4. The complement system Flashcards

1
Q

where are complement proteins produced

A

the liver

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2
Q

what is opsonization

A

coating of the pathogen with antibodies for recognition by phagocytic cells

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3
Q

complement proteins in circulation

A

circulate in their inactive forms, “activated” in the presence of pathogens or antibodies bound to pathogens

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4
Q

3 different proteolytic pathways that lead to complement activation

A

first to act = alternative pathway
second to act = lectin pathway
third to act = classical pathway

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5
Q

many complement proteins are proteases and zymogens, what does this mean

A

complement proteins are synthesized as their inactive forms (zymogens) and successively cleave each other to become activated (proteases)

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6
Q

stages of complement activation

A
  • pattern recognition trigger
  • protease cascade amplification/C3 convertase
  • 1 of 3 effector pathways (inflammation, phagocytosis or MAC)
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7
Q

outcome of complement activation: inflammation

A

C3a and C5a recruit and activate leukocytes at site of infection

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8
Q

outcome of complement activation: opsonization

A

C3b bound to microbe surface is recognized by C3b receptor on phagocyte which destroys the pathogen

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9
Q

outcome of complement activation: membrane attack complex

A

insertion of complement proteins C5b-C9 into the pathogen membrane forms pores which disrupts the osmotic balance across the membrane and promotes pathogen death

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10
Q

exceptions in complement protein nomenclature

A
  • C2 product C2a is a larger fragment than C2b
  • C1q, C1r and C1s are not cleavage products but distinct proteins that compose C1
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11
Q

extra proteins in the alternative pathway

A

factor B (Ba and Bb) and factor D

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12
Q

complement proteins were named by…

A

their order of discovery (C1-4-2-3-5…)
* C4 acts before C2 and 3 but it was discovered first

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13
Q

which complement proteins are NOT in the alternative pathway

A

C1, 4 and 2

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14
Q

which complement protein is NOT in the lectin pathway

A

C1

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15
Q

lectin pathway initiation

A

initiated by mannose-binding lectin and ficolins
bind to carbohydrate structures on microbial surfaces
MASPs trigger the cleavage of complement routines (since there is no C1)

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16
Q

classical pathway initiation

A

initiated when C1 either recognizes a microbial surface via CRP or directly binds to antibodies already bound to a pathogen

17
Q

alternative pathway activation

A

initiated by spontaneous hydrolysis and activation of C3

18
Q

which complement pathway boosts the adaptive immune system

A

classical pathway (involves antibodies)

19
Q

where do all 3 complement pathways converge

A

the generation of C3 convertase - C3 is cleaved leaving C3 bound to the microbial surface and releases C3a to trigger inflammation

20
Q

role of C3a and C3b

A

C3a: an anaphylatoxin - activates inflammatory response by triggering degranulation of cells that cause inflammation
C3b: covalently attaches to the pathogen surface and marks it for destruction (more susceptible to phagocytosis)

21
Q

when C3 convertase creates C3a and C3b it exposes a…

A

highly reactive thioester bond in C3b

22
Q

composition of C3 convertase in the different complement pathways

A

lectin and classical: C4b2a
alternative: C3bBb

23
Q

composition of C5 convertase in the different complement pathways

A

lectin and classical: C4b2a3b
alternative: C3b2Bb

24
Q

how to MBL and ficolins initiate the lectin pathway

A
  • they form complexes with serine protease and recognize carbohydrates on protein surfaces
  • their associated MASPs cleave complement proteins to start the pathway
  • MBL: binds to mannose and fructose residues
  • ficolins: bind oligosaccharides containing acetylated sugars
25
Q

how does C3 convertase result in the binding of many C3b to the pathogen surface

A

MASP-2 (or C1s) cleaves C4 into C4a and C4b - C4b binds to microbial surface
C2 comes and MASP (or C1s) cleaves it - C2a joins and the C4b2a complex is created
C4b2a is an active C3 convertase - can cleave up to 1000 C3 proteins

26
Q

what is the role of each proteins that makes up C1

A

C1q: binds to pathogen surfaces at CRP or indirectly to antibody, allowing auto-activation of C1r
C1r: cleaves C1s to activate it
C1s: cleaves C2 and C4

27
Q

what are the roles of Factor B and D in the alternative pathway

A

Factor D: protease that functions to activate factor B
Factor B: protease zymogen which when activated functions as a subunit of C3 convertase

28
Q

why do we have the alternative pathway?

A

it is an amplification loop for C3b formation that is accelerated by properdin in the presence of pathogens
more C3b = more opsonization = more phagocytosis

29
Q

what is properdin (factor P)

A

a plasma protein that enhances the activity of the alternative C3 convertase to aid in complement fixation

30
Q

different complement receptors and their ligands

A

CR3 and CR4: ligand is C3b and iC3b
CR2: ligand is C3dg

31
Q

what is Factor I

A

a serine protease that inactivates C3b through its cleavage into iC3b - cannot function as a component of C3 convertase

32
Q

which complement receptor do macrophages express

A

CR1 - binds C3b to enhance recognition and phagocytosis

33
Q

what plasma proteins regulate complement activation

A

Factor H and Factor I: regulate cleavage of C3b

34
Q

how does factor H regulate complement activation

A

enhances the cleavage of C3b into iC3b by factor I
binds to cell membranes by interacting with sialic acid which inhibits complement activation

35
Q

what membrane proteins regulate complement activation

A
  1. DAF: breakdown the alternative C3 convertase
  2. MCP: binds to C3b and enhances its cleavage to inactive iC3b by factor I
    *these proteins are expressed by human cells to inhibit C3b fixation because it would destruct the cell
36
Q

what is the membrane attack complex

A

complement proteins C5b-C9 work together to form holes in bacterial and eukaryotic membranes

37
Q

how is the MAC regulated

A

plasma proteins: S protein, clusterin and factor J inhibit C6 and C7 from binding to the membrane
human cell-surface proteins: CD59 and HRF prevent C9 from binding to the membrane