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Phase 1 Block 4 > Complement Pathways > Flashcards

Complement Pathways Flashcards

1
Q

What are complements?

A

Circulating and cell membrane proteins that form part of the innate immune system

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2
Q

What is the function of complement proteins?

A

Help the innate system
Promote inflammatory and immune responses

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3
Q

What are the 3 complement activation pathways?

A
  • Classical
  • Lectin
  • Alternative
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4
Q

Why are there 3 pathways?

A

Redundancy in case 1 fails

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5
Q

How does the classical pathway act?

A

Antigen-antibody complexes —> complement activation

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6
Q

What are the 3 consequences of complement activation?

A
  • Inflammatory cell recruitment
  • Opsonization
  • Pathogen killing
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7
Q

How is the classical complement pathway activated?

A
  • C1 (complement component) binds to antigen-antibody complex via its C1q recognition region
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8
Q

How is the lectin pathway activated?

A

Mannan-binding lectin (MLB) binds to terminal polysaccharide on surface of microbe

-Not found on mammalian cell surfaces

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9
Q

How is the alternative pathway activated?

A

Deposition of complement component C3b on pathogen surface

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10
Q

At which complement component do the 3 different pathways converge?

A

C3

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11
Q

What is the relationship between the complement and immune system?

A

Bridge between the adaptive and immune system

Classical complement responds to the adaptive immune system (Ig production —> antigen-antibody complexes)
- Effector mechanism

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12
Q

What antibodies are involved in the classical pathway?

A

IgM or IgG
- Bind with antigen —> antibody-antigen complex
- Complex binds to C1q (subunit of C1)

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13
Q

What is C1q?

A

One of 3 proteins making up C1 protein complex - binding domain

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14
Q

What is the region that C1q binds to on the antibody called?

A

Fc region
The “pole” of the “Y” on antibodies

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15
Q

What Ig is most effective at activating C1?

A

IgM

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16
Q

What Ig cannot activate the complement system?

A

IgG4

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17
Q

What becomes active when a complex binds to C1q?

A

C1s and C1r proteases are activated

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18
Q

What does C1s esterase cleave?

A

C4 –> C4b & C4a –> C2 –> C2a & C2b

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19
Q

What happens in the classical pathway to form C3 convertase?

A

C4b complexes with C2a on the Ab-Ag membrane –> C4bC2a (aka classical pathway C3 convertase)

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20
Q

What is distinct about the MBL pathway?

A

Specific for pathogens that have mannose residues on their surface?

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21
Q

What are the steps of the MBL pathway?

A
  • MBL similar to C1q
  • MBL binding with mannose –> MASP-2 (protease) to cleave C4 and C2 –> C4bC2a on pathogen surface –> C3 convertase
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22
Q

How is MBL similar to the classical pathway?

A

MBL = C1q
MASP2 = C1s esterase

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23
Q

What are some substances that can trigger the alternative pathway?

A
  • Endotoxins
  • Necrotic cells
  • Some microorganisms
  • Aggregated Ig molecules
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24
Q

What are the steps in the alternative pathway?

A

C3b deposition on particle surface –> factor B (serum protein) combining with C3b –> C3bB –> factor D cleaves B –> Ba
Ba released into fluid phase
Bb associated with C3bBb
C3bBb –> C3 convertase and stabilized on cell surface with properdin

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25
Q

What is a common product of all 3 complement pathways?

A

C3 convertase

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26
Q

What parts make up C3 convertase in the classical and lectin pathways?

A

C4b and C2a = C4bC2a

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27
Q

What parts make up C3 convertase in the alternative pathway?

A

C3b and Bb = C3bBb

28
Q

Which C3 fragment after cleavage is released into the fluid phase?

A

C3a

29
Q

Which C3 fragment after cleavage binds to the cell surface?

A

C3b

30
Q

What does properdin (factor P) do?

A

Stabilizes C3bBb to cell surface –> rapid cleaving of C3 molecules –> C3b buildup on pathogen surface –> alternative pathway amplification loop

31
Q

What doe C5 convertase consist of?

A

C4b, C2a, and C3b = C3 convertase + C3b

32
Q

What C5 fragment after cleavage is released into the fluid phase?

A

C5a

33
Q

What C5 fragment after cleavage binds to the cell surface?

