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IMMUNOLOGY: CMOD-Week 1 > (04) Complement Cascades > Flashcards

(04) Complement Cascades Flashcards

1
Q

When are complement proteins made?

  • how are they secreted
  • importance of these components?
A

Made:
- ALL of the time in the LIVER

Secreted:
- in Zymogen form

** Can be in blood and extravascular fluid ALL of the time

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2
Q

What are order are the paths in the complement cascade activated?
- Innate or Acquired?

A
  1. Alternative Path (innate)
  2. Lectin Path (innate)
  3. Classical Path (aquired)
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3
Q

In general, how does each component in path in the complement cascade get activated?

A
  1. Alternative Path - pathogen surface creates local environment conducive to complement activation
  2. Lectin Path - Mannose-binding Lectin Binds pathogen surface
  3. Classical Path - C-reactive protein OR Antibody binds to specific antigen on pathogen surface
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4
Q

What is the primary opsonin made by the complement cascade pathway?

A

C3b

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5
Q

What 3 things begin acting after complement system is activated?
- what do they do?

A
  1. Anaphylatoxins
    - Activate Vascular Endothelium
    - Recruit phagocytes to inflammatory site
  2. Opsonins
    - Easily recognized by phagocytes so bound pathogens can be destroyed
  3. MAC (membrane attack complex)
    - Direct killing of pathogen by disrupting the outer envelope
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6
Q

What is the most important function of the complement cascade?

A

Classical and Alternative C3 convertases making C3b to deposit on the surface of pathogens

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7
Q

What is the importance of C3b?

A
  1. C3b is a component of C5 convertase and is needed for the formation of the MAC (membrane attack complex)
  2. C3b and its breakdown products bind directly and irreversibly to pathogen surfaces and mark them for phagocyte uptake (opsonization)
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8
Q

What causes be breakdown of C3 proteins?

- what are the products of this, and what do they do?

A

C3 is broken down via normal protein turnover to C3a and C3b

C3a
- Small Anphylatoxin

C3b (3 possibilities)

  1. No contact with anything
    - thioester bond is quickly hydrolyzed
  2. Attaches to host cell
    - Cascade control proteins prevent activation
  3. Attaches to pathogen
    - Alternative pathway begins
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9
Q

What is C3 convertase made of?

- what does it do?

A

C3b and Bb = C3bBb

  • Breaks down C3 to C3a and C3b
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10
Q

What happens if another C3b binds to C3 convertase?

- what does this do?

A

C5 convertase is formed (C3b2Bb)

  • Breaks down C5 to C5a and C5b
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11
Q

What is the significance of C5a and C5b?

A

C5a

  • Potent Anaphylatoxin
  • IMPORTANT CHEMOTACTIC FACTOR FOR NEUTROPHILS

C5b
- Required to form the pore that makes up the membrane attack complex (MAC)

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12
Q

What are the components of the MAC?

- how does it work?

A

made of:

  • C5b
  • C7
  • C6
  • C8
  • C9

*Creates a pore in the pathogen membrane that ruins its osmotic gradient

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13
Q

What causes initiation of the classical pathway?

A
  1. Complement Component C1 binds to antibody that is bound to complement antigen
  2. C1 part of Fc region on antibody becomes exposed
  3. C1 binds
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14
Q

What does Mannose Binding Protein do?

  • What is it specific for?
  • What binds to Mannose binding protein?
  • What forms as a result of this binding
A

Binds mannose, which is specific to BACTERIA (not found on mammals)

  • MASP 1 and 2 (mannan-binding Lectin-associated serum proteases)
  • Classic C3 convertase (C4bC2a) is formed as a result of this binding

**remember C3 convertase cleaves C3

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15
Q

What is the C1 molecule composed of?

  • what does it bind?
  • what happens when it is activated?
A
  • C1q stalks
  • C1r (serine protease)
  • C1s (serine protease)

Bind IgM** and IgG3 mainly (some IgG1)

On binding IgM (or IgG3)

  • C1r cleaves C1s
  • C1s cleaves C2 and C4
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16
Q

What is the order of components that can activate C1?

- explain the order

A
  1. IgM (+++)
  2. IgG3 (+++)
  3. IgG1 (++)
  4. IgG2 (+)
  5. IgA1/2 (+)

*IgM is #1 because its a pentamer and can bind 5/6 C1q stalks

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17
Q

Can the classical C3 pathway and lectin lead to MAC formation?
- does MAC structure differ?

A

Yes, the only difference is the C5 convertase that is used to cleave C5 leading to MAC formation

Classical C5 convertase:
C4bC2aC3b

Alternative C5 convertase:
(C3b)2C2a

**MAC structures are exactly the same in both paths

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18
Q

How does initiation of the alternative pathway differ from that of the classical pathway?

A

Alternative Initiation:
- C3b with thioester is intrinsically present in extravascular fluid and binds a pathogen surface

Classical Initiation:
- C1 binds an antibody (most likely IgM) and cascade starts

19
Q

How do the differences in initiation in the Alternative pathway vs. lectin and classical pathway affect the cascade response?

A

Alternative pathway is initiated by C3b (produced by all 3 pathways), therefore it serves as an important factor in AMPLIFICATION (in an immunocompetent person)

20
Q

Besides IgM (and the other antibodies) what can activate the classical pathway?

