THE COMPLEMENT SYSTEM OBJECTIVES: When you finish this section, you should be able to: 1. Describe the effects of complement activation. 2. Outline the Classical, Mannan-Binding (MB) Lectin and Alternative pathways of complement activation, including their activators. 3. Discuss the major regulatory points in complement activation and the consequences of deficiencies in complement or complement regulators. 4. Discuss the functions of the various complement receptors. 5. Discribe the biologic activities of complement and identify the components involved.
Complement: History Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min
COMPLEMENT ƒ Complex series of plasma proteins (C1-C9). ƒ Heat labile (inactivated at 56 C for 30 min). ƒ Synthesized in vivo by liver macrophages, hepatocytes and intestinal epithelia. ƒ Can be synthesized in vitro by monocytes and macrophages. ƒ C3 is most abundant (1g/L of plasma) and important complement component. ƒ Complement system ; Plays a major role in innate and adaptive immunity.
Complement functions Host benefit: opsonization to enhance phagocytosis phagocyte attraction and activation lysis of bacteria and infected cells clearance of immune complexes clearance of apoptotic cells Host detriment: Inflammation, anaphylaxis
Proteins of the complement system (nomenclature) C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 factors B, D, H and I, properdin (P) mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2)
Definitions C-activation: alteration of C proteins such that they interact with the next component C-fixation: utilization of C by Ag-Ab complexes Convertase/esterase: altered C-protein which acts as a proteolytic enzyme for another C-component
Activation product of complement proteins (nomenclature) When enzymatically cleaved, the larger moiety, binds to the activation complex or membrane and the smaller peptide is released in the microenvironment Letter b is usually added to the larger, membrane-binding, peptide and a to the smaller peptide (e.g., C3b/C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membranebinding moiety is C2a; the smaller one is C2b)
Pathways of complement activation CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY
THE CLASSICAL COMPLEMENT PATHWAY ƒactivated by Ag-Ab binding (can also be activated by viruses, Mycoplasma, DNA).
ƒ One IgM molecule can stimulate C1 since it is a pentamer with 5 Fc regions. At least 2 IgG molecules are required to activate C1. ƒ IgM more efficient complement binding (fixing) antibody than IgG. ƒ IgA and IgE lack C1q receptors and cannot activate complement. ƒ Activated C1q activates C1r which activates C1s.
Components of the Classical Pathway C3 C4 C1 complex
Classical Pathway Generation of C3-convertase
Classical Pathway Generation of C3-convertase C4b2a is C3 convertase C4b
Classical Pathway Generation of C5-convertase C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway C4b C3 b
Biological Activities of Classical Pathway Components Component Biological Activity C2a(or b) C3a C3b C4a Prokinin; cleaved by plasmin to yield kinin, which results in edema Anaphylotoxin; can activate basophils and mast cells to degranulate resulting in increased vascular permeability and contraction of smooth muscle cells, which may lead to anaphylaxis Opsonin Activation of phagocytic cells Anaphylaotoxin C4b Opsonin 24
Control of Classical Pathway Components Component Regulation All C3a C3b C4a C1-inhibitor (C1-INH); dissociates C1r and C1s from C1q C3a-inactivator Factors H and I; Factor H facilitates the degradation of C3b by Factor I C3a-INH 25
C1-inhibitor deficiency: hereditary angioedema
Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway
Components of the lytic pathway C6 C7 C 9
Lytic pathway C5-activation b C4b C3b
Lytic pathway: insertion of lytic complex into cell membrane C6 C C C 9 9 9 C C 9 C 9 C 9 9 C C 9 9 C7 b
MANNAN-BINDING LECTIN COMPLEMENT PATHWAY ƒ Activated by binding of a serum protein -mannose-binding lectin (MBL) to mannose-containing proteins or to carbohydrates on bacteria or viruses. ƒ Activates the classical pathway in an (antibody and C1) independent manner. ƒ MBL is structurally similar to C1q. Instead of C1r and C1s, MBL associates with mannose-binding lectin-associated serum proteases (MASP-1 and MASP-2) to activate C4 and C2 ƒ Activation by MBL:MASP complex generates C3 convertase which progresses as in the classical pathway to produce the membrane attack complex.
Components of mannose-binding lectin pathway MBL MASP1
Mannose-binding lectin pathway MASP1 C4b2a is C3 convertase; it will lead to the generation of C5 convertase MBL