Podcast
Questions and Answers
What product is released when C3 is cleaved by C3 convertase?
What product is released when C3 is cleaved by C3 convertase?
Which of the following complement components is involved in forming C5 convertase?
Which of the following complement components is involved in forming C5 convertase?
Which biological activity of complement involves the production of factors that enhance phagocytosis?
Which biological activity of complement involves the production of factors that enhance phagocytosis?
What is the most potent anaphylatoxin among C3a, C4a, and C5a?
What is the most potent anaphylatoxin among C3a, C4a, and C5a?
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Which complement receptor is present on red blood cells as well as phagocytic cells?
Which complement receptor is present on red blood cells as well as phagocytic cells?
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What are the three main complement pathways?
What are the three main complement pathways?
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Which complement component serves as the central element across all three complement pathways?
Which complement component serves as the central element across all three complement pathways?
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What is the primary biological role of complement activation?
What is the primary biological role of complement activation?
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In the classical complement pathway, which immunoglobulin is most effective in activating complement?
In the classical complement pathway, which immunoglobulin is most effective in activating complement?
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What components do all three complement pathways have in common?
What components do all three complement pathways have in common?
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Which of the following proteins is involved in the alternative pathway of complement activation?
Which of the following proteins is involved in the alternative pathway of complement activation?
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Which immunoglobulin does NOT activate complement in the classical pathway?
Which immunoglobulin does NOT activate complement in the classical pathway?
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What role do complement receptors play in the immune response?
What role do complement receptors play in the immune response?
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What is the primary role of Decay Accelerating Factor (DAF) in the complement system?
What is the primary role of Decay Accelerating Factor (DAF) in the complement system?
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Which condition is primarily associated with deficiencies in CD55 and CD59?
Which condition is primarily associated with deficiencies in CD55 and CD59?
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How do CD55 and CD59 get anchored to the cell membrane?
How do CD55 and CD59 get anchored to the cell membrane?
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What is the function of CD59 in the complement system?
What is the function of CD59 in the complement system?
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What therapeutic agents are used to target the complement system's C5 component?
What therapeutic agents are used to target the complement system's C5 component?
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What is the function of C1s esterase in the complement activation process?
What is the function of C1s esterase in the complement activation process?
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Which component forms the C3 convertase in the classical pathway?
Which component forms the C3 convertase in the classical pathway?
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What triggers the alternative pathway of complement activation?
What triggers the alternative pathway of complement activation?
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What is the role of Properdin in the alternative pathway?
What is the role of Properdin in the alternative pathway?
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In the Mannose Binding Lectin pathway, what is activated upon MBL binding to mannose residues?
In the Mannose Binding Lectin pathway, what is activated upon MBL binding to mannose residues?
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Which of the following correctly describes the formation of C4bC2a?
Which of the following correctly describes the formation of C4bC2a?
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What occurs during the amplification loop of the alternative pathway?
What occurs during the amplification loop of the alternative pathway?
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Which antigen characteristic prevents it from activating complement when bound to IgG4?
Which antigen characteristic prevents it from activating complement when bound to IgG4?
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What role does C5a play in the immune response?
What role does C5a play in the immune response?
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Which component binds first to C5b in the formation of the Membrane Attack Complex?
Which component binds first to C5b in the formation of the Membrane Attack Complex?
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What is the function of C9 in the formation of the Membrane Attack Complex?
What is the function of C9 in the formation of the Membrane Attack Complex?
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Which statement accurately describes the terminal components of the Membrane Attack Complex?
Which statement accurately describes the terminal components of the Membrane Attack Complex?
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What is the consequence of a deficiency in C9?
What is the consequence of a deficiency in C9?
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How are complement pathways activated during acute inflammation?
How are complement pathways activated during acute inflammation?
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Which interleukin acts on the liver to induce acute phase protein synthesis?
Which interleukin acts on the liver to induce acute phase protein synthesis?
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What is the primary function of the Membrane Attack Complex in the immune response?
What is the primary function of the Membrane Attack Complex in the immune response?
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What is the primary function of C5a binding to CR5a on mast cells?
What is the primary function of C5a binding to CR5a on mast cells?
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Which of the following describes the role of C1 inhibitor (CI-INH) in the complement system?
Which of the following describes the role of C1 inhibitor (CI-INH) in the complement system?
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What condition is primarily associated with a deficiency in C1 inhibitor (C1-INH)?
What condition is primarily associated with a deficiency in C1 inhibitor (C1-INH)?
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How does Factor H contribute to the regulation of the complement pathway?
How does Factor H contribute to the regulation of the complement pathway?
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Which complement regulator is responsible for cleaving both C3b and C4b?
Which complement regulator is responsible for cleaving both C3b and C4b?
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The deficiency of which regulator results in low levels of C4 during Hereditary Angioedema (HAE)?
The deficiency of which regulator results in low levels of C4 during Hereditary Angioedema (HAE)?
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What occurs when C4 binding protein (C4BP) functions in the complement pathway?
What occurs when C4 binding protein (C4BP) functions in the complement pathway?
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Which component is primarily responsible for the production of bradykinin during angioedema?
Which component is primarily responsible for the production of bradykinin during angioedema?
