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Terms in this set (42)
A set of plasma proteins that act together as a defense against pathogens in the extracellular space.
-Consists of about 30 plasma proteins
-Secreted as inactive proenzymes
>Activation of most components requires
-Pathogens becomes coated with complement proteins that facilitate its removal by
and that can also kill certain pathogens directly.
-Activation of the complement system can be initiated in several different ways: classical pathway, alternative pathway, and lectin pathway.
-During inflammation: activation of complement is greatly enhanced.
Complement System (Function)
Split products generated during complement activation promote inflammation.
-MAC (membrane attack complexes): Lysis of the foreign cells and bacteria.
>Not bind well to Gram +
-C3b, C3bi, C4b: Opsonization and bacterial phagocytosis
>Helps with binding to capsules
-C5a>C3a>>>C4a: Chemotactic anaphylatoxin (leukocyte chemoattractants)
>vasodilation (vascular permeability);
>granulocytes + mast cells activate and degranulate-> smooth muscle contraction.
>Complement proteins, Bradykinin (pain)
Complement System Pathways and initiators
-Alternative: C3b ("tick over")
Membrane Binding proteins and Opsonins
Peptide mediators of inflammation
Membrane attack proteins
Lectin Pathway (general)
Pathway triggered by Mannose-binding lectins (MBLs) or ficolins bound to bacteria
-MBL and ficolins recognize and bind to
on pathogen surface.
Uses soluble receptors that recognize microbial surfaces to activate the complement cascade
Classical Pathway (general)
Pathway that is initiated by C1 binding either directly to bacterial surface or to antibody bound to bacteria
-FLAGGING the bacteria as foreign.
-C1q interacts with pathogen surface or with the antibodies bound to the surface.
Alternative Pathway (general)
Pathway that is triggered by the presence of a pathogen in the absence of specific antibodies
-Part of the
innate immune system
-Production of complement protein
and its binding to the surface of the pathogen
-After: The pathways is the same as classical and lectin pathways of complement activation.
-C3 undergoes spontaneous hydrolysis to C3(H2O) to initiate eventual deposition of C3 convertase on microbial surface.
Enzyme complex that cleaves C3 to C3b and C3a on the surface of a pathogen.
-All pathways generate a C3 convertase, which cleaves the C3.
>Leaves C3b bound to the microbial surface
>C3a is RELEASED.
C3 cleavage (mechanism)
C3 protein is cleaved to generate a beta-chain and alpha chain that is held together by a disulfide bond.
-Before cleavage by c3 convertase: the thioester bond within Thioester-containing domain (TED) is protected from reacting.
-Cleavage of C3 releases C3a
>changes the conformation of C3b allows the thioester bond to react with a chemical group on the pathogen surface.
>The reactive thioester group of C3b is TED.
-C3b is bound to pathogen surface!
-C3b is inactivated via
The coating of the surface of a pathogen by antibody and/or complement that makes it more easily ingested by phagocytes.
>Prepares particles for phagocytosis by coating it with molecules for which phagocytes have receptors that can mediate internalization.
-One of the most important consequences of complement activation is to target bacteria for phagocytosis by "decorating" the bacterial surface with the
>C3b with tag bacterium for destruction, while C3a will recruit phagocytes.
Main opsonins: antibodies and complement components C3b and C4b-> bind directly to the surface of microbes
Encapsulated pathogens are RESISTANT to phagocytosis UNLESS they are opsonized.
Biologic Function of Complement Split Products
-All pathways generate a
that cleaves C3: leaves C3b bound to the microbial surface and releases C3a.
-C3a and C5a recruit phagocytic cells to the site of infection and promote inflammation.
Phagocytes with receptors for C3b
engulf and destroy the pathogen.
-Completion of the complement cascade leads to formation of a membrane-attack complex (MAC): disrupts cell membrane and causes lysis.
Lectin Pathway of Complement Activation (Mechanism)
Mannose-binding lectin (MBL) or ficolin binds carbohydrate on pathogen surface.
-MBL/ficolin, MASP-2 (mannose-binding lectin-associated serine protease) bind to C3 and C2.
