Complement Pathway Flashcards
What does the term complement mean?
The term complement refers to a set of 50-plus serum proteins that cooperates with both the innate and the adaptive immune systems to eliminate pathogens, dying cells, and immune
complexes from the body.
Once the complement system activates, what are the possible outcomes
Once activated, multiple possible outcomes
*Target cell membrane lysis
*Chemotaxis
*Opsonizationto enhance phagocytosis
*Inflammation
What are the three ways to activate the complement system?
Three activation pathways exist
* Classical
* Lectin
* Alternative
All three pathways generate C3b, an important, multifunctional complement protein
How is the complement activated via the classical pathway?
* IgM or IgG binds to a multivalent antigen
- C1q binds antigen-bound antibody, and induces a conformational change in one C1r mocule, activating it. This C1r then activates the second C1r and the two C1s molecules
- C1s cleaves C4 and C2. C4 is cleaved first and C4b binds to the membrane close to C1. C4b binds C2 and exposes it to the action of C1s. C1s cleaves C2, creating the C3 convertsae, C4b2a
- C3 convertase hydrolyzes many C3 molecules. Some combine with C3 convertase to form C5 convertase
- The C3b. component of C5 convertase binds C5, permitting C4b2a to cleave C5
What does C5 initiate
C5 initiates the generation of the Membrane Attack Complex (MAC)
- Membrane attack complex is the result of deposition of C5b, C6, C7, C8, and C9 in target cell membranes
- This pore structure disrupts osmotic integrity, resulting in cell death
How is the lectin pathway initiated?
The lectin pathway is initiated when soluble proteins recognize microbial antigens
- Lectins (e.g., mannose-binding lectin, or MBL) bind to microbial surfaces
- Lectins can serve as dockingsites for MBL-associated serine proteases (MASPs)
* MASPs cleave C4 and C2 to form the C3 convertase * Subsequent steps are thesame as the classical pathway
How can the alternative pathway be initiated?
The alternative pathway is initiated in three ways:
* alternative tickover pathway
* properdin-initiated pathway
* protease-initiated pathway
What is the difference between fluid-phase and membrane-bound C3 convertases?
What is the alternative tickover pathway?
- Small amounts of C3 are always being cleaved.
- Cleaved C3 is usually quickly inactivated if nothing is around for it to bind.
- Activated C3b binds to membrane of target cell.
- Factor B binds and is then cleaved by Factor D.
- C3bBb at the membrane is the C3 convertase.
- Properdin stabilizes the C3 convertase, which can then cleave many more C3 proteins.
- Newly active C3b binds to C3bBb to form C3bBbC3b, or the C5 convertase.
- C5 convertase cleaves many C5 proteins.
What is the alternative properdin-activated pathway
- Properdin can directly bind to a surface.
- Then, C3b and Factor B are recruited.
- Factor D is recruited and cleaves Factor B into Bb.
- The resultant C3bBb is an active C3 convertase.
- Subsequent steps are identical to alternative tickover pathway.
What is the alternative protease-activated pathway?
- Initiation of clotting cascades has also been shown to stimulate cleavage of complement proteins.
- Thrombin cleaves C3 and C5 in vitro
- Platelet activation releases ATP, calcium ions (Ca2+), and serine/threonine kinases that could stabilize C3b in fluid phase.
- This indicates that strong inflammatory reactions could potentially activate complement systems.
How does the complement enhance host defense against infection
Complement enhances host defense against infection
- MAC-induced cell death
- Promotion of inflammation
- Promotion of opsonization
- Opsonized microbes easier to ingest/destroy
- Opsonized immune complexes easier to clear
How does the complement receptors help B cells?
Complement receptors connect complement-tagged pathogens to effector cells
- CR2 on B cells
- Binds to C3d on opsonized bacteria/antigens
- Helps provide secondary signals to B cells through BCR complex for more efficient activation
The
interaction between CD21 on the B cell, and antigen-associated C3d, enhances the avidity of the B cell–antigen binding
How does the complement receptors help granulocytes
- C3aR/C5aRon granulocytes
- Stimulates release of proinflammatory cytokines and granule components from basophils, eosinophils, neutrophils
How does the complement aid in the contraction phase of the immune response?
- As lymphocytes are no longer required, complement aids in disposal of apoptotic cells and bodies
- Complement also aids in removal/disposal of immune complexes formed during responses
- These responses avoid damaging inflammation induction in the absence of antigens following clearance of an infection
At the close of an adaptive immune response, most of the lymphocytes that were generated in the initial proliferative phase undergo apoptosis (programmed cell death), leaving only a few antigen specific cells behind to provide immunological memory (see Chapters 10 and 11). We refer to this stage as the contraction phase of an immune response. At this stage, soluble antigen antibody complexes may still be present in the bloodstream and immune organs. If autoimmune disease is
to be avoided, these excess lymphocytes and immune complexes must be disposed of safely, without the induction of further inflammation, and complement components play a major role in these processes.
What is C1INH
The C1 inhibitor, C1INH, promotes dissociation of C1 components
* Binds in the active site of serine proteases
* Causes C1r2s2 to dissociate from C1q
* No further cleavage of C4 or C2 is possible
* Inhibits initiation of classical and lectin complement pathways
What are decay accelerating factors?
Decay accelerating factors promote decay of C3 convertases
* Several different proteins with similar activities
- DAF (CD55), CR1, C4BP (C4 binding protein)
- Factor H binds negatively charged cell surface sialic acid and heparin, molecules unique to eukaryotic cell surfaces
- Work to accelerate the decay of C4b2a (C3 convertase) on the surface of host cells
What are carboxypeptidase?
- Carboxypeptidases can inactivate the anaphylatoxins C3a and C5a
- By removing arginine residues from the C termini of C3a and C5a
- Creates des-Arg(without arginine)inactive forms
- Helps to shut down unnecessary or dangerous chemotactic and inflammation induction
