Complement System Flashcards
What are the 10 complement regulatory proteins? (found on the surface of human cells)
- C1 Inhibitor (C1-Inh)
- MCP
- DAF (CD55)
- CR1
- C4 Binding Protein (C4BP)
- Factor H
- Factor I
- CD59
- S Protein
- Vitronectin
Effects of MCP
- Cofactor for I-mediated cleavage of C3b and C4b
- Cofactor for inactivation of C3b complement fragment
Effects of C1 Inhibitor
- Inactivates C1r and C1s proteases, and MASP-1 and MASP-2
- IRREVERSIBLE inactivation prevents activation of the CP and LP initiating complexes
- Also inhibits the Kallikrein-Kinin (inactivates plasma kallikrein resulting in formation of Bradykinini which then causes swelling) and coagulation cascades
Effects of DAF (CD55)
- Destabilizes C3/C5 convertase of the CP and AP (decay accelerating activity) by inducing rapid dissociation of C2a or Bb
- Involved in protecting RBCs from lysis by complement
- One of the two GPI anchor proteins
Effects of CR1
- Decay accelerating activity of as well as cofactor activity for I-mediated cleavage of C3b and C4b
Effects of C4BP
- Binds to C4b in Lectin and CP
- Decay accelerating and cofactor activity
Effects of Factor H
- Binds to C3b
- Has decay accelerating activity of the AP C3 and C5 Convertases and cofactor activity
Effects of Factor I
- Degrades C3b and C4b aided by cofactors
Effects of CD59
- Blocks the C9 association with C5b-8 to prevent C5b-9 formation on host cells
- Involved in protecting RBCs from lysis by complement
- One of the two GPI anchor proteins
Effects of S-Protein
- Binds to C4b and inhibits C9 polymerization
What are the three different regulatory proteins that destabilize C3 convertase in the CP?
- DAF (CD55)
- CR1
- C4BP
What are the three different regulatory proteins that destabilize C3 convertase in the AP?
- DAF (CD55)
- Factor H
- CR1
Is DAF (CD55) soluble or membrane-bound?
Membrane-bound
Is CR1 soluble or membrane-bound?
Membrane-bound
Is C4BP soluble or membrane-bound?
Soluble
Is Factor H soluble or membrane-bound?
Soluble
Cleavage of C3b and C4b by _____ directly prevents the formation of the C3 Convertase and indirectly prevents the formation of C5 Convertase in all 3 pathways
Factor I
What are the three different regulatory proteins that act as cofactors for Factor I in inactivating C3b? (AP, CP and Lectin)
- MCP
- CR1
- Factor H
What are the three different regulatory proteins that act as cofactors for Factor I in inactivating C4b? (CP and Lectin)
- MCP
- C4BP
- CR1
Is MCP soluble or membrane-bound?
Membrane-bound
Is CD59 soluble or membrane-bound?
Membrane-bound
Is Vitronectin soluble or membrane-bound?
Soluble
Effects of Vitronectin
MAC inhibitory binding protein that prevents C9 binding and polymerization
Is S Protein soluble or membrane-bound?
Soluble
What are the effects of a C3 deficiency?
- Susceptibility to capsulated bacteria
- Increased numbers of severe bacterial infections with extracellular bacteria
What are the effects of a C1, C2, or C4 deficiency?
Immune-complex disease / autoimmune disease
What are the effects of a C5-C9 deficiency?
Susceptibility to Neisseria (large genus of gram-negative bacteria)
What are the effects of a Factor D or Properdin (Factor P) deficiency?
(involved in AP)
- Susceptibility to capsulated bacteria and Neisseria but no immune-complex disease
What are the effects of a Factor I deficiency?
Similar effects to deficiency of C3 – susceptibility to capsulated bacteria
What are the effects of a DAF (CD55) or CD59 deficiency?
Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH: consequence of the failure to regulate the formation of MAC, cells lack all surface proteins liknked through GPI anchor)
What deficiencies are most commonly associated with infections caused by neisseria meningitis?
Deficiencies in MAC formation (C5 to C9) OR deficiencies in the AP (i.e Factor B and Properidin)
What are the effects of a C1Inh deficiency?
Hereditary angioneurotic edema (HAE)
Which 3 protein fragment peptides are known as anaphylatoxins?
- C3a
- C4a
- C5a
Which two protein peptide fragments contribute to processes of inflammation?
C3a and C5a
What is often done to treat undesired inflammatory responses and tissue damage?
Target neutralization of C3a and C5a or inhibit their receptors (C3aR and C5aR)
What are the pathophysiological effects of C3a?
- Contraction of smooth muscle
- Increased permeability of blood vessels
- Degranulation of basophils
What are the pathophysiological effects of C5a?
- Contraction of smooth muscle
- Increased permeability of blood vessels
- Degranulation of basophils
- Chemotaxis, release of O2 radicals and lysosomal enzymes
What are the two most important glycosylphosphatidylinositol (GPI) anchor proteins? (essentially they link surface proteins to cellular membranes and help protect RBCs from lysis by complement)
CD55 (DAF) and CD59
Ab-based treatments can be used to restore the balance in the complement network in order to achieve therapeutic effects.
Activation can be achieved via Fc-induced complement activation – i.e antiCD20 for ___
B cell lymphomas
Ab-based treatments can be used to restore the balance in the complement network in order to achieve therapeutic effects.
Inhibition can be achieved by targeting key components of the complement cascade ___, __, __, __, and ___
C1, C3, C5, FI, FD
What test measures the CP and its terminal components?
CH50
What test measures the AP and its terminal components?
AH50
How are the CH50 and AH50 tests used to evaluate the AP and CP pathways?
Both tests involve measuring the ability of the patients serum (containing complement proteins) to lyse sheep RBCs
CH50 Test
Defined as the amount of the patient’s serum that will lyse 50% of sheep RBCs coated with antibody
AH50 Test
Defined as the amount of the patient’s serum that will lyse 50% of sheep RBCs that are NOT coated with antibody
What does it mean if both AH50 and CH50 test results are abnormal?
It is likely there is a deficiency in one of the terminal pathway components — defects in C5 and/or C9
When should LP be tested for a defect?
- If CH50 is abnormal and AH50 is normal
- Test involves measuring concentration of MBL in the blood by an ELISA
What makes up the C3 Convertase in the CP?
C4bC2a
What makes up the C5 Convertase in the CP?
C4bC2aC3b
What makes up the C3 Convertase in the AP?
C3bBb
What makes up the C5 Convertase in the AP?
C3bBbC3b
What makes up the C3 Convertase in the LP?
C4bC2a
What makes up the C5 Convertase in the LP?
C4bC2aC3b
What is the MAC made of?
C5bC6C7C8C9
What is required for C1 to bind in the CP?
One IgM or two IgG or C reactive protein
What is the role of C3b in the CP and LP?
Opsonization and phagocytosis
What is required for initiation of LP?
MBP binds to bacterial surface –> MASPs bind to MBP
What is required for initiation of AP?
Nothing - C3 undergoes spontaneous hydrolysis