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Study Notes
Complement Pathways
- Complement is a group of circulating and cell membrane proteins part of the innate immune system
- Major functions: assist the immune system in eliminating pathogens or damaged cells, either through opsonization and phagocytosis or cell lysis (killing of cells); promote inflammatory and immune responses
- The heat-sensitive component of serum identified by Jules Bordet and Paul Ehrlich
Lecture Objectives
- Demonstrate understanding of the three complement pathways
- Describe biological role of complement activation
- Explain the involvement of complement receptors in regulation of complement activity
- Explain the role of complement and complement receptors in removal of immune complexes
Complement Pathways & Nomenclature
- Classical Pathway: Complement components (C1, C4, C2, C3, C5, C6, C7, C8, C9) (activation, amplification, terminal)
- Lectin Pathway: Mannose-binding lectin (MBL), C4, C2, C3, C5, C6, C7, C8, C9 (activation, amplification, terminal)
- Alternative Pathway: Factors B, D, Properdin, C3, C5, C6, C7, C8, C9 (activation, amplification, terminal)
Overview of Complement Pathways
- Classical Pathway: Activated by antigen-antibody complexes
- MB-Lectin Pathway: Activated by lectin binding to pathogen surfaces
- Alternative Pathway: Activated by pathogen surfaces
Activation - The Classical Complement Pathway
- C1q has to cross-link the Fc of 2 Ig molecules – IgM or IgG, bonded to an antigen
- Note: soluble antigens bounded to IgG4 cannot activate complement
- Interaction of C1q with Ab-Ag complex activates proteases C1r & C1s
- C1s cleaves C4 and C2, resulting in C4b, C4a, C2a, and C2b
- C4b complexes with C2a on the Ab-Ag complex forming C3 convertase
Activation - The Mannose Binding Lectin (MBL) Pathway
- Terminal mannose residues not found on mammalian cells but expressed on numerous types of bacteria, fungi, and viruses
- MBL is structurally similar to C1q; circulating it is bound to MASP
- MBL binds to mannose residues causing MASP-2 to cleave C4 and C2, forming C4bC2a on the surface of the bacterium. (similar to classical pathway – C4bC2a forms C3 convertase)
Activation - The Alternative Pathway
- Triggered by various foreign substances (endotoxins, necrotic cells, microorganisms, aggregated Ig molecules)
- Hydrolysis of C3 results in small amounts of “preformed” C3b in the serum
- C3b deposited on a particle binds Factor B, forming C3bB
- Factor D cleaves B into Ba and Bb (Ba released into fluid phase); Bb remains associated with C3b
- C3bBb forms the C3 convertase & is stabilized by properdin.
Amplification: Generation of C3 & C5 Convertases
- C3 convertase is made from C4bC2a (classical and lectin pathways) or C3bBb (alternative pathway)
- The alternative pathway has an amplification loop with Properdin binding and cleaving large amounts of C3 to C3b, allowing more C3b to bind to the surface
- C3 convertase cleaves C3 into C3a (fluid phase) and C3b, depositing with C4bC2aC3b (classical/MBL) or C3bBb3b (alternative pathway)
- This forms C5 convertase
- C5 convertase cleaves C5 into C5a (fluid phase) and C5b, which binds to the surface
Main Biological Activities of Complement
- Production of opsonins (mediating phagocytosis)
- Production of anaphylatoxins (contributing to inflammation)
- Direct killing (lysis) of microbes by forming membrane attack complex (MAC)
Complement Receptors (CR)
- CR1 (CD35): found on phagocytic cells and erythrocytes; binds C3b, C4b, iC3b; enhances phagocytosis and transports immune complexes to the liver
- CR3 (CD11b): found on phagocytic cells; binds iC3b; stimulates phagocytosis
- CR4 (CD11c): similar to CR3
The Role of Complement and Complement Receptors in the Removal of Immune Complexes (IC)
- C3b + IC binds to CR1 on RBCs, which transport them to the liver and spleen
- Complexes bind to CR3 & Fc receptors on macrophages for degradation
- Deficiency in clearing IC results in IC deposition in vessels, joints, etc., leading to acute inflammation
Complement Receptors cont'd
- C5a receptor (CR5a): found on various cells (smooth muscle, endothelial, mast cells, basophils); binding of C5a to CR5a promotes anaphylatoxin-like response and inflammation; found on phagocytes (neutrophils); presence of C5a enhances chemotaxis
- C3a receptor (CR3a): binds C3a; similar cell distribution and function as CR5a
Complement Regulators
- Group of plasma and cell membrane proteins preventing excessive complement activation
- Regulation occurs at three steps in the complement pathway: initiation and activation, amplification (C3 and C5 convertases), and membrane attack complex
Complement Regulation - Regulatory Proteins Found in the Plasma
- C1 Inhibitor (C1-INH): binds activated C1r and C1s; removes them from C1q
- C4 binding protein (C4BP): dissociates C3 convertase subunits in classical pathway; cofactor for Factor I-mediated cleavage of C4b
- Factor I: cleaves C3b and C4b
- Factor H: dissociates C3 convertase subunits in the alternative pathway; cofactor for Factor I-mediated cleavage of C3b
Clinical Relevance (C1-INH & Angioedema)
- Genetic mutation in C1NH gene causes Hereditary Angioedema (HAE)
- C1-INH regulates interconnecting pathways (coagulation, fibrinolytic, and kinin)
- Production of large amounts of bradykinin (potent vasodilator) contributes to angioedema
Membrane Proteins that Regulate Complement Activation
- Decay Accelerating Factor (DAF) or CD55: found on many cell types; important in regulating amplification by dissociating C3 convertase subunits; defect affects all three pathways
- CD59: found on many cell types; regulates the membrane attack complex by binding C5b-C8 to block C9 binding & formation of MAC
Resource Material
- Relevant articles and videos for further study on complement pathways, regulators, and their roles in acute inflammation and other health conditions
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Description
This quiz covers the three complement pathways involved in the innate immune system. It includes the classical and lectin pathways, their activation, biological role, and regulation through complement receptors. Test your understanding of key components and functions in immune response.
