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Questions and Answers
What is the primary role of the complement system?
How are complement proteins denoted in nomenclature?
What initiates the classical pathway of the complement system?
What happens to complement proteins when activated?
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What temperature and duration inactivate complement proteins in the lab?
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What is the primary role of C1 in the classical pathway of complement activation?
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Which complement proteins are cleaved by the activated C1 complex?
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What is the role of C3b in the immune response?
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Which statement correctly describes the function of C5a?
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What results from the combination of C2b and C4b?
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What is the significance of the C3 activation complex?
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Which complement component is primarily involved in boosting the inflammatory response by stimulating mast cells?
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What are the products of the cleavage of C3 by the C3 activation complex?
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What is the primary function of the Membrane Attack Complex (MAC)?
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Which component is involved in the formation of the C3 activation complex in the alternative pathway?
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Which protein is crucial for stabilizing the C3bBb complex in the alternative pathway?
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What initiates the alternative pathway of complement activation?
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Which of the following statements about the C5 activation complex is true?
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What is the role of C5b in the complement system?
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Which of the following is NOT a characteristic of the alternative pathway?
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What ultimately happens to the integrity of a cell when the MAC is active?
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What type of immunity is primarily associated with the classical pathway?
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Which component is involved in the activation of the mannose binding lectin (MBL) pathway?
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What is the role of C3b in the complement system?
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Which regulatory protein prevents spontaneous activation of the classical pathway?
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What conditions result from a deficiency in the MAC component of the complement system?
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Which complement component is both anaphylatoxin and chemotaxin?
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What does the CH50 test measure in terms of complement activity?
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What is the function of Decay Accelerating Factor (DAF) in the complement system?
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Study Notes
The Complement System
- A defensive system consisting of over 30 proteins (activators and regulators) produced by the liver and found in circulating blood serum
- Discovered by Jules Bordet in 1896
- Inactivated in the lab by heating serum at 56 degrees Celsius for 30 minutes
Complement System Nomenclature
- Beta-1 and Beta 2 globulins are fractions of serum proteins separated by electrophoresis
- Complement proteins are included in these globulins, especially C3 and C4
- Complement proteins are named with a capital "C", followed by a number (e.g., C3)
- A small letter after the number indicates the size of the protein after activation
- 'a' indicates a smaller fragment that diffuses away from the surface
- 'b' indicates a larger fragment that binds to the cell surface
- Nomenclature is based on order of discovery, NOT order of activation (C1, C4, C2, C3)
Classical Pathway
- Considered part of the specific/adaptive immune response as it relies on antibodies
- Activators:
- Antigen-antibody complex
- Apoptotic cells
- Certain viruses / gram-negative bacteria
- CRP bound to ligand
- Initiated when C1 binds to the ends of antibodies (at least 2 CH2 domains)
- IgM is more effective at complement fixation than IgG
Recognition Unit (Classical Pathway)
- C1 complex is the recognition unit of the Classical Pathway
- C1 recognizes at least 2 CH2 domains of antibodies
- C1 has 3 subunits: C1q, C1r, C1s
