CLP: precursore linfoide comuneCMP: precursore mieloide comuneGMP: precursore macrofagi/polimorfo nucleatiMEP: precursore eritrociti/megacariociti
Cellule di derivazione mieloide
Cellule di derivazione linfoide
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Le cellule dendritiche come APC professionali
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Le cellule dendritiche catturano l’antigene
dalla cute o dalle mucose e migrano nei linfonodi
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Le cellule dendritiche catturano l’antigene
dalla cute o dalle mucose e migrano nei linfonodi
Gli antigeni presenti in circolo sono catturati dalle APC
spleniche
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Funzioni delle cellule dendritiche (DC)
Follicular DCLangerhans’ DC
CD21+CD23+
Immature DCs patrol via the blood systems throughout the body and can invade peripheral tissues to take up antigens
from infected or dying cells via macropinocytosis, phagocytosis, and endocytosis
(Steinman et al., 1999)111
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Two types of dendritic cells
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Le cellule dendritiche (DC)
IL-12producing
IFN-a
producing
Follicular DC
-Passively present IC to B cells-are present in B cell areas of spleen, lns, MALT-Non migratory-Lack MHC II-Are CD21 and CD35 + and CD16+-Mesenchimal origin
Langerhans’ DC
-Usually reside in skin and mucosal sites-Migrate as ‘veiled cells’ to lns (paracortex)IDCs-Are highly MHC class II positive
Granuli di Birbeck
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Le cellule dendritiche (DC)
IL-12producing
IFN-a
producing
Follicular DC
-Passively present IC to B cells-are present in B cell areas of spleen, lns, MALT-Non migratory-Lack MHC II-Are CD21 and CD35 + and CD16+-Mesenchimal origin
Langerhans’ DC
-Usually reside in skin and mucosal sites-Migrate as ‘veiled cells’ to lns (paracortex)IDCs-Are highly MHC class II positive
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Le cellule dendritiche (DC)
IL-12producing
IFN-a
producing
Follicular DC
-Passively present IC to B cells-are present in B cell areas of spleen, lns, MALT-Non migratory-Lack MHC II-Are CD21 and CD35 + and CD16+-Mesenchimal origin
Langerhans’ DC
-Usually reside in skin and mucosal sites-Migrate as ‘veiled cells’ to lns (paracortex)IDCs-Are highly MHC class II positive
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Hematopoietic progenitor cells (HPCs) in the bone marrow give rise to monocytes
circulating in the blood.
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Hematopoietic progenitor cells (HPCs) in the bone marrow give rise to monocytes
circulating in the blood. After interacting with inflamed endothelium,
monocytes cross the endothelial barrier and encounter a cytokine microenvironment triggered by pathogen.
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Hematopoietic progenitor cells (HPCs) in the bone marrow give rise to monocytes
circulating in the blood.
Stromal cells (epithelial cells, keratinocytes and fibroblasts), mast cells, plasmacytoid DCs and
natural killer cells respond to microbes by secreting various cytokines. These include interleukin 15 (IL-15), transforming growth factor- (TGF-) and tumor
necrosis factor (TNF), all of which can skew monocyte differentiation into LCs.
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Hematopoietic progenitor cells (HPCs) in the bone marrow give rise to monocytes
circulating in the blood.
LCs undergo maturation either by direct interaction with a
microbe or in response to products of
surrounding cells and migrate through
lymphatic vessels into T cell zones of draining lymph nodes, where
they secrete chemokines that attract naive T cells and induce their
proliferation and differentiation. Other
DCs, such as interstitial DCs, stimulate other
types of immune responses.
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Le cellule dendritiche (DC)
IL-12producing
IFN-a
producing
Follicular DC
-Passively present IC to B cells-are present in B cell areas of spleen, lns, MALT-Non migratory-Lack MHC II-Are CD21 and CD35 + and CD16+-Mesenchimal origin
Langerhans’ DC
-Usually reside in skin and mucosal sites-Migrate as ‘veiled cells’ to lns (paracortex)IDCs-Are highly MHC class II positive
CD123+BDCA-2+BDCA-4+
CD21+CD23+
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Popolazioni principali di DCs e loro marcatori
Cellula dendritica mieloide Cellula dendritica plasmacitoide
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Plasticità delle cellule dendritiche (DC)
CD80, CD86, ICAM
FcR, Recettoriper mannosio
MHC Classe IIEmivita circa 10 ore > 100 ore
N° molecole circa 106 circa 7x106
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Maturation of dendritic cells causes acquisition of novel markers
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• CD14+/- (se da Mo.)• CD40+• MHC II+• CD83-• CD80+• CD86+• CCR5+• CCR6+• CXCR4+/-• TREM-2 (MDC)• TLR9 (PDC)• TLR-8 (MDC)• TLR7 (MDC, PDC)• TLR-4, TLR-2 (MDC)
• CD14-
• CD40+++
• MHC IIhi
• CD83+
• CD80+++
• CD86+++
• CCR5-
• CCR6-
• CCR7+
• CXCR4+
Monitoraggio del fenotipo:iDC e mDC
iDC mDC
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CD86
Medium LPS 10 ng/ml LPS 100 ng/mlCD14-der D
CCD34-der D
CCD34-der(+
IL-4) D
CC
D8
0
22.7 17.3
9.4
11.3 86.5
1.1
30.4 67.3
0.4
52.9 29.5
2.9
10.9 34.5
13.9
13.4 30.1
5.0
7.4 39.0
4.0
50 43.8
3.4
12.6
30.813.5
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CD1a
4° C
30 min 4 hCD14-der D
CCD34-der D
CCD34-de
r(+
IL-4) D
C
0.3 0.1
0.4
33.4 27.0
7.4
27.7 22.1
11.9
0.1 0.1
0.4
49.8 17.3
2.5
69.2 18.4
1.2
10.8 44.6
6.8
32.0 45.9
3.1
BS
AF
IT
C
37° C
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Dendritic cells as plastic APCs
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Regulatory dendritic cells
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Regulatory dendritic cells
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Cancer immunotherapy: optimization of cellular vaccines
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DC2 matura
PRECURSORI DELLE DC E LORO MATURAZIONE IN VITRO
In vitro
In vivo
HPC CD34+
- Midollo osseo
- Sangue di cordone ombelicale
- Sangue periferico
Cellula plasmocitoide
CD123+ BDCA2+ CD4+
- Timo - Linfonodi
- Tonsille - Sangue periferico
Monocita (CD14+)
- Sangue periferico
DC1 immatura DC2 immatura
Cellula di LangerhansDC1 matura
GM-CSF
TNF-a
SCF, FlT3-L
IL-3GM-CSF
IL-4
TGF-bTNF-a or
LPS or
MCM or
CD40-L
CD40-L or
CpG
CD34low+ CLA+
GM-CSF, G-CSF
SCF, FlT-3,
IL-3, IL-7
Linea mieloide Linea linfoide
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Provenge as the only commercially available dendritic-based vaccine
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