Le rôle des cellules dendritiques

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Le rôle des cellules dendritiques
CR4
CMH
Classe II
CCR7
CMH
Classe II
Dec 205
ICAM-2
B7.1
CMH
Classe I
CMH
Classe I
LFA-1
LFA-1
LFA-3
LFA-3
ICAM-1
DC-CK
ICAM-1
DC-SIGN
Cellules dendritiques immatures
Tissus périphériques
B7.2
DC-SIGN
Cellules dendritiques
Tissus lymphoides
population hétérogène, origine mal connu
Molécules associées aux DC
Langerine
Dectine -2
lectine
lectine
+++
+++
formation de granules de birbeck
ingestion ag
DC-SIGN
lectine
+++
interaction avec cellules T/ ICAM-3
DC-LAMP
DEC-205
glycoprotéine lysosomale +++
lectine
+++
présentation ag
ingestion ag
DC-CKI
TARC
MDC
chimiokine
chimiokine
chimiokine
attraction cellules T naives
attraction lymphocytes memoires act.
attraction lymphocytes memoires act.
+++
++
+
Les populations de DC
DCs myéloides : de monocytes (in vitro, GM-CSF)
Dcs lymphoides : voie thymique , expression CD8 (TCR-)
Cellules plasmacytoides : Dc immature,
origine lymphoide ou myéloide ?
CD11c-, secrètent IFN-α,
dépendants d ’IL-3 mais pas GM-CSF
pour Dc matures
DC1 (TH1) ?
Multifonctionnel ?
DC2 (TH2) ?
Fonction limitée ?
Les populations de DC
DC du sang : précurseurs CD11c+
précurseurs CD14-CD1+ GM-CSF+ TNF-α
DC épithéliales (cellules Langerhans) : uniquement épithélium
Fcγ et Fc ε , CD1a, Langerin (migration, ingest. Ag)
DC interstitales : CD68 , pas de marqueurs LC
DC monocytaires : GM-CSF + IL-4
DC centre germinal ganglion : CD11c+, CD4+, CD3-, stim. CD4+
DC plasmocytoides (DC2) : dépendants de IL-3, CD11c-, CXCR3
Origine des
cellules
dendritiques
Génération
de DC
in vitro
(homme)
Génération
de DC
in vitro
(souris)
Morphologie and confocal microscopy analysis of MDCs and PDCs isolated from AML
patients : CD11c+ MDCs were isolated from patient UPN71 and cultured in vitro for 3
days with GM-CSF, IL-4, and CD40L. (A) They display dendritic morphology as shown
by interferential contrast transmission microscopy (x100).Three colors immuno-fluorescence stainning was performed. (B) HLA-DR expression is shown in red, (C) CD83
in blue, and (D) DC-LAMPin green. (E) Giemsa staining of freshly isolated PDCs from
patient UPN109. Original magnification x1000.
La maturation des DC
FLT3-L
GM-CSF, IL-4, IL-3
TGFβ (LC)
DC précurseurs
Sécrétion de cytokines
Pro-inflammatoires et
Antivirales
IFN-a, TNF-a, Il-1
LPS, DNA, RNA,
Cytokines inflammatoires
TNF-α, IL-1
HSP (gp96,Cellules
nécrotiques
Se fixe sur CD91
DC immatures
Capacité
Capture antigène
Endocytose/
phagocytose
DC matures
Présentation Ag
CD54
CD56
DC-LAMP
IL-12
Activation terminale : par cellules T spécifiques CD40/CD40L
Les stades importants des DC
Migration - mobilité :
précurseurs
sang tissus (DC immatures : faible densité)
stimulation (bactéries, virus) : accumulation locale
expression CCR2 et CCR6 récepteurs chimiokines migration vers pathogène,
perte de récepteurs à des cytokines inflammatoires
réponse à des chimiokines
migration vers organes lymphoides
Ingestion antigène - présentation :
Cellules immatures : macropinocytose, endocytose (récepteur lectine),
récepteur toll-like, récepteur Fc, CD36 et αvβ3, αvβ5
Présentation d ’antigène :
CMH classe II
, complexe pendant plusieurs jours
CMH classe I : voie endogène et exogène : « crosspresentation »
2 voies : TAP indépendant, endosomes
TAP indépendant
(tumeurs, virus; tolérance)
La voie de LPS par le récepteur Toll
LPS
LBP
CD14
TLR4
LPS est fixé par le
LPS-binding protein LBP
Le complexe LPS : LBP
se fixe sur CD14
TNF-α
α
B7
Après fixation ,
CD14 interagit avec TLR-4
Activation de NF-KB
Activation des récepteurs Toll -like
Fonctions des DC
Activation de CD4+ CD8+ naives
Différenciation TH1, TH2 par MDC
GM-CSF + IL-4 +LPS
IL-12 , d ’abord TH1, puis TH2
PDC CD11c- + Il-3 + CD40L + cellules T naives réponse TH1
Cellules T activent DCs via CD40/CD40L
Activation lymphocytes B et NK
Maladies auto-immunes
Stimulation antigénique via DC inflammation locale
Immunothérapie avec DC Ag tumeur (cellules normales) : maladie autoimmune
Réactions allergiques
Poumon : présentation Ag inhalé à TH
inflammation chronique
Régulation de lymphocytes T
DC traité avec IL-10 : peu expression CMH et mol costim.
