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Core Infection, Immunity and Haematology | ME2362 > L7 - Complement > Flashcards

L7 - Complement Flashcards

1
Q

What is humoral immunity?

A

The aspect of immunity that is mediated by macromolecules in extracellular fluids.

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2
Q

What are the key components of humoral immunity?

A

Secreted antibodies, complement proteins, and certain antimicrobial peptides.

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3
Q

Where are the components of humoral immunity located?

A

Extracellular fluids.

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4
Q

What is the complement system?

A

A group of >30 proteins, including regulators, that play a key role in immune defense.

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5
Q

Where are most components of the complement system produced?

A

Most components are produced by the liver.

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6
Q

Where are complement system proteins found?

A

Plasma (highest concentration) and tissues (concentration increases during inflammation).

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7
Q

What happens to the expression of complement components during infection?

A

Expression of some components, such as C3 and MBL, increases upon infection, often induced by IL-6.

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8
Q

What triggers the increase in complement system components?

A

Infection and inflammatory signals, such as the release of IL-6.

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9
Q

How does inflammation affect the complement system?

A

Inflammation increases the concentration of complement proteins in tissues to help fight infection.

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10
Q

What happens if there is a deficiency in the complement system?

A

Deficiency can lead to increased susceptibility to infections, particularly bacterial infections.

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11
Q

What can happen if the complement system is unregulated or excessively activated?

A

Unregulated or excessive activation can lead to pathology (tissue damage or autoimmune diseases).

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12
Q

How are complement pathways activated?

A

The intrinsic properties of complement proteins prevent random activation. The cascade is activated only under specific circumstances (e.g., infection or injury).

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13
Q

What is the role of Mannose Binding Lectin (MBL) in the complement system?

A

MBL is the recognition molecule in the lectin pathway, which initiates complement activation.

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14
Q

How does Mannose Binding Lectin (MBL) recognize pathogens?

A

MBL recognizes specific sugars on the surface of pathogens, including mannose and N-acetylglucosamine (NAG).

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15
Q

How does the lectin pathway function once MBL binds to the pathogen?

A

MBL has 6 globular heads that act as carbohydrate recognition domains.
When MBL binds to the pathogen, it slightly changes conformation, which activates MASP-1 and MASP-2 (MBL-associated serine proteases).

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16
Q

What is the function of MASP-1 and MASP-2 in the lectin pathway?

A

MASP-1 and MASP-2 are enzymes that, once activated, help trigger the complement cascade.

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17
Q

What is the significance of the arrangement of sugars in the lectin pathway?

A

The spacing and arrangement of sugars on the pathogen’s surface are crucial because they allow MBL (or ficolins) to bind and initiate the lectin pathway of complement activation

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18
Q

What happens when MBL binds to a pathogen?

A

Binding of MBL (or ficolins) to the pathogen causes a conformational change in the MBL structure, which activates the associated MBL-associated serine proteases (MASPs).

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19
Q

How do MBL-associated Serine Proteases (MASPs) contribute to the complement activation?

A

MASPs are serine proteases that are initially inactive.
Once activated by MBL binding, they cleave and activate the next complement molecule in the cascade, such as C4.

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20
Q

Why is the initial inactivity of MASPs important?

A

The MASPs exist in their inactive form until they recognize a pathogen, ensuring intrinsic regulation and preventing unwanted activation.
This regulation ensures they only activate in response to proper pathogen recognition.

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21
Q

What initiates the classical pathway of complement activation?

A

The classical pathway is initiated by the C1q recognition molecule, which is part of the C1 complex.

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22
Q

What does C1q recognize in the classical pathway?

A

C1q recognizes antibodies (specifically IgG or IgM) that are bound to the surface of pathogens, such as bacteria.

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23
Q

What is the structure of C1q in the classical pathway?

A

C1q has a collagen tail and globular recognition domains at the bottom.
Serine proteases are attached to the C1q complex, similar to the lectin pathway’s MBL-associated serine proteases.

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24
Q

What antibodies can C1q bind to in the classical pathway?

A

C1q can bind to either IgG or IgM antibodies that are attached to the surface of the pathogen.

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25
Q

What is important about the arrangement of antigens/antibodies in the classical pathway?

A

The spacing/arrangement of antigens and antibodies in regular repeating patterns is critical because IgG binds to the target in these regular patterns.

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26
Q

How does C1q initiate the classical pathway of complement activation?

A

C1q binds to IgGn:Ag (IgG bound to antigen, where n > 1) to trigger the pathway.

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27
Q

What happens after C1q binds to IgGn:Ag in the classical pathway?

A

C1q undergoes a conformational change after binding to IgGn:Ag, which allows the activation of the associated serine proteases.

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28
Q

What is the first step after C1q undergoes a conformational change?

A

C1r autoactivates, leading to the activation of C1s.

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29
Q

What does C1s do after being activated in the classical pathway?

A

C1s cleaves and activates C4, which is the same protein activated by the lectin binding pathway.

