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46 Cards in this Set
- Front
- Back
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Q: Define the complement system?
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-the complement system is a group of more than 30 serum and cell surface proteins that interact with other molecules in the immune system and with one another in a highly regulated fashion to provide many of the effector functions of humoral immunity and inflammation
-the complement system is very important in both prevention of infectious disease and as a contributor to immunopathology |
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Q: Describe the origin of the term complement.
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-Jules Bordet studied Ab-mediated killing of Vibrio cholera in 1895
-found killing of bacteria by immune serum, but there was no killing by serum that lacked Ab or serum that contained Ab but was heated at 56C -concluded that the immune serum contained a heat-labile factor that complemented the action of anti-Vibrio Ab |
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Q: How is the complement system able to amplify the response to microbes?
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-there is a cascade of enzymatic/proteolytic steps
-zymogens are used which are substrate proteins (proenzymes) that once cleaved acquire proteolytic activity -there is also amplification by the action of the proteases (they cleave proteins which activated many molecules of the next component |
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Q: What are the three modes for initiation of the complement cascade?
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-classical pathway (Ab initiated)
-classical pathway (lectin initiated, MASP -> activated MASP via mannan-MBP complex) -alternative pathway -the CP and AP converge in a common membrane attack complex (MAC) |
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Q: What are the biological activities of the complement system?
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-activities due to binding of cleavage fragments to target cells
-activities due to biologically active soluble cleavage fragments -also plays a role in membrane modification (lysis or opsonization), inflammation (degranulation of mast cell or neutrophil chemotaxis) and clearance of immune complexes |
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Q: What is the nomenclature for the complement system?
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-a capital C identifies complement protein
-CP uses Arabic numbers (C1, C2) -AP uses capital English letters (factor B and factor I) -lower case letters indicate cleavage fragments (except C1r and C1s) -i before a protein indicates an enzymatically inactive form |
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Q: For the C1 (C1qC1r2C1s2) what are the component proteins and what are there functions?
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-C1q-binds to Fc of Ab, activates C1r
-C1r-serine protease that cleaves C1s -C1s-serine protease that cleaves C4 and C2 |
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Q: For the C4 protein, what are its components and what are there functions?
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-C4a-peptide mediator of inflammation (weak)
-C4b-covalently binds to target and binds C2 for cleavage by C1s |
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Q: For the C2 protein, what are its components and what are there functions?
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-C2b-no known function
-C2a-active enzyme of the classical pathway C3/C5 |
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Q: For the C3 protein, what are its components and what are there functions?
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-C3a-peptide mediator of inflammation
-C3b-covalently binds to target, is a potent opsonin and binds C5 for cleavage by C2a |
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Q: What initiates the classical pathway by Ab?
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-C1q binds to Cgamma2 domain of IgG or Cu3 domain of IgM (C1q does not bind to IgA, IgD or IgD
-human IgG subclasses differ in efficiency (IgG3 = IgG1 > IgG2 >>> IgG4) -C1q binding produces a conformational change that activates C1r |
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Q: How do the requirements for activation by IgG vs. IgM differ?
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-for both IgG and IgM, C1q must bind to two Fc regions
-IgG requires two adjacent molecules while IgM only requires one molecule therefore IgM is considered a more efficient activator that IgG |
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Q: What is a prerequisite for the Abs that activate the complement system?
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-IgG activates when in immune complexes which provides proximity
-IgM in a planar form (free) does not activated complement system, but IgM in a staple (bound to antigen) form activates because relevant Fc regions are exposed |
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Q: What are the properties of C1?
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-is a large, multimeric protein complex
-C1q has six globular heads connected to a central stalk that has recognition function (Fc) -C1q is a member of the collectin family (lectins with collagen-like stalks) |
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Q: Describe Mannan-binding lectin (MBL).
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-MBL is a member of the collectin group of C-type (Ca++-dependent) lectins
-MBL is a multimeric protein with structure similar to C1q -MBL binds to mannose and N-acetylglucosamine -MBL co-purifies with a protease named MBL-assocaited serine protease (MASP) |
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Q: Describe MASP.
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-MASP has sequence and activities similar to C1r and C1s, it cleaves C2 and C4 in a manner similar to C1s
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Q: What does MBL/MASP complex do?
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-MBL/MASP initiates the classical pathway by binding to mannose or N-acetylglucosamine on microorganisms
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Q: What happens with deficiencies in MBL?
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-deficiencies are associated with common (5-10%) defective opsonization and INC susceptibility to several infections
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Q: In terms of the alternative pathway for complement activation, what is the function of C3b?
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-covalently binds to taget cell, binds factor B for cleavage by factor D, C3b,Bb is C3 convertase while C3b2Bb is a C5 convertase
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Q: For factor B, what are its components and what are there functions?
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-factor Ba-a small fragment of B with unknown function
-factor Bb-active enzyme of C3 convertase C3b,Bb and C5 convertase C3b2Bb |
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Q: What is the function of Factor D?
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-plasma serine protease that cleaves B when it is bound to C3b
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Q: What is the function of properdin?
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-stabilizes AP C3 and C5 convertase
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Q: Describe the assembly of the membrane attack complex (MAC).
