Complement06
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Transcript of Complement06
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Introduction
Complement – A series of serum proteins involved in the effector role of the immune response to pathogens
Made up of approximately 30 circulating and membrane-bound proteins.
Synthesized in the liver and by cells involved in the inflammatory response.
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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
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Complement functions
• Host benefit:– opsonization to enhance phagocytosis– phagocyte attraction and activation– lysis of bacteria and infected cells– regulation of antibody responses– clearance of immune complexes– clearance of apoptotic cells
– Host detriment:
Inflammation, anaphylaxis
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Proteins of the complementsystem (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)
• C1 inhibitor (C1-INH, serpin), C4-binding protein (C4-BP), decay accelerating factor (DAF), Complement receptor 1 (CR1), protein-S (vitronectin)
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• C-activation: alteration of C proteins such that they interact with the next component
• C-fixation: utilization of C by Ag-Ab complexes
• C-inactivation: denaturation (usually by heat) of an early C-component resulting in loss of hemolytic activity
• Convertase/esterase: altered C-protein which acts as a proteolytic enzyme for another C-component
Definitions
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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, membrane-binding moiety is C2a; the smaller one is C2b)
Activated component are usually over-lined: e.g. C1qrs
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COMPLEMENT
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Biological Activities of Classical Pathway Components
Component Biological Activity
C2b Prokinin; cleaved by plasmin to yield kinin, which results in edema
C3a 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
C3b Opsonin
Activation of phagocytic cells
C4a Anaphylotoxin
C4b Opsonin
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Product Biological Effects Regulation
Biological properties of C-activation products
anaphylactic as C3, but much more potent;attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release
C5a (chemotactic factor)
carboxy-peptidase-B (C3-INA)
C5b67 protein-Schemotaxis, attaches to other membranes
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Control of Classical Pathway Components
Component Regulation
All C1-inhibitor (C1-INH); dissociates C1r and C1s from C1q
C3a C3a-inactivator
C3b Factors H and I; Factor H facilitates the degradation of C3b by Factor I
C4a C3a-INH
C4b C4 binding protein (C4-BP) and Factor I; C4-BP facilitates degradation of C4b by Factor I; C4-BP also prevents the association of C2a with C4b thus blocking formation of C3 convertase
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Biological effects of C5a
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Overview of Complement-mediatedOverview of Complement-mediatedBiological EffectsBiological Effects
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Biological Functions ofBiological Functions ofComplementComplement
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Complement Deficiencies and DiseaseClassical Pathway
Pathway Component Disease Mechanism
C1INH HereditaryAngioedema
Overproduction of C2b (prokinin)
C1, C2, C4 Predisposition to SLE
Opsonization of immunecomplexes help keepthem soluble, deficiencyresults in increasedprecipitation in tissuesand inflammation
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Complement Deficiencies and DiseaseLectin Pathway
Pathway Component Disease Mechanism
MBL Susceptibility to bacterial infections in infants orimmunosuppressed
Inability to initiate lectin pathway
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Complement Deficiencies and DiseaseAlternative Pathway
Pathway/Component Disease Mechanism
Factors B or D Susceptibility to pyogenic (pus-forming) bacterial infections
Lack of sufficient opsonization of bacteria
C3 Susceptibility to bacterial infections
Lack of opsonization and inability to utilize the membrane attack pathway
C5, C6, C7 C8, or C9
Susceptibility to Gram-negative infections
Inability to attack the outer membrane of Gram-negative bacteria
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Complement Deficiencies and DiseaseAlternative Pathway cont.
Pathway Component Disease Mechanism
Properdin (X-linked) Susceptibility meningococcal meningitis
Lack of opsonization of bacteria
Factors H or I C3 deficiency and susceptibility to bacterial infections
Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3
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Enhancing B Cell Responses to Antigens
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Removal of Immune Complexes
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Removal of Necrotic cells and Subcellular Membranes
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Responses to Viruses
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The Assay Contains Three Components and Three Steps
Components:
1. The test system Incubate serum + test antigen
2. Complement Add complement
3. The indicator system Add the indicator system
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Complement FixationAssay
(positive test)
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Complement Fixation Assay
(negative test)
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The End