>MASP split C4 and C2.
-C3 convertase activity
>C3a and C5a: peptide mediators for inflammation and phagocyte recruitment.
>C3b: Binds to complement receptors on phagocytes, opsonization of pathogens, and removal of immune complexes
>C5-C9: Membrane attack complex, lysis of certain pathogens and cells.
Binding specificity of MBL allows detection of pathogens
-MBL monomers form trimeric clusters of carbohydrate-recognition domains
-MBL binds with high avidity to mannose and fructose residues.
The serene protease MASP-2 associated with MBL or ficolin cleaves C4 to C4a and C4b, which binds to microbial surface.
-C4b then binds C2, which is cleaved by MASP-2 to C2a and C2b.
-C4b2a is an active
-C2a enzyme that cleaves C3 and C5
-C3 convertase cleaves C3 to C3a and C3b (binds to microbial surface)
MASPs are serene proteases that split C4 and C2 which help make up the C3 convertase
Classical Pathway Complement Activation (mechanism)
Antigen:antibody complexes on pathogen surfaces
-Initiated by activation of
and is homologous to the Lectin pathway.
-C1q interacts with pathogen surface or with antibodies bound to the surface.
>The classical pathway is initiated by activation of the C1 complex.
>If antibodies: C1q interacts with antibodies bound to the antigen; activated by immune complexes (Ag/Ab complexes)
>If directly binding to pathogen surface: C1 binding to
on the pathogen surface activates the classical pathway of complement fixation (
exception to adaptive initiation
-C1q, C1r, and C1S (C1 complex), C4, and C2 are present
-C3 convertase is formed and cleaves C3
-C3a and C5a: peptide mediators of inflammation, phagocyte recruitment
-C3b stays bound to complement receptors on phagocytes
>Opsonization of pathogens and removal of immune complexes
-Terminal complement components (C5-C9): Membrane-attack complex, lysis of certain pathogens and cells.
Proteins of the classical pathway of complement activation
C1q: Bind directly to pathogen surface or indirectly to antibody bound to pathogen; allows activation of C1r
C1r: Cleaves C1s active protease
C1s: Cleaves C4 and C2.
Alternative pathway of Complement Activation (mechanism)
Pathway that is triggered by the presence of a pathogen in the absence of specific antibodies
-Pathogen surface bound with
C3, B, and D
of plasma membrane C3 to generate C3b which binds to the pathogen surface.
>C3 undergoes spontaneous hydrolysis to C3(H2O) that noncovalently binds to factor B allowing it to be cleaved by factor D into Ba and Bb.
>C3(H2O)Bb complex is a C3 convertase, cleaving more C3 into C3a and C3b.
>C3 convertase is stabilized by
Properdin (Factor P)
-C3 convertase activity: C3b formed and binds to pathogen surface
>If pathogen surface is UNAVAILABLE for C3b: will be rapidly inactivated (
-C3a and C5a: peptide mediators for inflammation and phagocyte recruitment.
-C3b: Binds to complement receptors on phagocytes, opsonization of pathogens, and removal of immune complexes
-C5-C9: Membrane attack complex, lysis of certain pathogens and cells.
Spontaneous hydrolysis= "Tick Over"
Proteins of Alternative Pathway
C3b: Binds to pathogen surface, binds B for cleavage by D
-C3bBb is C3 convertase
Factor B (B): Bb is active enzyme of C3 convertase.
Factor D (D): Plasma serine protease that cleaves B when it is bound to C3b into Ba and Bb.
Factor P (P): Plasma protein that binds to bacterial surfaces and stabilizes the C3 convertase of the alternative pathway.
(Alternative, Lectin, and classical order)
Initiate Serine Pathway: D, MASP, C1S
Covalent binding to cell surface: C3b and C4b (Lectin and classical)
C3/C5: Convertase: Bb and C2a (lectin and classical)
Initiation of effector pathway: C5b (pores)
Local inflammation: C5a and C3a
Stabilization: P (only in alternative pathway->unique)
C3 convertase deposits
Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates
C5 convertase activity
Complement protein that is cleaved to release:
-Proinflammatory peptide C5a: Phagocyte recruitment (macrophages, neutrophils)
-Larger fragment C5b: that initiates the formation of a membrane-attack complex from the terminal components of complement.