Résistance à la maturation
Tumeurs qui produisent Il-10, peau après UV
CT reg : stimulation de CD4+ naives avec Dc immatures IL-10 agit sur TH1
Thymus : génération de Treg - knockout de T reg : maladies autoimmunes
Contact T-T
Différenciation de cellules T dépendante
du stade de maturation des DC
Modèle pour l ’induction de la tolérance d ’une
Tumeur par des DC in vivo
Les prions
Prions, VIH et le système immunitaire
Souris rag-/- reconstituées avec des cellules
de foie foetal Prnpo/o - rôle des FCD ’S
Lower row: confocal double-color immunofluorescence analysis of splenic germinal centers in Rag-1¯/¯ mice
reconstituted with Prnpo/o FLCs after i.p. inoculation with RML prions. Sections were stained with antibody FDCM1 to follicular dendritic cells (green, left) and with antiserum R340 to PrPc (red, middle). Regions in which both
signals are detectable appear yellow in superimposed image (right, magnification 250?). Most of the PrPc signal in
germinal centers and appeared to co-localize with the FDC network.
Modèles de transport dans le PNS
Accumulation de PrPsc dans greffes de cerveau
Réplication des prions et
l ’inhibition par des anticorps
Summary of the HIV/AIDS epidemic, December 2001.
People infected with HIV in 2001
Total
5 Million
Adults
4.3 Million
Women
1.8 Million
Children < 15 years 800,000
No. of people living with HIV/AIDS
AIDS deaths in 2001
Total
40 Million
Adults
Women
Children <15 years
37.2 Million
17.6 Million
2.7 Million
Total
Adults
Women
Children <15 years
3 Million
2.4 Million
1.1 Million
580,000
Total no. of AIDS deaths since the beginning of the epidemic until 2001
Total
21.8 Million
Adults
17.5 Million
Women
9 Million
Children <15 years 4.3 Million
STAGE 1
This stage of infection lasts for a few weeks and is often accompanied by a short flu like illness which occurs
just after infection. This flu like illness is sometimes referred to as seroconversion illness. In up to about 20% of
people the symptoms are serious enough to consult a doctor, but the diagnosis is frequently missed. Even if an
HIV antibody test is done at this time, it may not yet be positive. During this stage there is a large amount of
HIV in the peripheral blood and the immune system begins to respond to the virus by producing HIV antibody
and cytotoxic lymphocytes.
Clinically Asymptomatic Stage
STAGE 2
This stage lasts for an average of ten years and as its name suggests, is free from any symptoms, although
there may be swollen glands. The level of HIV in the peripheral blood drops to very low levels but people
remain infectious and HIV antibodies are detectable in the blood. Recent research has shown that HIV is not
dormant during this stage, but is very active in the lymph nodes. Large amounts of T helper cells are infected
and die and a large amount of virus is produced.
A new test is now available to measure the small amount of HIV that escapes the lymph nodes. This test which
measures HIV RNA (HIV genetic material) is referred to as the viral load test, and it has an increasingly
important role in the treatment of HIV infection.
Symptomatic HIV Infection
STAGE 3
Over time the immune system loses the struggle to contain HIV. This is for three main reasons
The lymph nodes and tissues become damaged or 'burnt out' because of the years of activity;
HIV mutates and becomes more pathogenic, in other words stronger and more varied, leading to more T
helper cell destruction; The body fails to keep up with replacing the T helper cells that are lost.
As the immune system fails, so symptoms develop. Initially many of the symptoms are mild, but as the immune
system deteriorates the symptoms worsen.