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30
Q

Why is the spacing of the target antigen important in the classical pathway when IgM is involved?

A

The spacing of the target antigen is important because IgM binds to the antigen, causing a conformational change of IgM from a planar to a spider-like shape (staple conformation).

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31
Q

What happens when IgM binds to the target antigen in the classical pathway?

A

Upon binding to the target antigen, IgM undergoes a conformational change from a flat “snowflake” shape to a staple shape (resembling an “angry crab”).

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32
Q

Why is the “staple” conformation of IgM important?

A

The staple conformation of IgM allows C1q to bind to the tail of IgM, initiating the classical pathway.

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33
Q
A
34
Q

What happens after C1q binds to the staple conformation of IgM?

A

C1q undergoes a conformational change, which activates the associated serine proteases.

35
Q

What are pro-enzymes/zymogens?

A

Pro-enzymes or zymogens are inactive forms of enzymes. They exist in an inactive state to prevent premature or unwanted activity.

36
Q

Why do enzymes exist as pro-enzymes or zymogens?

A

Enzymes can be dangerous if activated prematurely, so they are kept inactive as pro-enzymes or zymogens for regulation and safety.

37
Q

How are pro-enzymes/zymogens activated?

A

Pro-enzymes are activated through cleavage, usually by another protease. This cleavage causes a conformational change, exposing the enzyme’s catalytic active site.

38
Q

What is the significance of activating pro-enzymes/zymogens?

A

The activation of pro-enzymes/zymogens is a mechanism of intrinsic regulation that ensures enzymes are only active when needed.

39
Q

What is the role of antibodies in the classical complement pathway?

A

Antibodies bind to antigens on the surface of pathogens, which activates the complement system through the recognition molecule C1q.

40
Q

What are the components of the C1 complex in the classical pathway?

A

The C1 complex consists of the recognition molecule C1q and the serine proteases C1r and C1s.

41
Q

How does the lectin pathway get activated?

A

The lectin pathway is activated when mannose-binding lectin (MBL) binds to sugars on the surface of pathogens, triggering the complement cascade.

42
Q

Q: How do proenzymes contribute to the complement pathway?

A

Proenzymes (zymogens) are inactive enzymes that, when cleaved by other proteases, become active and help amplify the complement cascade.

43
Q

What is the role of C3 convertase in the complement pathway?

A

C3 convertase cleaves C3 into C3a and C3b, with C3b binding to the surface of pathogens or the convertase itself, leading to opsonization and amplification of the immune response.

44
Q

Q: How is C3 convertase formed?

A

C3 convertase is formed when C4b, deposited on the bacterial surface, undergoes a conformational change that allows C2 to bind. C2 is cleaved by C1 or MASP2, forming the C4b2a complex, which is C3 convertase

45
Q

Q: What happens to C3b after it is cleaved by C3 convertase?

A

C3b is deposited on the surface of the pathogen, promoting opsonization. Some C3b remains bound to the C3 convertase, forming C4b2a3b (C5 convertase).

46
Q

What is the function of C5 convertase?

A

C5 convertase, formed by the binding of C3b to C3 convertase, cleaves C5 into C5a and C5b, which is crucial for initiating the membrane attack complex (MAC) and inflammation.

47
Q

What happens when C3 is cleaved into C3a and C3b?

A

A thioester group is exposed on C3b, which is highly reactive and unstable, with a short half-life. If C3b does not bind to a pathogen, it is hydrolyzed by water.

48
Q

Why is the thioester group on C3b highly unstable?

A

The thioester group is unstable due to its high reactivity from the number of electrons, which causes it to either be hydrolyzed by water or covalently bond to a pathogen surface.

49
Q

How does the thioester group on C3b contribute to immune regulation?

A

The short half-life of the thioester group ensures that C3b only binds to pathogens and not to human cells, preventing accidental targeting of host cells.

50
Q

What is the role of C3b in opsonization?

A

C3b binds to the surface of pathogens, marking them for phagocytosis by immune cells, which helps clear the infection.

51
Q

What surfaces does C3b deposit on during opsonization?

A

C3b is deposited on the surface of bacteria, apoptotic cells, and immune complexes.

52
Q

What is the function of C3b in opsonization?

A

C3b acts as an “eat me” signal, marking the target for recognition by phagocytic cells.

53
Q

Which cells recognize C3b during opsonization?

A

Complement Receptor 3 (CR3) on phagocytic cells such as macrophages, neutrophils, and dendritic cells recognizes C3b.

54
Q

What are the roles of CR3 and CR4?

A

CR3 and CR4 are phagocytic receptors that aid in the recognition of opsonized targets for phagocytosis.

55
Q

Are CR1 and CR2 phagocytic receptors?

A

No, CR1 and CR2 are not phagocytic receptors; they function as regulators in the immune system.

56
Q

What is the role of the Fc region of antibodies?

