Lecture 5 - Innate Immunity (part II)

Question 1

What are the three pathways for complement activation

L5 S24

Answer 1

• classical
• lectin
• alternative

Question 2

What are the steps of complement activation that are common to all three pathways?

L5 S26

Answer 2

• C3 convertase cleaves C3 into C3a and C3b
• C3b covalently binds microbial surface
• C3 convertase binds C3b becoming C5 convertase
• C5 convertase cleaves C5 into C5a and C5b
• C5b covalently binds microbial surface
• C5b stimulates the formation of membrane attack complex (MAC) consisting of C6, C7, C8, and C9

Question 3

What are the initiating steps of the alternative pathway of complement activation?

L5 S28

Answer 3

• C3 spontaneously cleaves into C3a to C3b at a rate of 1%/hr
• C3b covalently binds microbial surface
• Factor B binds C3b
• Factor D binds factor B cleaving it into Ba and Bb
• C3 and Bb form C3 convertase
• C3 convertase cleaves additional C3 into C3a and C3b

Question 4

What are the initiating steps of the classical pathway of complement activation?

L5 S33

Answer 4

• C1q recognizes and binds Fc portion of Ab-Ag complexes thus becoming activated
• C1q activates C1r which activates C1s
• C1s cleaves C2 into C2a/C2b and C4 into C4a/C4b
• C2a and C4b combine to form C3 convertase

Question 5

What are the initiating steps of the lectin pathway of complement activation?

L5 S35

Answer 5

• mannose-binding lectin (MBL) recognizes and binds terminal mannose residue of microbial structure becoming activated
• MBL activates MASP1/2
• MASP1/2 cleave C2 into C2a/C2b and C4 into C4a/C4b

Question 6

What prevents complement from targeting mammalian cells?

L5 S40

Answer 6

DAF (decay-accelerating factor):

• prevents interaction of C2 with C4b
• enhances dissociation of C4bC2a complex

CR1 (complement receptor 1):

• enhances dissociation of C4bC2a complex
• cleaves C4b and C3b

FI (factor I):
-cleaves C4b and C3b

Question 7

What are the soluble complement fragments and what are their functions?

L5 S42

Answer 7

C3a:
-activation of mast cells and basophils

C4b:
-activation of PMNs

C5a:
-activation of monocytes/Mφ

All result in the released of substance that induce inflammation

Question 8

How can compliment activation lead to phagocytosis?

L5 S45

Answer 8

C3b on microbial surface binds CR1 (complement receptor 1) on macrophages, stimulating phagocytosis.

Question 9

What are the functions of the different cytokines?

IL-1; IL-2; IL-4; IL-6; IL-8; IL-10; IL-12; IL-18; TNF; IFN-γ

Answer 9

IL-1: Systemic response; production of APPs; FEVER
IL-2: T cell activator
IL-4: produced by Th2 cells to activate B cell response
IL-6: Systemic response; production of APPs
IL-8: Neutrophil chemoattractant factor
IL-10: Inhibition of inflammation
IL-12: Th1 activator; increase NK cytotoxic function
IL-18: NK activation; IFN-γ production
TNF: expression of CAM/activation of immune cells; fever
IFN-γ: activation of Mφ