A

C5b

34
Q

What are the main activities of the complement system?

A
  • Opsonin production
  • Anaphylatoxins that add inflammation
  • Direct lysis of microbes
35
Q

How does the complement system carry out opsonization?

A

C3b binding marks antigens for immune cell recognition
Cells of the innate immune system have complement receptors (CRs) that bind to C3b

36
Q

What cells is CR1 found on?

A

Phagocytic cells

37
Q

What cells is CR3 found on?

A
  • Monocytes
  • Granulocytes
  • NK cells
38
Q

What cells is CR4 found on?

A
  • Myeloid cells
  • others
39
Q

What complement proteins are involved in opsonization?

A

C3b and C4b

40
Q

What is an anaphylatoxin?

A
  • Bind to receptor on mast cell —> rxn similar to allergic hypersensitivity rxn
41
Q

List the anaphylatoxin complement proteins (3)

A

C3a
C4a
C5a

42
Q

What is triggered by anaphylatoxin binding to its cell receptor?

A

Histamine and other mediator release
Increases smooth muscle contraction
More vascular permeability and fluid accumulation in tissue

43
Q

What anaphylatoxin is also chemoattractant?

A
  • C5a attracts neutrophils
44
Q

These 3 complement proteins bind in sequence to C5b to form membrane attack complex

A

C6 binds to C5b
C7 binds to C6
C8 binds to C7

45
Q

What is the consequence of a membrane attack complex forming?

A

Essential for cell lysis
Allows water to enter the cell —> lysis

46
Q

Where are complement proteins made?

A

Mainly made in the liver

47
Q

What acts on the liver to induce synthesis of acute phase proteins?

A

IL-6

48
Q

This protein interacts with C1q to trigger the classical pathway in the absence of antibody

A

CRP

49
Q

What does CRP bind to —> phagocytosis?

A

Phosphorylcholine on liposaccharides in microbial cell walls

50
Q

What does an immune complex consist of?

A

Ab-Ag

51
Q

What cell transports immune complexes to the liver and spleen?

A

RBCs

52
Q

On what receptor does the immune complex bind to be carried to the liver and spleen?

A

CR1

53
Q

What is a consequence of not clearing immune complexes from circulation?

A

IC deposit on vessel —> acute inflammation and immune pathology

54
Q

What complement receptor is associated with acute inflammation?

A

CR5a

55
Q

What cells is CR5a found on?

A

Causes inflammatory response
Smooth muscle cells
Endothelial cells
Mast cells
Basophils
Enhances chemotasix
- Phagocytes

56
Q

This receptor has similar distribution to CR5a

A

CR3a — binds C3a (anaphylatoxin)

57
Q

What 3 steps can regulation occur in the complement pathway?

A

Initiation and activation
Amplification
Membrane attack complex

58
Q

How does C1 inhibitor work?

A

Binds activated C1r and C1s, removes them from C1q
- Controls activation and initiation

59
Q

How is C4-binding protein involved in complement regulation?

A

Controls amplification
Dissociates C3 convertase subunits in classical pathway
Cofactor for Factor I-mediated cleavage of C4b

60
Q

How is Factor I involved in complement regulation?

A

Controls amplification
- Cleaves C3b and C4b

61
Q

How is Factor II involved in complement regulation?

A

Controls amplification
Dissociated C3 convertase in alternative pathway
cofactor for Factor I mediated cleavage of C3b

62
Q

What can C1 inhibitor deficiency cause?

A

Angioedema

63
Q

Would C4 levels be expected to be high or low in C1 inhibitor deficiency?

A

Low
R/t spontaneous C4 activation and consumption

64
Q

What is decay accelerating factor?

A

CD55 — Controls amplification
Membrane protein
Dissociates C3 convertase subunits

65
Q

What pathways are impacted if there is a defect in CD55 (decay accelerating factor)?

A

All 3 pathways since it impacts C3 convertase (convergence point for all 3 pathways)

66
Q

What does CD59 do?

A

Membrane protein that regulates membrane attack complex
- Acts by blocking C9 binding and forming of MAC

67
Q

What is a consequence of CD55 and CD59 deficiencies?

A

Cells more susceptible to lysis

Phase 1 Block 4 (17 decks)

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