- C1q recognizes 2 CH2, activates C1r, which in turn activates C1s
C3 Activation Complex (Classical Pathway)
- Activated C1 cleaves C2 and C4 into halves
- C2 is cleaved into C2a and C2b
- C4 is cleaved into C4a and C4b
- C2b and C4b bind together on the bacterial surface
- C2a and C4a diffuse away
- C2b and C4b form the C3 activation complex/C3 convertase
- C3 activation complex cleaves C3 into C3a and C3b
- This is the pivotal point where all 3 pathways converge
- All pathways lead to C3 cleavage, forming C5 convertase
C3b
- Many C3b molecules are produced
- C3b binds and coats the bacterial surface
- C3b is an opsonin – molecules that bind to both bacteria and phagocytes
- Opsonization increases phagocytosis by 1,000 fold
C3a, C4a, C5a
- C3a, C4a, C5a disperse away from bacteria
- These small fragments act as anaphylatoxins and trigger inflammation
- C3a binds to mast cells and causes histamine release
- C5a is the most powerful chemotactic factor known for leukocytes
C5 Activation Complex (Classical Pathway)
- The C5 activation complex (C4b2b3b) cleaves C5 into C5a and C5b
- C5b binds to C6, initiating the formation of the Membrane Attack Complex (MAC)
Membrane Attack Complex (MAC)
- C5b binds to C6, activating C6 which binds to C7
- C7 binds to C8, which binds to many C9s
- These proteins form a circular complex, the Membrane Attack Complex (MAC)
- MAC causes cytolysis by creating a channel in the cell membrane
- Cytoplasm rushes out and Na+ ions and H20 rush in
- The cell's integrity is compromised, leading to cell death
The Alternative Pathway
- Part of the non-specific/innate defense
- Activated by fungal cell wall (zymosan), snake venom, lipopolysaccharide, bacterial polysaccharides, and tumor cells
- Activated spontaneously on microbial surfaces without antibodies
Factor B (Alternative Pathway)
- C3b on the bacterial surface binds to Factor B
- C3b + Factor B = C3bBb
- Factor B resembles C2 in the classical pathway
Factor D (Alternative Pathway)
- Factor D cleaves Factor B into Ba and Bb
- Bb remains bound to C3b, while Ba and Factor D disperse
- The C3bBb complex is stabilized by Properdin (Factor P)
- C3bBbP makes up the C3 activation complex for the alternative pathway
C3 Activation Complex (Alternative Pathway)
- The C3 activation complex produces more C3b
- This amplifies the initial steps of the pathway
C5 Activation Complex (Alternative Pathway)
- An additional C3b binds to the C3 activation complex, converting it into the C5 activation complex
- The C5 activation complex cleaves C5 into C5a and C5b
- C5b initiates MAC formation
Classic vs. Alternative Pathways
-
Classical Pathway:
- Specific, acquired immunity
- Initiated by antibody
- Involves all components
- Properdin system is NOT involved
-
Alternative Pathway:
- Non-specific, innate immunity
- Initiated by bacterial endotoxin, capsule, etc.
- C1, C4, and C2 are bypassed
- Properdin system IS involved
Mannose Binding Lectin (MBL) Pathway
- Part of the non-specific, innate immunity
- MBL is a protein present in humans
- Mannose is a sugar absent in humans but present in microbes
- MBL is homologous to C1q in structure
- MBL binds to mannose residues on microbial surfaces
- MBL-associated serine proteases (MASP) - MASP1 and MASP2 - activate the pathway
Biological Functions of the Complement System
- Lysis of target cells: MAC
- Opsonization: C3b
- Anaphylatoxins: C3a, C4a, C5a (trigger inflammation)
- Increased vascular permeability: C2a
- Chemotaxis: C5a (recruits neutrophils)
Complement Regulators
- C1 Inhibitor (C1 INH): Prevents spontaneous activation of the classical pathway
- C4b-Binding Protein (C4b-BP): Prevents C4b and C2b binding
- Decay Accelerating Factor (DAF): Dissociates C3 convertases in the classical, lectin, and alternative pathways
- Factor I: Cleaves C4b into smaller fragments (C4c and C4d)
- CD59: Prevents association of C5b678 with C9
- Factor H: Prevents binding of C3b to Factor B, cleaves C3b into C3c and C3d
Diseases and Disorders Associated with Complement Component Deficiencies
- C1 Inhibitor Deficiency: Hereditary Angioedema
- DAF Deficiency: Paroxysmal Nocturnal Hemoglobinuria
- MAC Deficiency: Recurrent infections (especially Neisseria meningitidis)
Total Complement Activity (CH50, CH100)
- Measures the integrity of the classical complement pathway (screening test)
- Based on the ability of serum to lyse sheep RBCs coated with anti-sheep antibodies
- One CH50 unit is defined as the volume or dilution of serum that lyses 50% of erythrocytes in the reaction mixture.
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Description
This quiz explores the Complement System, a crucial component of the immune response, consisting of over 30 proteins produced by the liver. You will learn about its discovery, nomenclature, and the classical pathway involved in immune responses. Prepare to test your knowledge on the mechanisms of this vital system.