  • when does this occur?
  • how does it work
A
  • C-reactive protein (CRP)

- CRP is released from the liver during septic shock and it binds to phosphocholine, which is ONLY found on BACTERIA

21
Q

What is the effect of the complement cascade on different phagocytic cells?

A

Macrophages and Neutrophils:

  • Have receptors that allow them to recognize C3b or its breakdown products on cells.
  • Cells with this are phagocytosed

B-cells:
- CR2 (complement receptor 2) on B cells increases B cell signaling without the help of a helper T cell

22
Q

Besides phagocytic cells, what other cell type posses complement receptors?

A

Follicular Dendritic Cells (FDCs)

23
Q

Why do phagocytes have a difficult time engulfing encapsulated bacteria?
- how is this overcome?

A
  • THERE ARE NO PHAGOCYTE RECEPTORS THAT RECOGNIZE CAPSULAR MATERIAL

Overcome by complement system:

  1. Antibodies bind to antigen
  2. CR1 on macrophages and phagocytic cells recognize this and phagocytose this material
24
Q

What important antibody do macrophages NOT have Fc Receptors for?

A

Lack Fc Receptors for IgM

Have receptors for IgGs and IgAs

25
Q

Where is the CR1 receptor found?

- what molecules activate this receptor?

A

CR1 - found on macrophages, and erythrocytes

  • C3b, C4bi
26
Q

Why are CR1 receptors on erythrocytes so important?

- what happens if they are absent?

A

CR1 needed so Erythrocytes can bind small immune complexes and carry them to the liver and spleen

Failure = vascularitis or kidney failure

27
Q

Why can’t the complement cascade be left to run by itself?

A
  • Its a positive feedback loop and it would eventually damage the host
28
Q

What are the 2 divisions of regulation?

- how do we know these proteins will be present when we need them?

A
  1. Passive

2. Active - these protein are constitutively produced, so in an immunocompetent person they should always be around.

29
Q

What does passive regulation consist of?

- what proteins are passively regulated?

A

Passive Regulation is controlled by hydrolysis of thioester bonds on LARGE fragments of:
C2, C3, C4, C5, and Bb

30
Q

Where are active regulatory proteins located for the complement cascade?

A
  • Soluble

- embedded in the surface of host cells

31
Q

Where does C1 inhibitor (C1INH) work in the complement cascade and what does it do?

  • soluble or membrane bound?
  • what happens if you lack C1 inhbitor?
A
  • Binds C1 and causes release of C1r and C1s
  • Soluble
  • causes HANE - Hereditary Angioneurotic Edema
  • Treatment = monthly injection of C1INH
32
Q

What tissue is most affected by HANE?

A
  • Lips
33
Q

What does C4 binding protein do?

- membrane bound or soluble?

A

C4 Binding Protein binds to C4bC2a (aka Classic C3 convertase) causing C2a to dissociate

  • Leaves C4b susceptible to cleavage by FACTOR I
  • Soluble
34
Q

What does Factor H do?

- membrane bound or soluble?

A

Causes C3b to be susceptible to cleavage by factor I

  • cleavage converts it to iC3b, which CAN’T BE REUSED IN ALTERNATIVE PATH (can’t bind factor B)
  • also cleaves C5 Convertase
  • Soluble
35
Q

What does factor I do?

  • why would it be bad to lose factor I?
  • Membrane bound or soluble?
A

Protease that cleaves:
- C4b after it has dissociated from C2a

  • C3b and C3b from C5 convertase
  • *Loss of Factor I:
  • C3 depletion from constitutive activation of C3 convertase in Classic and Alternative Paths
  • iC3b (an opsonin) would not be created
  • Soluble
36
Q

What is the overall affect of the regulating mechanisms of the complement cascade?

A

Limit the duration of the immune response

37
Q

What is the overarching purpose of membrane bound complement cascade regulators?

A
  • To minimize host cell damage
38
Q

What are the 4 SOLUBLE complement cascade controlling proteins?

A
  1. C1 Binding protein
  2. C4 Binding protein
  3. Factor I
  4. Factor H
39
Q

What are the 3 Membrane Bound complement cascade regulating proteins?
- what do they do?

A
  1. DAF (decay accelerating factor/CD55)
    - Dissociates C3 from convertase enzymes
  2. MCP (membrane cofactor protein)
    - Binds to either C3b or C4b and make them susceptable to Factor I cleavage
  3. CR1 (complement receptor 1)
    - Binds to either C3b or C4b and make them susceptable to Factor I cleavage
40
Q

What does DAF do?

A

Decay Accerating Factor

- dissociates C3 convertase enzymes

41
Q

What proteins shut down C3 convertase?

A
  1. C4 Binding Protein via Fact. I
  2. DAF (CD55)
  3. MCP
  4. CR1
42
Q

What proteins change the activity of C3?

A
  1. Factor H
  2. MCP
  3. CR1
43
Q

What complement cascade membrane proteins have the same abilities and affect?

A
  • CR1 and MCP

- Bind C3b or C4b to inhibit C3 convertase and C3b itself

44
Q

What is protectin 59?

- what happens if you lack protectin 59?

A

Protects host cell from MAC-mediated damage

**Most bacteria have to way to prevent MAC formation

No protectin 59:

  • Paroxymal Nocturnal Hemoglobinuria
  • Causes intravascular RBC lysis because they can’t prevent host cell MAC attack

IMMUNOLOGY: CMOD-Week 1 (10 decks)

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