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-C6-C9 combine spontaneously with C5b to form the MAC
-produces lysis of membrane, hemolysis if the target is an erythrocyte and leakage of Hb occurs -MAC formation can be initiated by either the classical or alternative pathways |
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Q: What are the component proteins of the MAC and what are their functions?
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-C5a-small peptide mediate of inflammation (highly active)
-C5b-initiates assembly of MAC -C6-binds C5b and forms acceptor for C7 -C7-binds to C5b,6, amphiphillic complex that inserts into the lipid bilayer -C8-binds to C5b,6,7, initiates C9 polymerization -C9-polymerizes to C5b,6,7,8 to form a membrane spanning channel that lyses the cell |
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Q: Why is there a control system for the complement cascade?
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-control is essential to prevent unregulated activation of either the classical pathway or the alternative pathway with consequent depletion of complement proteins
-control si also necessary to prevent lysis of self cells -there are also many complement components that are inherntyl unstable |
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Q: What complement proteins are unstable?
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-C4b,2a can spontaneously dissociate
-C3b,Bb is unstable, properdin stabilizes it and extends half-life -metastable C3b (C3b with activated thioester) has half-life of 60 us, must bind to substate or lose activity |
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Q: What are some examples of control proteins in blood plasma?
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-C1 inhibitor (C1INH), Factor H and Factor I
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Q: What does C1 inhibitor (C1INH) do?
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-serine protease inhibitor that binds to C1r and C1s and dissociated them from C1q
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Q: What does factor H do?
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-binds to C3b displacing Bb, cofactor for factor I as well
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Q: What does Factor I do?
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-serine protease that cleaves C3b and C4b, aided by factor H, MCP, C4BP or CR1
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Q: What is decay-accelerating factor (DAF)?
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-is a control protein found on cell membranes
-is a membrane protein that displaces Bb from C3b and C2a from C4b |
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Q: Describe complement mediated cytolysis.
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-can lyse mammalian cells (self) if the regulatory systems are overcome
-can lyse infectious agents with outer membranes (gram- bacteria and viruses) -mediated by C5-C9 and MAC forms pores in membranes |
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Q: Describe opsonization via the complement system.
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-mediated by cell bound C3b and iC3b
-directly mediates attachment of complement and ingestion of cells (with C3b or iC3b on membrane) through interaction with phagocyte complement receptors -acts synergistically in Fc-mediated phagocytosis |
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Q: Describe the inflammation/vascular reponse of the complement system.
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-mediated by C5a > C3a > C4a
-C5a, C3a and C4a stimulate histamine release, C5a stimulates smooth muscle contraction |
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Q: Describe anaphylatoxins.
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-degranulation of mast cells mediated by C5a > C3a > C4a
-also releases vasoactive mediators (histamine), can cause smooth muscle contraction -chemotaxis and activation of PMN (primarily C5a which is a chemoattractant and stimulates PMN oxidative metabolism) |
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Q: Describe phagocytic clearance of immune complexes via the complement system.
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-immune complexes bind to complement receptor (CR1) on erythrocytes
-immune complexes are removed from erythrocyte surface by phagocytic cells of liver and spleen |
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Q: What role does the complement systems have on B cells?
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-enhances B cell response by stimulation of B cell complement receptor type 2 (CR2) with ligands for CR2 (C3dg)
-helps in initiation of Ab response -enhanced by interaction between C3 fragments and receptor on B cells |
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Q: Describe complement receptor type 1.
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-AKA CR1, C3b receptor, CD35
-ligands include C3d >> C4b = iC3b -found in erythrocytes, neutrophils, monocytes, macrophages, B cells and T cells -functions in clearance of immune complexes, cofactor for factor I in cleavage of C3b to iC3b, receptor active in phagocytosis of C3b-caoted cells |
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Q: Describe complement receptor type 2.
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-AKA CR2, C3d receptor, CD21
-ligands include C3d, C3dg, EBV -found in B lymphocytes, nasopharyngeal epithelial cells -functions in B cell activation, mode of EBV infection |
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Q: Describe complement receptor type 3.
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-AKA Mac-1, CR3, CD11b/CD18
-ligands include iC3b -found in monocytes, macrophages, neutrophils, NK cells -functions in cellular adhesion protein, surface adhesion and phagocytosis |
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Q: Describe complement receptor type 4.
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-AKA CR4, CD11c/CD18
-ligands iC3b -found in neutrophils, monocytes, platelets -functions in enhancing Fc-recpetor-mediated phagocytosis, mediates Fc receptor-independent phagocytosis |
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Q: Describe C5aR.
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-is a receptor for the soluble fragment of complement proteins
-found in mast cells and basophils for degranulation -found in endothelial cells to INC vascular permeability -found in PMN and monocytes for chemotaxis -found in smooth muscle for contraction |
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Q: What happens if you have C3 deficiency in the CP of complement system?
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-get defective CP and AP activation, associated with immune complex and pyogenic infections
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Q: Describe deficiencies in C5-C9.
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-get a defective MAC formation which is associated with Neisseria infection
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Q: Describe deficiencies in C1INH.
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-get deregulated CP activation and consumption of C3
-associated with hereditary angioedema (edema at sites of trauma or antigenic stimulation |
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Q: Describe deficiencies in DAF and CD59.
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-get impaired regulation of C3 and C8 deposition on host cells
-associated with PNH (intravascular hemolysis) |
