le compl©ment

Download Le  Compl©ment

Post on 18-Mar-2016

57 views

Category:

Documents

0 download

Embed Size (px)

DESCRIPTION

Le Complément. Dr Alessandra Rosenthal Laboratoire Central d’Immunologie (Prof. A. Bernard) CHU de Nice. Système Immunitaire. Immunité naturelle Immunité acquise. Immunité Naturelle. Composants cellulaires : Cellules phagocytaires (neutro, mono, macrophages) - PowerPoint PPT Presentation

TRANSCRIPT

  • Le ComplmentDr Alessandra RosenthalLaboratoire Central dImmunologie(Prof. A. Bernard)CHU de Nice

  • Systme ImmunitaireImmunit naturelle Immunit acquise

  • Composants cellulaires :

    Cellules phagocytaires (neutro, mono, macrophages)Cellules relarguant des mdiateurs (baso, eosino, mast cells)Cellules NK

    Composants molculaires :

    ComplmentProtines de la phase agueCytokines (IFN etc)

    Immunit Naturelle

  • VoieInitiateurs

    ClassiqueImmuno-complexesCellules apoptotiquesCertains virus et bacteries Gram-CRP lie au ligand

    des lectinesMicroorganismes avec groupementsmannoses terminaux

    AlterneBactries, champignons, virus,cellules tumoralesLes trois voies dactivation du Complment

  • Walport NEJM 2001Activation du Complment

  • Assembly of C1 during the Classical Complement PathwayThe Fab of IgG or IgM bind to epitopes on an antigen. C1q, C1r, and C1s then assembles on the Fc portion of the antibodies to form C1, the first enzyme of the classical complement pathway. The enzyme C1 is able to cleave C4 into C4a and C4b, as well as C2 into C2a and C2b.

  • Formation of C3 Convertase during the Classical Complement PathwayThe enzyme C1 is able to cleave C4 into C4a and C4b. The C4b binds to adjacent proteins and carbohydrates on the surface of the antigen. C2 then binds to the C4b and C1 cleaves C2 into C2a and C2b. The C4a2b functions as a C3 convertase that can subsequently cleave hundreds of molecules of C3 and C3b.

  • Formation of C5 Convertase during the Classical Complement PathwayThe C4a2b functions as a C3 convertase that can subsequently cleave hundreds of molecules of C3 into C3a and C3b. Much of the C3b binds to adjacent proteins and carbohydrates on the antigen to participate in opsonization while C3a can stimulate inflammatory responses. Some of the C3b binds to C4b2a to form C4b2a3b, a C5 convertase that can cleave C5 into C5a and C5b.

  • The Membrane Attack Complex (MAC) Causing Cell Lysis This C5b6789 membrane attack complex (MAC), puts pores into lipid bilayer membranes of human cells to which antibodies have bound. This results in cell lysis. MAC can also damage the envelope of enveloped viruses and put pores in the outer membrane and cytoplasmic membrane of gram-negative bacteria causing their lysis

  • Activation of the alternative complement pathway and formation of C3 convertaseActivation of the alternative complement pathway begins when C3b (or C3i) binds to the cell wall and other surface components of microbes. Alternative pathway protein Factor B then combines with the cell-bound C3b to form C3bB. Factor D then splits the bound Factor B into Bb and Ba, forming C3bBb. A serum protein called properdin then binds to the Bb to form C3bBbP that functions as a C3 convertase capable of enzymatically splitting hundreds of molecules of C3 into C3a and C3b.

  • Some of the C3b subsequently binds to some of the C3bBb to form C3bBb3b, a C5 convertase capable of enzymatically splitting hundreds of molecules of C5 into C5a and C5bFormation of C5 convertase during the alternative complement pathway

  • Rgulation du clivage of C3 par le Factor H et Factor IWalport NEJM 2001

  • Les trois principales activits physiologiques du systme complmentaireActivitProtines responsables

    Dfense contre les infections :OpsonisationC3 et C4Chimiotactisme et activationAnaphylotoxines (C5a, C3a et C4a)Lyse des bactries et des cellulesMAC (C5b-C9)

    Interface entre immunit naturelles et spcifique :Augmentation de la rponse AbC3b et C4b lis aux CI; C3R sur B et APCPotentialisation de la mmoire Imm.C3b et C4b lis aux CI; C3R sur FDC

    limination des cellules endommages:Clearance des CI dans les tissusC1q; fragments de C3 et C4Clearance des cellules apoptotiquesC1q; fragments de C3 et C4

  • The Fab portion of IgG binds to epitopes of an antigen. The Fc portion can now attach the antigen to Fc receptors on phagocytes for enhanced attachment. This is especially important against encapsulated microbes. C3b and C4b from the complement pathways can also attach antigens to phagocytes. Once attached to the phagocyte by way of IgG, C3b, or C4b, the microbe can be engulfed more efficiently and placed in a phagosome. As lysosomes fuse with the phagosome the microbe is digested. Opsonization of a Bacterium

  • . Extracellular Killing After OpsonizationThe Fab portions of IgG or C3b bind to epitopes on human cells recognized as foreign, such as virus-infected cells, tumor cells, or cells involved in autoimmune reactions. This enables phagocytes to attach to the cell by way of their Fc and C3b receptors. The phagocytes now destroy the cell by discharging their lysosomal contents

  • Chemotactict effect of C5a and C3bMost C3b binds to antigens on the microbial surface. Some C3b combines with C2a and C4b to form the third enzyme of the complement pathway that is able to split C5 into C5a and C5b. C5a stimulates mast cells to release histamine for inflammation and diapedesis. It also functions as a chemoattractant for phagocytes. The phagocytes are then able to bind to the C3b attached to the surface of the microorganism allowing for opsonization (enhanced attachement)

  • Rcepteurs du complmentNomLigand(s) DistributionFonction

    CR1 (CD35)iC3b, C4bB, phagocytes, GR,CFD limination des CI lis aux GR opsonisation activation B

    CR2 (CD21)iC3b, C3dgB, cellules epithelialesactivation Brc. EBV CR3 (CD11b/CD18)iC3b, ICAM-1 Phagocytes, NK CFDOpsonine, lectine, adhesion molecule

    CR4 (CD11c/CD18)iC3bPhagocytes molcule dadhsionopsonisation

  • Effets cliniques des principaux dficits hrditaires du ComplmentDficitConsquences sur lact. du CAssociations cliniques

    C3incapacit dopsonisationInfections pyognesincapacit activer le MACGN membrano-prolifrative

    C3Properdineincapacit former le MACInfections NeisseriaMAC

    C1q, C1r,incapacit activer la voie LESC4, C2 classique

  • AnomalieClinique Ethiopathognse

    C3 nef- Glomrulonphrite Auto-Ab qui stabilise le C3bBbmembrano-prolifrative

    Dficit en facteur H, I- GlomrulonphriteDfaut de rgulation de lactivation membrano-prolifrativede C3, avec inflammation chronique - Syndr. Hmolyt. Urm.dans le glomrule et dficit secondaire en CDficit en C1 inhibiteur- Oedme angioneurotiqueDfaut de la srine-protase qui inactive le C1 et le systme de kinines-bradikinines

    Hmoglobinurie paroxystique- Hmolyse intravasculaireDficit de rgulation du MAC par nocturne dfaut dexpression des molcules GPI (CD55 et CD59)Pathologie du complment - anomalies de rgulation

Recommended

View more >