Basic Complement Flashcards
What are the complement pathways?
Classical (adaptive)
Alternative (innate)
Lectin (innate)
C3 convertase cleaves C3 into what?
C3a – stimulates inflammation; chemoattractant for neutrophils
C3b – Attaches to microbial surface as opsonin; Attracts phagocytosis
C3 convertase binds with C3b to form what?
C5 convertase
C5 convertase cleaves C5 into what?
C5a – Soluble; Very potent chemoattractant that induces changes in permeability of blood vessels
C5b – Initiates formation of MAC
What does the complement system work in cooperation with?
- Blood coagulation pathway
- - Kinin-Kallikrein pathway (regulates vascular permeability)
How is the alternative pathway activated?
Via autoactivation because of a process called “tickover” of C3
***Tickover occurs spontaneously to C3, generating C3a and C3b
(AP) C3b is capable of binding ________ that can be cleaved into _____ and ______ by the constitutively active serum protease ________.
Factor B
Ba
Bb
Factor D
(AP) The Bb associates with C3b, which forms _________. This can then cleave additional C3 molecules, generating more C3b.
C3 convertase (C3bBb)
(AP) The successive proteolytic steps is enhanced by a serum protein _________, which stabilizes C3bBb interactions during the process.
Properdin
Explain the formation of the MAC complex.
- C5b binds C6 and C7
- C5b67 complexes bind to membrane via C7
- C8 binds to complex, inserts into membrane
- C9 binds to complex, polymerizes
- 1-16 molecules of C9 bind to form pore in membrane
This pathway is Ab-mediated.
Classical pathway (CP)
(CP) A plasma protein called _____ recognizes and binds to Ag-Ab complexes (hence why it’s ADAPTIVE immunity).
C1q
(CP) Once C1q binds to the ______ portion of Abs, two associated serine proteases, called ______ and ______, become active.
Fc
C1r
C1s
(CP) C1r activates C1s so that it can, in turn, activate _____ and ______.
C2
C4
What is the C3 convertase complex for the CP and LP? The C5 convertase complex?
C4bC2a
C4bC2aC3b
How is the Lectin pathway activated?
Binding of Mannose-binding Lectin (MBL) to bacterial surface and activation of MBL-associated serine proteases MASP1 and MASP2
(LP) MBL recognizes terminal mannose residues on microbial glycoproteins and glycolipids (similar to the mannose receptor on _______).
Phagocytes
(LP) After MBL binds to microbes, two zymogens called ______ and ______ are activated. These have similar functions to C1r and C1s, and initiate downstream cascade IDENTICAL to the CP.
MASP1
MASP2
The CP requires what Abs to activate it?
IgM
2x IgG
C1
What are the complexes for C3 convertase and C5 convertase for the alternative pathway?
C3bBb
C3bBbC3b
The cleavage of C3b and C4b by ________ prevents them from forming active convertases and requires cofactor activity.
Factor I
For C3b, the cofactors needed with Factor I are…
MCP
CR1
Factor H
For C4b, the cofactors needed with Factor I are…
MCP
CR1
C4BP
These cofactors inhibit assembly of new C3 convertases and shorten the half-life of the preformed convertases. For the classical pathway they are…
DAF
CR1
C4BP
These cofactors inhibit assembly of new C3 convertases and shorten the half-life of the preformed convertases. For the alternative pathway they are…
DAF
CR1
Factor H
The MAC is the lytic complex of complement and its assembly can be inhibited by…
CD59
Vitronectin
S protein
Complement is not activated on the surface of (BACTERIAL/MAMMALIAN) cells because they express regulatory proteins that inhibit, disassemble, or cleave the convertases.
Mammalian
These inflammatory mediators are often released from phagocytes after adhesion of soluble complement fragments.
PG (prostaglandins)
ROS (reactive oxygen species)
RNS (reactive nitrogen species)
Most _______ diseases are immunology in origin. They are the result of either the deposition of immune complexes or the result of Abs directly binding to Ags in the kidney.
Glomerular
T/F. CP attracts neutrophils via C5a and C5b-9 form the MAC. The production of ROS and inflammatory cytokines by the attracted inflammatory cells and production of proteases are both though to play a pathogenic role in glomerulonephritis.
True
This is the inflammation of the vessels, which most commonly has an infectious or immune-mediated cause.
Vasculitis
Immune-Mediated vasculitis occurs due to one of two mechanisms, which are…
- Immune-complex deposition
- - Direct antibody interaction
Abs induced by the disease process bind Ags. This interaction forms an immune complex (IC) that deposits within the vessel wall. Deposition of the ICs causes vasculitis through the ________ pathway of complement activation.
Classical
This is a very rare and potentially life-threatening genetic condition. Symptoms include edema in various parts of the body, excruciating abdominal pain, nausea, and vomiting due to swelling in intestinal wall. Swelling of the airway or throat can cause death by asphyxiation.
Hereditary angioedema (HAE)
HAE patients have a defect in the gene that controls a blood protein called _______. This defect causes a biochemical imbalance that produces swelling.
C1 inhibitor (C1-INH)
***HAE is also known as C1 Inhibitor Deficiency
T/F. C1-INH can inactivate enzymes that are not part of the complement cascade, so without it there is continuous activation of the plasma complement.
True
C1-INH also inactivates plasma kallikrein, an enzyme that cleaves a plasma kininogen to produce _________. This is the cause of the swelling seen in HAE (because C1-INH is deficient and can’t inactivate the kallikrein).
Bradykinin
This disease is a striking example of the consequences of the failure to regulate the formation of MAC. It is a somatic mutation that causes a deficiency of ______.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
GPI
PNH cells lack all the proteins linked through the GPI anchor to their cellular membranes. Two of the most important GPI anchor proteins are ______ and ______. These are complementary regulatory proteins involved in protecting the RBCs from the action of complement. Without these, RBCs are more susceptible and intravascular hemolysis can occur.
DAF (CD55)
CD59
This is on the surface of all cells and inhibits C3 convertases and C5 convertases by inducing rapid dissociation of C2a or Bb.
DAF
This inhibits the formation of the MAC by binding to sites on C8 and C9, thus blocking the uptake and incorporation of multiple C9 molecules into the complex.
CD59
