Complement - Regal Flashcards
What order is complement activated in?
C142356789
What is the function of the complement system?
A group of plasma proteins that acts as an auxiliary system in immunity, both on its own and in conjunction with humoral immunity.
Define the complement system
A primitive surveillance system for microbes, independent of T-cells and antibodies.
What are the 6 specific functions of complement?
- Lysis of microorganisms
- Opsonization of antigen
- Mediators of inflammatory response
- Solubilization and clearance of immune complexes
- Clearance of apoptotic cells
- Augments stimulation of B-cell
What are the 3 pathways of Complement Activation?
Classical Pathway
Lectin Pathway
Alternative Pathway
What are the 5 additional proteins operating in the alternative pathway?
Factors B, D, H, I, P = Properdin
What types of interactions occur after C5 is cleaved?
C6, C7, C8, and C9 only have protein-protein interactions.
When C1 is cleaved, what remains?
C1q = binds antigen-antibody complex C1qr2s2 = cleaves C4 C1r2s2 = cleaves C2
When C4 is cleaved by C1 esterase (C1qr2s2), what remains?
C4b and C4a (little)
When C2 is cleaved by C1s, what remains?
C2a and C2b (little)
What cleaves C3?
C4bC2a Enzyme C3 Convertase
When C3 is cleaved by C4bC2a, what remains?
C3b and C3a (little)
What cleaves C5?
C4bC2aC3b Enzyme C5 Convertase
When C5 is cleaved, what remains
C5b and C5a (little)
How is the Classical Pathway activated?
Antigen-Antibody Complexes with IgG (dimer) or IgM (pentamer)
How is the Mannose-Binding Lectin Pathway activated?
Mannose, sugar, polysaccharides on microbes
How is the Alternative Pathway activated?
Recognizes LPS/Endotoxin, foreign surfaces, carbohydrates, nucleophiles, Human IgA, IgG, IgE complexes by complement itself
What enzyme catalyzes the cleavage of complements?
Serine Esterases
Define Activating Surface.
Deficient in Sialic Acid, free hydroxyl or amino groups, rich in carbohydrates
MBL is similar to C1qr2s2 in what way?
C4bC2 is cleaved by MBL interacting with MASP-1 and MASP-2 to C4bC2a similar to the C1q-C1r-C1s interaction
Define Deactivating Surface.
Lots of Sialic Acid
What is C3 Tickover?
A little bit of C3 all the time in the blood is getting hydrolyzing thioester and picking up water. This causes Factor B to bind to C3 [C3(H20)B]. Then Factor D comes in and enzymatically cleaves Factor B to C3(H20)Bb.
True/False: C3 activates itself via C3(H20)Bb cleaving C3 to C3b.
True
How is C3b inactivated on a non-activated bacterial surface?
Factor I and Factor H
C3 Convertase
C4b2a
C3bBb
C5 Convertase
C4b2aC3b
C3bBbC3b
What Complement Deficiencies would cause SLE?
C1, C4, C2, C3
What Complement Deficiencies are associated with high incidence of immunocompromised disease?
C1, C4, C2
Infections of encapsulated bacterial infections or pyogenic infections
Classical Pathway
Immune Complexes
MBL pathway Complement Deficiency is common where and increases susceptibility to what?
Common in UK
Increased susceptibility to Bacterial Infections
What Complement Deficiency is associated with Glomerulonephritis (Immune Complex)?
C3
What Complement Deficiencies cause Neisseria Meningococcal Infections?
Membrane Attack Complex
C5, C6, C7, C8, C9
Alternative pathway and terminal lytic pathway
What is complement good for?
Lysing Bacteria and Clearing Immune Complexes
Where is complement?
In the plasma protein system, but also in secretions (bronchoalveolar lavage fluid)
What starts the Classical Complement Pathway?
Antigen Antibody Complexes
What starts the Mannose-Binding Lectin Pathway?
Mannose-Binding Lectin
Mannose-Associated Serine Protease 1 or 2
What components of the complement system covalently bind to the surface of the bacteria?
C4b and C3b via thioester bonds
C1 Inhibitor Deficiency
HAE (Hereditary Angioedema)
Recurrent episodes of localized edema in skin, GI, or larynx
C1 Inhibitor inhibits C1 esterase
Uncontrolled activation leads to consumption of C4 and C2
What is the treatment for Hereditary Angioedema?
Anabolic steroids to increase synthesis of C1 Inhibitor or give purified C1 Inhibitor
Kallikrein inhibitors and B2 receptor inhibitors => less edema
Decay Accelerating Factor (CD55) & CD59 Deficiency
Increased susceptibility of erythrocytes to MAC-mediated lysis
Complement-mediated intravascular hemolysis in Paroxysmal Nocturnal Hemoglobinuria (PNH)
Treatment of DAF Deficiency
Antibody to C5 to reduce hemolysis = Eculizumab
Where is complement synthesized?
Liver hepatocytes and tissue macrophages
Epithelial cells, fibroblasts, monocytes
Activation of the complement system by antibody coated Streptococcus pneumoniae leads to the formation of a C3 convertase enzyme. The subunit composition of this enzyme is most likely:
C4bC2a
Classical Antibody-Antigen Complex Pathway
Which of the following complement proteins covalently binds to surfaces after enzymatic cleavage and exposure of an internal thioester bond?
C4b or C3b
Excessive complement activation in immune complex disease would most likely result in depletion of which of the following components?
C4
Terminal Lytic Pathway
Formation of the Membrane Attack Complex (MAC)
Describe the steps of the Terminal Lytic Pathway
C5 Convertases cleave C5 into C5a and C5b. C5b attaches via protein-protein interactions to C6, C7, C8, C9s leading to a hole in the membrane.
True/False: Lysis cannot occur in the absence of C9.
False - it’s just slower
Limitations to Complement Activation
Short half-life
Non-activator surfaces
Fluid phase inhibitors - so active fragments don’t stray
Membrane bound inhibitors - so C3b and C4b can’t attach and lyse our own cells
C5b-7 can bind to what in order to prevent membrane insertion and MAC formation?
S protein in the fluid phase
How does CD59 (Protectin) offer protection for your own cells?
Inhibits binding of C9 and its polymerization on self- membranes
Factor H is a fluid phase inhibitor of what?
C3 Convertase Can also be a cofactor for cleavage of C3b by Factor I
What if you have deficiencies of the complement control system?
Uncontrolled lysis and consumption of complement components leading to secondary complement deficiency.
Anaphylatoxin Receptors
Complement peptides that bind to G-Protein coupled receptors to trigger inflammatory and anaphylactic response
C3 fragment interaction with CR2 complement receptor on lymphocytes does what?
Augments humoral immunity
What does CR1 (CD35) do?
Ligands: C3b, C4b
Transports immune complexes by RBC and blocks formation of C3 convertase
Cells: RBC, PMN, Macrophages
What does CR2 (CD21) do?
Ligands: C3d, C3dg, C3bi
Augments stimulation of the B-cells
Affinity for envelope protein of EBV (allowing for viral entry into B-Cells)
Cells: B-Cells
What does CR3 (CD11b/CD18) and CR4 (CD11c/CD18) do?
Ligand: C3bi
Phagocytosis and cell adhesion
Cells: Monocytes, macrophages, neutrophils, NK cells
Numerous C3b molecules are deposited on the surface of bacteria X. The C3b favors the phagocytosis of the bacteria by neutrophils by binding to which of the following?
CR1
