Lecture 20: CIS - Basic Complement System

Question 1

Alternate Complement Pathway

Answer 1

• autoactivation (1% of total C3 per hour = C3a and C3b)
• C3b binds Factor B, which is cleaved by Factor D

C3 convertase: C3bBb –> cleaves additional C3 moles

• Properdin: stabilizes C3bBb during process

C5 convertase: C3bC3bBb –> cleave C5

Question 2

MAC Formation and Bacteria Lysis

Answer 2

• C5bC6C7 bind to membrane via C7
• C8 binds to complex and INSERTS into membrane
• C9 binds to complex and polymerizes (1-16 molecules)
• pore formed in membrane

Question 3

Classical Complement Pathway

Answer 3

• Ab-mediated (1 IgM or 2 IgG)
• C1q binds to Ag-Ab complexes (Fc portions) and activates C1r/C1s (serine proteases)
• C1r activates C1s, which activates C4 and C2

C3 convertase = C4bC2a

C5 convertase = C4bC2aC3b

Question 4

Lectin Complement Pathway

Answer 4

• Mannose Binding Lectin binds to terminal mannose on glycolipids and glycoproteins (similar to C1q)
• zymogens MASP1 and MASP2 activate –> initiate downstream cascade similar to C1r and C1s

C3 convertase = C4bC2a

C5 convertase = C4bC2aC3b

Question 5

What does the C1 inhibitor do?

Answer 5

• inactivates C1r and C1s, MASP-1 and MASP-2

Question 6

What does the Decay-Accelerating Factor (DAF) do?

Answer 6

• destabilizes C3/C5 convertases of CP and AP
• blocks C4b:C2 interaction
• enhances dissociation of C4bC2a

Question 7

What does Membrane Cofactor Protein (MCP) do?

Answer 7

• cofactor for Factor 1-mediated cleavage of C3b and C4b

- involved with Factor 1 to cleave C3b and C4b, and prevent them from forming active convertases

Question 8

What does Complement Receptor Type-1 (CR1) do?

Answer 8

• decay accelerating activity as well as cofactor activity Factor 1-mediated cleavage of C3b and C4b

Question 9

What does MAC Inhibitory Complex (CD59) do?

Answer 9

• blocks C9 association w/C5b-8 to prevent C5b-9 formation on cells
• also vitronectin and clusterin

Question 10

What immune cells do C3a and C5a affect?

Answer 10

C3a –> mast cell/basophil –> vasoactive substances

C5a –> monocyte/macrophage –> IL-1/IL-6, prostaglandins, ROS/NOS

Question 11

Glomerulonephritis and Complement

Answer 11

• most glomerular diseases IMMUNOLOGIC in origin
• deposition of immune complexes/Abs binding to Ags in kidney
• MAC activates mesangial/epithelial cells –> release proteases; C5a attracts neutrophils
• ROS/inflammatory cytokine production by attracted inflammatory cells and proteases both play a role in glomerulonephritis

Question 12

Vasculitis and Complement

Answer 12

• vessel inflammation –> immune-complex deposition or direct Ab interaction (usually immune-mediated mech)
• immune complexes deposited on vessel walls, causing vasculitis through classical complement pathway
• seen in patients with hepatitis B/C and SLE (LUPUS)

Question 13

Hereditary Angioedema (HAE)

Answer 13

• very rare, potentially life-threatening genetic condition
• edema (hands, feet, THROAT), intense abdominal pain, nausea, vomiting
• SWELLING OF AIRWAY/THROAT = Asphyxiation
• defect in gene controlling C1 inhibitor (inactivate enzymes that are NOT part of complement cascade)

Question 14

What is HAE also known as?

Answer 14

C1 Inhibitory Deficiency

Question 15

What does C1-INH do?

Answer 15

• C1 Inhibitor
• inactivates enzymes that are not part of complement cascade
• inactivates plasma kallikrein, which helps produce bradykinin (causes of swelling)

Question 16

Paroxysmal Nocturnal Hemoglobinuria (PNH) and Complement

Answer 16

• failure to regulate formation of MAC
• somatic mutation = glycosylphosphatidylinositol deficiency
• lack GPI anchor proteins DAF (CD55) and CD59, which normally protect RBCs from action of complement
• intravascular hemolysis is caused by increased susceptibility of RBCs to complement