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.