Complement Flashcards
What are the effects of complement activation?
- recruit phagocytes
- killing the pathogen through lysis (MAC)
- opsonization and antigen clearance
- generate an inflammatory response
Define complement activation.
Complement components create complexes on the surface of pathogenic antigens to facilitate an immune response. Soluble fragments are also produce that are important. There are 3 pathways.
What are the complement activation pathways and their stimuli?
- Classical pathway = antibody binds to antigen
- Lectin pathway = MBL/ficolin binds to mannose/oligosaccharides
- Alternative pathway = components bind directly to pathogen surface
Describe the sequential events for C1qrs activation.
- antibody binds to antigen, opening up a site on the Fc for C1q
- 2 C1q globular heads must simultaneously bind to the antibody
- Once bound, C1r cleaves C1s => C1s is active
Describe the sequential events for MASP activation.
- Mannin Binding Lectin (MBL) or ficolin bind to mannose/oligosaccharides on pathogen surface
- MBLs and ficolin have 2 associated serine proteases (MASP1/MASP2)
- MASP1 cleaves MASP2 => MASP2 is now active
Describe the sequential events that lead to MAC in classic/lectin pathway
- Activation of C1s and MASP2 (see previous cards)
- C1s/MASP2 cleave C4 => C4a and C4b
- C4b binds to the pathogen surface
- C2 binds to C4b
- C1s/MASP2 cleave C2 => C2b and C4b2a
- C4b2a is a C3 convertase => cleave C3 => C3a and C4b2a3b
- C4b2a3b is a C5 convertase => cleaves C5 => C5a and C5b
- C5a is a soluble inflammatory mediator
- C5b complexes with C6, 7, 8, and 9 to create the MAC
What is important about C3 convertase?
major point of amplification
- 1 C3 convertase can cleave 1000s of C3s
What complex is a C5 convertase?
- C4b2a3b
- C3bBb3b
What complex is a C3 convertase?
- C4b2a
- C3(H2O)Bb
- C3bBb
Describe the sequential events that lead to MAC formation by the alternative pathway.
- C3 is hydrolyzed to form C3(H2O)
- C3(H2O) binds to Factor B
- Factor D cleaves C3(H2O)-B => Ba and C3(H2O)Bb
- C3(H2O)Bb is a C3 convertase => C3a and C3b
- Most C3b is degraded, but some attaches to the pathogen surface
- Factor B binds to C3b on the surface
- Factor D cleaves Factor B => Ba and C3bBb
- Properdin (Factor P) binds to C3bBb and stabilizes it
- C3bBb is a C3 convertase => C3a and C3bBb3b
- C3bBb3b is a C5 convertase => C5a and C5b
- C5b complexes with C6, 7, 8, 9 to form MAC
What effects do soluble components C3a and C5a have?
- recruit phagocytes
- promote inflammation
- C5a also stimulates phagocytosis
What is the receptor for C3b?
CR1 found on phagocytes
What are the functions of C4b2a3b?
- C5 convertase
- powerful opsonin
- enhances antigen uptake
How does complement activation lead to cell lysis?
- formation of MAC
- pore disrupts homeostasis
- causes lysis
- also works on viruses
How does complement activation lead to opsonization?
- phagocytic leukocytes (neutrophils and macrophages) express CR1
- CR1 binds to C3b or C4b on an antigen and enhances adherence and ingestion
How does complement activation lead to antigen clearance?
- antigen:antibody complexes bind to CR1 (via C3b) on circulating RBCs
- RBCs go to spleen or liver, where resident phagocytes remove the complex from their surface
How does complement activation lead to inflammation?
Chemotaxis
- C5a attracts phagocytes via a C5a gradient in activation areas
Vascular Changes
- C3a, C4a, C5a bind to receptors on mast cells and basophils
- cause histamine release
- increase vascular permeability => fluid leakage and immune cell recruitment
What are anaphylatoxins?
C3a, C4a, C5a
cause increase in vascular permeability
Describe inhibition of C1.
via C1 INH
- dissociates C1r and C1s from C1qrs
Describe inhibition of C3 convertase.
inhibition of C3 convertase causes dissociation of C4b2a
- decay-accelerating factor (DAF)
- C4-binding protein (C4BP)
- complement receptor 1 (CR1)
- membrane cofactor protein (MCP)
- Factor I
Describe inhibition of C5 convertase.
inhibition of C5 convertase causes dissociation of C4b2a3b
- Factor I
- Factor H
- complement receptor 1 (CR1)
What inhibits both C3 and C5 convertase?
- Factor I
- CR1
How is MAC formation regulated?
CD59 prevents complexing with C9
What do deficiencies in early complement components of the classical pathway lead to?
- deficient in C1, 2, 4
- immune complex disease
What do deficiencies in early complement components of the lectin pathway lead to?
- deficient in MBL, ficolin, MASP1/MASP2, C2, C4
- bacterial infections
What do deficiencies in early complement components of the alternative pathway lead to?
- deficient in factor B and factor D
- pyogenic bacterial infection, Nisseria, NO immune complex disease
What does a C3 deficiency lead to?
- pyogenic bacterial infections
- Nisseria
- some immune complex disease
What do deficiencies in C5-9 lead to?
Nisseria infection only
Describe Hereditary Angioneurotic Edema.
- C1 INH deficiency
- overactive C1
- fluid accumulation, epiglottal swelling
Describe Paroxysmal Nocturnal Hemoglobinurea.
- impaired CD59
- increased MAC formation
- RBC lysis
