Complement Pathways Flashcards
What are complements?
Circulating and cell membrane proteins that form part of the innate immune system
What is the function of complement proteins?
Help the innate system
Promote inflammatory and immune responses
What are the 3 complement activation pathways?
- Classical
- Lectin
- Alternative
Why are there 3 pathways?
Redundancy in case 1 fails
How does the classical pathway act?
Antigen-antibody complexes —> complement activation
What are the 3 consequences of complement activation?
- Inflammatory cell recruitment
- Opsonization
- Pathogen killing
How is the classical complement pathway activated?
- C1 (complement component) binds to antigen-antibody complex via its C1q recognition region
How is the lectin pathway activated?
Mannan-binding lectin (MLB) binds to terminal polysaccharide on surface of microbe
-Not found on mammalian cell surfaces
How is the alternative pathway activated?
Deposition of complement component C3b on pathogen surface
At which complement component do the 3 different pathways converge?
C3
What is the relationship between the complement and immune system?
Bridge between the adaptive and immune system
Classical complement responds to the adaptive immune system (Ig production —> antigen-antibody complexes)
- Effector mechanism
What antibodies are involved in the classical pathway?
IgM or IgG
- Bind with antigen —> antibody-antigen complex
- Complex binds to C1q (subunit of C1)
What is C1q?
One of 3 proteins making up C1 protein complex - binding domain
What is the region that C1q binds to on the antibody called?
Fc region
The “pole” of the “Y” on antibodies
What Ig is most effective at activating C1?
IgM
What Ig cannot activate the complement system?
IgG4
What becomes active when a complex binds to C1q?
C1s and C1r proteases are activated
What does C1s esterase cleave?
C4 –> C4b & C4a –> C2 –> C2a & C2b
What happens in the classical pathway to form C3 convertase?
C4b complexes with C2a on the Ab-Ag membrane –> C4bC2a (aka classical pathway C3 convertase)
What is distinct about the MBL pathway?
Specific for pathogens that have mannose residues on their surface?
What are the steps of the MBL pathway?
- MBL similar to C1q
- MBL binding with mannose –> MASP-2 (protease) to cleave C4 and C2 –> C4bC2a on pathogen surface –> C3 convertase
How is MBL similar to the classical pathway?
MBL = C1q
MASP2 = C1s esterase
What are some substances that can trigger the alternative pathway?
- Endotoxins
- Necrotic cells
- Some microorganisms
- Aggregated Ig molecules
What are the steps in the alternative pathway?
C3b deposition on particle surface –> factor B (serum protein) combining with C3b –> C3bB –> factor D cleaves B –> Ba
Ba released into fluid phase
Bb associated with C3bBb
C3bBb –> C3 convertase and stabilized on cell surface with properdin
What is a common product of all 3 complement pathways?
C3 convertase
What parts make up C3 convertase in the classical and lectin pathways?
C4b and C2a = C4bC2a
What parts make up C3 convertase in the alternative pathway?
C3b and Bb = C3bBb
Which C3 fragment after cleavage is released into the fluid phase?
C3a
Which C3 fragment after cleavage binds to the cell surface?
C3b
What does properdin (factor P) do?
Stabilizes C3bBb to cell surface –> rapid cleaving of C3 molecules –> C3b buildup on pathogen surface –> alternative pathway amplification loop
What doe C5 convertase consist of?
C4b, C2a, and C3b = C3 convertase + C3b
What C5 fragment after cleavage is released into the fluid phase?
C5a
What C5 fragment after cleavage binds to the cell surface?
C5b
What are the main activities of the complement system?
- Opsonin production
- Anaphylatoxins that add inflammation
- Direct lysis of microbes
How does the complement system carry out opsonization?
C3b binding marks antigens for immune cell recognition
Cells of the innate immune system have complement receptors (CRs) that bind to C3b
What cells is CR1 found on?
Phagocytic cells
What cells is CR3 found on?
- Monocytes
- Granulocytes
- NK cells
What cells is CR4 found on?
- Myeloid cells
- others
What complement proteins are involved in opsonization?
C3b and C4b
What is an anaphylatoxin?
- Bind to receptor on mast cell —> rxn similar to allergic hypersensitivity rxn
List the anaphylatoxin complement proteins (3)
C3a
C4a
C5a
What is triggered by anaphylatoxin binding to its cell receptor?
Histamine and other mediator release
Increases smooth muscle contraction
More vascular permeability and fluid accumulation in tissue
What anaphylatoxin is also chemoattractant?
- C5a attracts neutrophils
These 3 complement proteins bind in sequence to C5b to form membrane attack complex
C6 binds to C5b
C7 binds to C6
C8 binds to C7
What is the consequence of a membrane attack complex forming?
Essential for cell lysis
Allows water to enter the cell —> lysis
Where are complement proteins made?
Mainly made in the liver
What acts on the liver to induce synthesis of acute phase proteins?
IL-6
This protein interacts with C1q to trigger the classical pathway in the absence of antibody
CRP
What does CRP bind to —> phagocytosis?
Phosphorylcholine on liposaccharides in microbial cell walls
What does an immune complex consist of?
Ab-Ag
What cell transports immune complexes to the liver and spleen?
RBCs
On what receptor does the immune complex bind to be carried to the liver and spleen?
CR1
What is a consequence of not clearing immune complexes from circulation?
IC deposit on vessel —> acute inflammation and immune pathology
What complement receptor is associated with acute inflammation?
CR5a
What cells is CR5a found on?
Causes inflammatory response
Smooth muscle cells
Endothelial cells
Mast cells
Basophils
Enhances chemotasix
- Phagocytes
This receptor has similar distribution to CR5a
CR3a — binds C3a (anaphylatoxin)
What 3 steps can regulation occur in the complement pathway?
Initiation and activation
Amplification
Membrane attack complex
How does C1 inhibitor work?
Binds activated C1r and C1s, removes them from C1q
- Controls activation and initiation
How is C4-binding protein involved in complement regulation?
Controls amplification
Dissociates C3 convertase subunits in classical pathway
Cofactor for Factor I-mediated cleavage of C4b
How is Factor I involved in complement regulation?
Controls amplification
- Cleaves C3b and C4b
How is Factor II involved in complement regulation?
Controls amplification
Dissociated C3 convertase in alternative pathway
cofactor for Factor I mediated cleavage of C3b
What can C1 inhibitor deficiency cause?
Angioedema
Would C4 levels be expected to be high or low in C1 inhibitor deficiency?
Low
R/t spontaneous C4 activation and consumption
What is decay accelerating factor?
CD55 — Controls amplification
Membrane protein
Dissociates C3 convertase subunits
What pathways are impacted if there is a defect in CD55 (decay accelerating factor)?
All 3 pathways since it impacts C3 convertase (convergence point for all 3 pathways)
What does CD59 do?
Membrane protein that regulates membrane attack complex
- Acts by blocking C9 binding and forming of MAC
What is a consequence of CD55 and CD59 deficiencies?
Cells more susceptible to lysis