-C5 cleaved by C2a or Bb.
Enzyme complex that cleaves C5 to C5a and C5b.
Terminal complement Proteins
The terminal complement proteins polymerize to form pores in the membrane that can kill certain pathogens
-Gram negative bacteria are most susceptible to lysis by MAC (membrane-attack complexes) than gram positive bacteria.
C5a: Small peptide that mediates inflammation (high activity)
C5b: Initiates assembly of the membrane-attack system
-C6-C9: Help with pore formation-> Lyses the cell.
-C5b binds to C6 and C7.
-C5b67 complex finds to membrane via C7.
-C8 binds to the complex and inserts into the cell membrane.
-C9 molecules bind to the complex and polymerize.
-Multiple C9 binds to form a PORE in the membrane.
Cell-surface proteins that recognize and bind complement proteins that have become bound to an antigen such as a patoghen.
-Complement receptors on phagocytes enable them to identify and bind pathogen coated with complement proteins, and ingest/destroy them.
-CR1, CR2, CR3, CR4, CRIg, C5a receptor, C3a Receptor
Binding of C5a activates G protein
-Endothelial cells, mast cells, phagocytes
Binding of C3a actuates G protein
Local inflammatory response
Small fragments of some complement proteins initiate a local inflammatory response
-C5a, C3a, and C4a chemotactic
-Act on BVs to increase vascular permeability and cell adhesion molecules.
-Increased permeability allows for increased fluid leakage from BVs and extrvasation of immunoglobulins and complement molecules.
-Migration of macrophages, PMNs, and lymphocytes is increased.
Overview of function of complement
C3b: Opsonization, activation of lymphocytes/phagocytes, and transport of immune complexes (erythrocytes)
C3a, C5a: Release of inflammatory mediators (mast cells/basophils)
C5a: Also does chemotaxis (neutrophils/macrophages)
C5b-9: Lysis of cell
Complement activation is largely confined to the surface on which it was initiated
Complement Control Proteins
Regulate all three pathways of complement activation and protect the host from their destructive effects.
-C4 binding protein
Stages at which complement activity is regulated (Classical pathway)
-C1q binding to antigen:antibody complexes activates C1r and C1s
-C1 INH dissociates C1r and C1s from the active C1 complex.
Deficient levels or defective C1INH results in HAE
-Edema is due to excessive levels of C2b.
C3 Convertase disruption
C4b2a is active C3 convertase, cleaving C3
DAF, C4BP, and CR1
displace C2a from the C3b2a complex
-C4b bound by
C4BP, MCP, or CR1
is cleaved by a soluble protease I to inactive forms of C4d and C4c.
Paroxysmal Nocturnal Hemoglobinuria
-Mutation in the PIGA gene cause PNH
-Acquired, de novo mutations
DAF (CD55), CD59, and MCP (CD46) are GPI-anchored proteins.
Cleavage of C3b
CR1, Factors H and I cleave C3b to iC3b
-Complement activity is regulated
-CR1 and Factor H displace C3b
-H acts as a cofactor in the cleavage of C3b by I.
-Factor I is the serine protease
Blockage of membrane attack complex
CD59: Prevents formation of membrane attack complex: expressed on membranes
-Blocks membrane attack complex assembly
-The terminal components of complement form a membrane pore (membrane attack complex)
>CD59 prevents final assembly of the membrane attack complex at the C8 to C9 stage.
Pathogen associated molecular Pattern
-Viral nucleic acid
-Lipids etc. of intracellular bacteria
Pathogen Recognition Receptor
-TLR3, TLR7, RIG-I
Membrane Attack Complex of complement can cause lysis of susceptible pathogens
Gram negative √
Enveloped viruses √
Gram positive X (must opsonize the bacteria so phagocyte can destroy)
Encapsulated pathogens X (use lysozymes)
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