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MICI3115 > Lecture 5: Complement System > Flashcards

Lecture 5: Complement System Flashcards

1
Q

Activation of the complement pathway can occur in 1 of 3 ways:

A
  • Classical pathway
  • Alternative Pathway
  • Lectin pathway
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2
Q

Activation of the complement system involves:

A

Sequential proteolytic cleavage of substrates that results in a cascade reaction

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3
Q

Functions of the complement system (4)

A
  • Lyse target cells
  • Promote phagocytosis
  • Induce inflammatory response
  • Clear immune complexes
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4
Q

What activates the classical pathway?

A

Antigen binding to antibody

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5
Q

What activates the lectin pathway?

A

Microbial cell wall

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6
Q

What activates the alternative pathway?

A

Microbial surfaces

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7
Q

Initiators involved in complement activation

A

C1q, MBL, ficolins

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8
Q

Convertase activators

A

C1r, C1s, C4b, C2a

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9
Q

Enzymatic mediators

A

C3 convertase, C5 convertase

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10
Q

Convertase activators and enzymatic mediators lead to the activation of:

A

Opsonins, anaphylatoxins, membrane attack complex, complement receptors

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11
Q

Anaphylatoxins trigger

A

Inflammation by sending signals that cause neutrophils and monocytes to travel to the site of infection

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12
Q

What ensures that there is no excessive or inappropriate activation of complement?

A

Regulatory proteins

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13
Q

Activation of the classical complement pathway requires

A

One or more antibody-antigen complexes containing IgM or IgG.

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14
Q

C1qr2s2

A

A molecule that binds a single IgM molecule or two IgG molecules

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15
Q

Why is IgM a better activator of complement than IgG?

A

C1qr2s2 only needs to bind one IgM molecule, but it has to bind two IgG molecules.

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16
Q

Steps of C1qr2s2 complex binding to antibody

A
  1. C1q binds antigen-bound antibody, inducing a conformational change in one C1r molecule (activating it)
  2. C1r molecule activates the second C1r molecule and the two C1s molecules
  3. C1s cleaves C4 (first) and C2.
  4. C4b (from cleavage above) binds membrane close to C1 and then binds C2, exposing it to C1s action.
  5. C1s cleaves C2, creating the C3 convertase
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17
Q

How is the membrane attack complex formed?

A

After C5b complexes with C6, C7, C8, and C9 are recruited to the cell membrane. C5b678 causes the polymerization of C9, which creates the MAC.

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18
Q

The alternative complement pathway is involved in (innate/adaptive) immunity

A

Innate

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19
Q

Alternative complement pathway is triggered by

A

A range of molecules of microbial origin, as well as nonpathogenic molecules. Not triggered by antibody-antigen.

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20
Q

Function of C3 in alternative complement pathway

A

The spontaneous hydrolysis of C3 initiates the alternative complement pathway

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21
Q

C3bBb

A

Generated in the alternative complement pathway. Has C3 convertase activity.

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22
Q

C3bBb is stabilized by

A

Properdin, a serum protein

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23
Q

C3bBb3b has the activity of

A

C5 convertase

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24
Q

What happens when C5b deposits on the surface of the microorganism?

A

It sequentially binds C6, C7, and C8 which leads to the polymerization of C9 and the formation of the MAC.

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25
Q

Lectin complement pathway is involved in (innate/adaptive) immunity

A

Innate

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26
Q

The lectin complement pathway is activated by:

A

The interaction of mannose-binding lectin (MBL) with mannose residues on glycoproteins and carbohydrates expressed by certain microorganisms

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27
Q

Structurally, MBL looks like

A

C1

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28
Q

What happens once MBL binds mannose residues?

A

MASP-1 and MASP-2 bind MBL, forming a complex that is able to cleave C4 and C2

29
Q

Pathogenic and particles of microbial origin that initiate the alternative pathway of complement activation (7)

A
  • gram negative bacteria
  • LPS from gram negative bacteria
  • Gram positive bacteria
  • TA from gram positive bacteria
  • Fungal and yeast cell walls (zymosan)
  • Some viruses and virus infected cells
  • Some tumor cells (Raji)
  • Parasites (trypanosomes)
30
Q

Nonpathogens that initiate the alternative pathway of complement activation

A
  • Human IgG, IgA, and IgE in complexes
  • Rabbit and guinea pig IgG in complexes
  • Cobra venom factor
  • Heterologous erythrocytes (rabbit, mouse, chicken)
  • Anionic polymers (dextran sulfate)
  • Pure carbohydrates (agarose, inulin)
31
Q

Why is it important that many complement components are labile?

A

Complement components being labile/easily broken down ensures that only appropriate targets such as invading microbes are attacked by the complement system

32
Q

When in the pathway is the complement system subject to regulation?