Antiretroviral Agents Currently Available
(generic name/Trade name)
Nucleoside Analogs
zidovudine/Retrovir (AZT, ZDV)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
stavudine/Zerit (d4T)
lamivudine/Epivir (3TC)
abacavir/Ziagen (ABC)
Non-Nucleoside Reverse Transcriptase Inhibitors
nevirapine/Viramune (NVP)
delavirdine/Rescriptor (DLV)
efavirenz/Sustiva (EFV)
Nucleotide Analogue
tenofovir DF/Viread (TDF)
Protease Inhibitors
indinavir/Crixivan
ritonavir/Norvir
saquinavir/Invirase, Fortovase
nelfinavir/Viracept
amprenavir/Agenerase
lopinavir/ritonavir, Kaletra
HIV attacks a macrophage (top middle) and a Helper T Cell (lower left). New virus particles then bud from the
macrophage. A B-lymphocyte (bottom right) gives rise to Plasma Cells (reddish cells on right) that produce
antibodies (Y shaped molecules in red) that bind to HIV. A killer cell (bottom middle) will attack virus infected cells.
The interaction of HIV and the immune system is very complex and varies over time. The original is 4,000 pixels
across
VIH et les réponses humorales et cellulaires
CD4
CCR5 (CXCR4)
Les voies d ’entrée
Les réponses de l ’immunité naturelle
Les stratégies d ’échappements au système immunitaire
Distribution des cellules T CD4+ CCR5+
Comparison of the coexpression of CC-chemokine receptor 5 (CCR5) and CD45RA on
CD4+ T cells in various tissues of macaques. Note that the majority of viral target
cells (CCR5+CD45RA-), shown in red, resides in mucosal tissues (e.g. intestinal and
reproductive tracts). Plots were generated by gating on CD4+ lymphocytes.
Distribution de la perte de cellules CCR5+CD45RA- après
infection avec SIV
- Élimination de cellulesCD4+ T mémoires CCR5+ CD45RA- Apparition de cellules CD4+ naives (CCR5+CD45RA+)
Perte de cellules CD4+ (11-14 jours après infection primaire :
Réplication lytique du virus
Hypothèse pour la pathogénicité de l ’infection par SIV et HIV
Après destruction lytique de cellules CD4+CCR5+ (cellules mémoires)
Candidiasis
Cytomegalovirus
Herpesvirus
pneumocystis
Les problèmes pour un vaccin anti-HIV
General mechanisms of immune evasion by HIV
Role of HIV regulatory genes in immune evasion
LTR
gag
pol
vpr rev
vif tat vpu
env
revnef
tat
LTR
HIV : Components of the innate and adaptive immune systems
The innate immune system
Cellular components:
The adaptive immune system
Dendritic cells (including related cells :
Langerhans' cells and microglia)
Cellular components:
Macrophages
Interferon-producing cells (IPCs)
Dendritic cells (including related cells,
such as Langerhans' cells and microglia) Natural killer (NK) cells
Neutrophils
Macrophages
Eosinophils
B cells
T cells
CD4+ T cells
NK-T cells
CD8+ T cells with cytotoxic activity
CD8+ T cells with noncytotoxic antiviral activity
B1 cells
Soluble components:
Antibodies
Certain cytokines (e.g. IL-2)
Components of the innate and
adaptive immune systems
Soluble components:
Cytokines (e.g. interferons)
Chemokines
Complement
Lectin-binding proteins or collectins
(e.g. mannose-binding lectin)
Defensins
Acute phase reactants
(e.g.cathelicidins and pentraxins)
Features of the CD8+ T-cell noncytotoxic antiviral response (CNAR)
Observed only with CD8+ T cells, predominantly those expressing HLA-DR and CD28.
Blocks HIV replication in acutely infected CD4+ T cells and macrophages.
Does not involve cell killing.
Does not require HLA compatibility.
Suppression of HIV replication is dose-dependent
(correlates directly with the number of CD8+ T cells added to infected CD4+ T
cells in culture) and can occur at low CD8+:CD4+ T-cell ratios (e.g.1:4).
Shows clinical relevance; it has strong activity in healthy individuals and decreased
activity with progression to disease.
Active against all HIV-1, HIV-2 and SIV strains tested:
Inhibits HIV replication at the level of transcription and does not affect any process
before virus integration.
Mediated (at least in part) by a soluble protein, termed CD8+ T-cell antiviral factor (CAF).
Evidence that CNAR is part of the innate immune system
Not HIV-specific; affects the long terminal repeat of several different retroviruses.
Not restricted by HLA class I or class II molecules.
Provides a rapid early response to HIV infection.
Found in exposed uninfected individuals and is lost over time if there
is no further exposure to HIV (i.e. no memory response).
Mediated (at least in part) by a secreted cytokine that affects viral transcription.
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