A

The Fc region of antibodies is recognized by Fc receptors, which helps mediate immune responses, including phagocytosis when combined with C3b binding to CR3.

57
Q

What is required for phagocytosis by CR3?

A

Phagocytosis requires two signals: antibody Fc region recognition and C3b binding to CR3.

58
Q

How does complement-mediated phagocytosis work?

A

Complement-mediated phagocytosis is efficient because the bacteria are first covered with antibodies (opsonins), which then bind to Fc receptors, while iC3b binds to CR3, leading to phagocytosis.

59
Q

What receptors are involved in complement-mediated phagocytosis?

A

In complement-mediated phagocytosis, IgG binds to Fc receptors, and iC3b binds to CR3 on phagocytic cells.

60
Q

Why is C3b opsonisation alone insufficient for complement-mediated phagocytosis?

A

C3b opsonisation alone is insufficient because phagocytes need to be “primed” by C5a binding to C5aR to enhance phagocytosis.

61
Q

How does C5a influence complement-mediated phagocytosis?

A

C5a activates macrophages to phagocytose via CR3, enhancing the phagocytosis of bacteria coated with C3b.

62
Q

What is the role of the alternative complement pathway?

A

The alternative pathway is involved in the activation of complement in response to pathogen surfaces, amplifying the immune response by generating C3b, which leads to opsonisation and activation of other complement components.

63
Q

How is the alternative pathway activated?

A

The alternative pathway is activated spontaneously by the hydrolysis of C3, which then binds to factor B. Factor D cleaves factor B, generating C3bBb, the C3 convertase of the alternative pathway.

64
Q

What is the significance of C3bBb in the alternative pathway?

A

C3bBb is the C3 convertase in the alternative pathway, which cleaves C3 into C3a and C3b, continuing the complement cascade and promoting opsonisation of pathogens.

65
Q

How does the alternative pathway amplify the immune response?

A

The alternative pathway amplifies the immune response by continuously generating C3b on pathogen surfaces, further activating the complement cascade and promoting opsonisation, inflammation, and formation of the membrane attack complex (MAC).

66
Q

What are the two forms of C5 convertases?

A

The two forms of C5 convertases are C4bC2aC3b and C3bBbC3b.

67
Q

What is the function of C5 convertases?

A

C5 convertases cleave C5 into C5a and C5b. C5a acts as a potent anaphylatoxin, while C5b initiates the formation of the terminal complement complex.

68
Q

What happens to C5b after cleavage?

A

After C5b is cleaved, it undergoes a conformational change, releasing it from the C5 convertase and exposing a binding site for the recruitment of terminal pathway components (C6, C7, C8, and C9).

69
Q

How does the terminal complement pathway lead to cell lysis?

A

C5b recruits C6, C7, C8, and C9 to form the membrane attack complex (MAC), with C9 forming a pore in the pathogen membrane, leading to cell lysis.

70
Q

What is the role of C5a?

A

C5a is a potent anaphylatoxin that induces inflammation, attracting immune cells to the site of infection.

71
Q

What triggers the formation of the MAC pore?

A

The formation of the MAC pore is triggered by conformational changes in C5b, which binds to C6, C7, C8, and C9, leading to membrane insertion.

72
Q
A
73
Q

How do the components of the MAC complex contribute to pore formation?

A

C7 is slightly lipophilic, and C8 is highly lipophilic, allowing it to insert into the membrane. This recruits C9, which forms the pore, leading to cell lysis.

74
Q

How is intrinsic regulation involved in MAC formation?

A

Intrinsic regulation ensures that complement components only bind and activate when needed, with conformational changes and exposure of lipophilic sites on components like C5b, facilitating membrane insertion.

75
Q

What happens when only C3b is deposited on the surface of pathogens?

A

If only C3b is deposited on the surface, it facilitates opsonisation, leading to phagocytosis by immune cells, without causing direct lysis through MAC formation.

76
Q

What are C3a and C5a in the complement system?

A

C3a and C5a are anaphylatoxins that attract and activate cells through their receptors (C3aR and C5aR).

77
Q

What is the role of C3a and C5a in chemotaxis?

A

C3a and C5a attract phagocytes to the site of infection by binding to C3a and C5a receptors on immune cells.

78
Q

How do C3a and C5a activate immune cells?

A

C3a and C5a activation of immune cells leads to mast cell degranulation (releasing pro-inflammatory content), enhances phagocytosis, and stimulates immune cells to secrete cytokines and prostaglandins.

79
Q

What is the result of excessive activation of C3a and C5a receptors?

A

Excessive activation of C3a and C5a receptors can lead to inflammation due to increased immune cell activation and cytokine release.

80
Q

What is the function of CD59 in the complement system?

A

CD59 binds to C5b678 on human cells and prevents the binding of C9, thus inhibiting the formation of the membrane attack complex (MAC) and protecting host cells from lysis.

81
Q
A

Core Infection, Immunity and Haematology | ME2362 (7 decks)

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