A
  • Before and after the assembly of C3 convertase (C4b2a and C3bBb)
  • At the terminal stage of MAC assembly
33
Q

C1 inhibitor (C1INH)

A
  • Fluid phase
  • Classical and lectin pathways
  • Induces dissociation and inhibition of C1r2s2 from C1q; serine protease inhibitor
34
Q

Decay Accelerating Factor (DAF) CD55

A
  • Membrane bound
  • Classical, alternative, and lectin
  • Accelerates dissociation of C4b2a and C3bBb (C3 convertases).
35
Q

Factor H

A
  • Soluble
  • Alternative pathway
  • Blocks formation of, or accelerates dissociation of C3bBb C3 convertase
  • Cofactor for factor I in C3b degradation
36
Q

Factor I

A
  • Soluble
  • Classical, alternative, and lectin pathways
  • Serine protease: cleaves C4b and C3b using cofactors
37
Q

Protectin (CD59)

A
  • Membrane bound (all cells have it)
  • Affects all pathways
  • Binds C5b678 on host cells, blocking binding of C9 and the formation of MAC. Keeps own cells from being attacked by the complement system.
38
Q

Carboxypeptidases N, B and R

A
  • Soluble
  • Affects anaphylatoxins produced by all pathways
  • Cleaves and inactivates the anaphylatoxins C3a and C5a. These factors trigger mast cells to release inflammatory factors
39
Q

C1r2s2 (C1) -> C1q + C1r2s2 by

A

C1INH

40
Q

Decay accelerating activity for C3 convertases in Classical pathway

A

C4b2a –> C4b + C2a by DAF (CD55), CR1 (CD35) and C4BP

41
Q

Decay accelerating activity for C3 convertases in alternative pathway

A

C3bBb -> C3b + Bb by DAF (CD55), CR1 (CD35) and Factor H

42
Q

C3b -> C3c + iC3b + C3dg by

A

Factor I, MCP (CD46), CR1 (CD35) and Factor H

43
Q

C4b -> C4c + C4d by

A

Factor I, MCP (CD46), CR1 (CD35), C4BP

44
Q

Inhibition of lysis: Inhibition of C9 binding and polymerization by

A

Protectin (CD59), Vitronectin/S protein

45
Q

Cleavage of C3a (anaphylatoxin):

A

C3a -> C3a des Arg via Carboxypeptidase N, Carboxypeptidase B, Carboxypeptidase R

46
Q

Cleavage of C5a (anaphylatoxin)

A

C5a -> C5a des Arg via Carboxypeptidase N
Carboxypeptidase B
Carboxypeptidase R

47
Q

Function of C3a, C4a, and C5a

A

Anaphylatoxins that stimulate inflammation by acting on mast cells

48
Q

Function of C3a and C5a

A

Chemotactic (attractive) for granulocytes/monocytes (so that they will go to the tissue and phagocytose) and cause platelet aggregation

49
Q

Function of C3b, C3bi, and C4b

A

Opsonization of microbes to promote phagocytosis

50
Q

C5a function

A

Activates phagocytes (works similarly to PAMPs)

51
Q

How are viruses neutralized?

A

Aggregation, opsonization, and lysis (of enveloped viruses) reduces infectivity

52
Q

Clearance of particulate immune complexes occurs via phagocytosis in the

A

Spleen

53
Q

Soluble immune complex clearance occurs via:

A

C3b interaction with CR1 on erythrocytes

54
Q

Augmentation of antibody responses occurs via

A

C3b and C4b and their proteolyzed fragments bound to immune complexes and antigen; C3 receptors on immune cels

55
Q

Enhancement of immunologic memory occurs via

A

C3b and C4b and their fragments bound to antigen and immune complexes; receptors for complement components of follicular dendritic cells

56
Q

Antigen presentation is enhanced by:

A

MBL, C1q, C3b, C4b, and C5a

57
Q

____ have potential effects on T cells

A

C3, C3a, C3b, C5a

58
Q

Clearance of immune complexes from tissues occurs via

A

C1, C2, C4; covalently bound fragments of C3 and C4

59
Q

Clearance of apoptotic cells occurs via

A

C1q; covalently bound fragments of C3 and C4. Loss of CD46 triggers immune clearance

60
Q

Induction of regulatory T cells occurs via

A

CD46. This inhibits T helper cell responses

61
Q

Mutual function of C3b and IgG

A

C3b and IgG function as opsonins for phagocytes. When IgG binds the bacterium, complement is activated and C3b binds the bacterium. There is then binding to the Fc receptor (IgG) and CR1 receptor (C3b) on a phagocyte. The bacterium will then be phagocytosed.

62
Q

Ligands for CR1 (aka CD35)receptor

A

C3b, C4b, C1q, iC3b

63
Q

CR1 function

A

Clearance of immune complexes, enhancement of phagocytosis, regulation of C3 breakdown

64
Q

Ligands for CR3 receptor (aka CD11b/CD18, Mac1)

A

iC3b and factor H

65
Q

Function of CR3 receptor

A

Binding to adhesion molecules on leukocytes; facilitates extravasation; iC3b binding enhances opsonization of immune complexes

66
Q

Ligand for CR4 receptor (aka CD11c/CD18)

A

iC3b

67
Q

Function of CR4 receptor

A

iC3b-mediated phagocytosis

68
Q

Ligand for and function of C3aR receptor

A

Ligand: C3a
Function: induces degranulation

69
Q

Ligand for and functions of C5aR receptor (aka CD88)

A

Ligand: C5a
Functions:
-Induces degranulation
-Chemoattraction
-Acts with Il-1beta and/or TNF-alpha to induce acute phase response
-Induces respiratory burst in neutrophils

MICI3115 (3 decks)

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