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Transcript
TR056/PG2003 Lecture 14 The Complement Cascade Dr Neil Docherty My Teaching Objectives • To explain the role of the complement system as a key pathogen recognition and targeting system in response to infection • To illustrate how the complement system components are generated by three main routes all of which rely on cascades of enzyme activation • To emphasise the “classical” activation route as a salient example of the concept that innate and adaptive immune responses are functionally linked Complement Cascade • • 30 plasma and cell-surface complement components mainly liver derived Originally shown to complement antibody mediated opsonisation and killing of bacteria (Nobel Prize Physiology or Medicine 1919 Jules Bordet) 3 pathways involved in complement attack upon pathogens 1. Classical pathway 2. Alternative pathway 3. Mannose-binding lectin pathway (MBL-MASP) Complement Effects 1. 2. 3. 4. 5. Initiation of an inflammatory response Recruitment of phagocytes to site of infection Direct destruction of gram negative bacteria Assistance in phagocytosis Promotion of phagocyte oxidative burst activity and granule release 6. Generation of a humoral immune response 7. Clearance of soluble immune complexes from circulation Alternative Pathway • C3 convertase formation splits C3 into C3b (large) and C3a (small) • C3bBb convertase requires 3 other serum proteins: factors B & D, properdin and C3b • Activity is harmless at host cell surface • Activity is increased on surface of bacteria, fungi, protozoa • Large amounts of C3b deposited Lectin Pathway • • • • • Mannose-binding lectin (MBL) recognise microbial surfaces to generate C3 convertase Sugars such as mannose are expressed on microbial cell surfaces that MBLs can bind to. Activate proteases • MASP-1 & MASP-2 (Major Binding Protein –associated serine protease) Cleave 2 complement components: C4 & C2 Results in the formation of C3 convertase C4b2a, acts similarly to C3bBb Mannose Binding Lectins (MBLs) and C3 Activation • MBLs recognize sugar patterns that are unique to pathogens (hidden by sialic acid on vertebrate cells) • Collectins since they have a collagen like domain & globular lectin domain • MASPs are proteases that generate the active C3 convertase • Classical pathway has analogous components (next slide) Classical Pathway Note that the basic Structures are similar • • • Antigen complexed antibodies are bound by complement component C1q via constant regions of heavy chains C1q action with other complement proteins, C1r+C1s, induces cleavage of C4 and C2 to form the C4b2a component (C3 convertase) N.B. Not just sugar residue restricted response as it occurs via antibody Classical C3 Convertase Formation Effector Pathways Downstream of C3 Conversion • Common downstream cascade for 3 complement pathways • C3b is the primary mediator of biological effects of complement activation • Once C3b binds to a pathogen; it attaches to C3b receptors on phagocytic cells inducing phagocytosis • C3b cleaves C5 to C5b; associates with C6, C7, C8 & C9 components to form a membrane attack complex (MAC) • MAC inserted into membranes of microbes eg gram (-) bacteria; induces leakage and death • Small fragment C3a & C5a promotes inflammation by binding to mast cells Cascade of events during classical complement activation AntigenAntibody complex C1 C2a C4b C3 C3b C5 C5a C3b C3a C5b C6,C7,C8,C9 Centrally Important Product=C3 Processes -Zymogen activation -Opsonisation and phagocytosis -MAC formation -Pro-inflammatory Signalling Opsonisation • Opsonisation is the process whereby plasma factors act on bacteria to facilitate phagocytic attraction • Opsonins -Antibody -Complement proteins (C3b is main opsonin) • Coated bacteria bind to receptors on neutropils cell membrane and trigger lysis of cell and respiratory burst Phagocytosis and Complement Receptors Type 1, 3,4 Bind C3b Phagocytosis Which cells? How might this link with antigen presentation? Complement Components and Receptors (More Than Phagocytosis) Receptor Expressed by Binds to Effect on cell func6on CR1 (CD35) Dendri>c cells, B cells, macrophages C3b, C4b Binds immune complexes, phagocytosis with C5a CR2 (CD21) B cells, dendri>c cells C3d,C3dg,iC3b Binds EBV, B cell ac>va>on (component of B-‐cell receptor complex) CR3 (CD11b) Macrophages, Neutrophils, NK cells iC3b Phagocytosis, Cell adhesion CR4 (CD11c) Monocytes, Macrophages, Neutrophils iC3b Phagocytosis C3a/4aR Mast cell, basophils C3a, 4a Degranula>on C5aR Mast cells, basophils, C5a monocytes, macrophages Degranula>on, migra>on, adhesion of phagocytes to endothelium Formation of MAC How would a large pore potentially disrupt and Kill the bacteria i.e. What is the physiological Consequence? Regulation of complement C1 Inhibitor Binds to C1r, C1s and removes it from C1q CD46 Inac>vator of C3b & C4b Factor I Serine protease cleaves C3b & C4b aided by H C4-‐Binding protein Binds C4b & displaces C2b or Binds C3b displaces Bb Factor H Binds C3b Cofactor for I Decay Accelera>ng Factor (DAF) Displaces Bb from C3b & C2b from C4b Pathogens can escape from complement control Anti-complement mechanisms: • Peptidoglycan of Gram-positive membranes prevent insertion of the MAC complex • Leishmania can expel MACcomplex from its membrane & reseals • Elastase of Pseudomonas destroy C3b and C5a • Proteins of viruses, bacteria and others mimic the inhibitors of complement which are involved in its regulation Complement defects Decreased C1s esterase inhibitor Low levels of C1, C2 or C4 Low levels of C2 & C4 Decrease in clearance of an>gen-‐an>body complexes Inflamma>on & >ssue swelling Hereditary Angiodema Deposi>on of immune complexes damages kidney Lupus erythematosus Low levels of C5-‐ C9 Absence of C3 Forma>on of ly>c membrane-‐ aYack complex Survival extremely rare Predisposed to infec6ons such as gonorrhoea & meningococcal meningi6s Your Learning Objectives Your learning should focus on being able to; 1) Explain how the complement system components are generated by three main routes all of which rely on cascades of enzyme activation 2) Describe the “classical” activation route as a salient example of the concept that innate and adaptive immune responses are Functionally linked