Phase 1 Block 4 > Complement Pathways > Flashcards

Complement Pathways Flashcards

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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
What is a common product of all 3 complement pathways?
C3 convertase
26
What parts make up C3 convertase in the classical and lectin pathways?
C4b and C2a = C4bC2a
27
What parts make up C3 convertase in the alternative pathway?
C3b and Bb = C3bBb
28
Which C3 fragment after cleavage is released into the fluid phase?
C3a
29
Which C3 fragment after cleavage binds to the cell surface?
C3b
30
What does properdin (factor P) do?
Stabilizes C3bBb to cell surface --> rapid cleaving of C3 molecules --> C3b buildup on pathogen surface --> alternative pathway amplification loop
31
What doe C5 convertase consist of?
C4b, C2a, and C3b = C3 convertase + C3b
32
What C5 fragment after cleavage is released into the fluid phase?
C5a
33
What C5 fragment after cleavage binds to the cell surface?
C5b
34
What are the main activities of the complement system?
- Opsonin production - Anaphylatoxins that add inflammation - Direct lysis of microbes
35
How does the complement system carry out opsonization?
C3b binding marks antigens for immune cell recognition Cells of the innate immune system have complement receptors (CRs) that bind to C3b
36
What cells is CR1 found on?
Phagocytic cells
37
What cells is CR3 found on?
- Monocytes - Granulocytes - NK cells
38
What cells is CR4 found on?
- Myeloid cells - others
39
What complement proteins are involved in opsonization?
C3b and C4b
40
What is an anaphylatoxin?
- Bind to receptor on mast cell —> rxn similar to allergic hypersensitivity rxn
41
List the anaphylatoxin complement proteins (3)
C3a C4a C5a
42
What is triggered by anaphylatoxin binding to its cell receptor?
Histamine and other mediator release Increases smooth muscle contraction More vascular permeability and fluid accumulation in tissue
43
What anaphylatoxin is also chemoattractant?
- C5a attracts neutrophils
44
These 3 complement proteins bind in sequence to C5b to form membrane attack complex
C6 binds to C5b C7 binds to C6 C8 binds to C7
45
What is the consequence of a membrane attack complex forming?
Essential for cell lysis Allows water to enter the cell —> lysis
46
Where are complement proteins made?
Mainly made in the liver
47
What acts on the liver to induce synthesis of acute phase proteins?
IL-6
48
This protein interacts with C1q to trigger the classical pathway in the absence of antibody
CRP
49
What does CRP bind to —> phagocytosis?
Phosphorylcholine on liposaccharides in microbial cell walls
50
What does an immune complex consist of?
Ab-Ag
51
What cell transports immune complexes to the liver and spleen?
RBCs
52
On what receptor does the immune complex bind to be carried to the liver and spleen?
CR1
53
What is a consequence of not clearing immune complexes from circulation?
IC deposit on vessel —> acute inflammation and immune pathology
54
What complement receptor is associated with acute inflammation?
CR5a
55
What cells is CR5a found on?
Causes inflammatory response Smooth muscle cells Endothelial cells Mast cells Basophils Enhances chemotasix - Phagocytes
56
This receptor has similar distribution to CR5a
CR3a — binds C3a (anaphylatoxin)
57
What 3 steps can regulation occur in the complement pathway?
Initiation and activation Amplification Membrane attack complex
58
How does C1 inhibitor work?
Binds activated C1r and C1s, removes them from C1q - Controls activation and initiation
59
How is **C4-binding protein** involved in complement regulation?
Controls amplification Dissociates C3 convertase subunits in classical pathway Cofactor for Factor I-mediated cleavage of C4b
60
How is Factor I involved in complement regulation?
Controls amplification - Cleaves C3b and C4b
61
How is Factor II involved in complement regulation?
Controls amplification Dissociated C3 convertase in alternative pathway cofactor for Factor I mediated cleavage of C3b
62
What can C1 inhibitor deficiency cause?
Angioedema
63
Would C4 levels be expected to be high or low in C1 inhibitor deficiency?
Low R/t spontaneous C4 activation and consumption
64
What is decay accelerating factor?
CD55 — Controls amplification Membrane protein Dissociates C3 convertase subunits
65
What pathways are impacted if there is a defect in CD55 (decay accelerating factor)?
All 3 pathways since it impacts C3 convertase (convergence point for all 3 pathways)
66
What does CD59 do?
Membrane protein that regulates membrane attack complex - Acts by blocking C9 binding and forming of MAC
67
What is a consequence of CD55 and CD59 deficiencies?
Cells more susceptible to lysis
Phase 1 Block 4
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