The complement Flashcards

1
Q

how was the complement system originally described as in the serum

A

a heat-labile component of normal serum that augmented the opsonization of bacteria by a heat-stable component of serum (antibodies)

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2
Q

where did the name “the complement” come from

A

this activity exhibited by the complement helped the antibacterial activity of antibodies

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3
Q

T/F the complement can be activated earlier infection without antibodies

A

True

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4
Q

what is the complement

A

complement is a system of proteins that is activated by the presence of pathogens

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5
Q

how many plasma proteins makes up the complement

A

over 30

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6
Q

most of the protein components are __________ that become active only after cleavage

A

most of the protein components are inert enzymes that become active only after cleavage

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7
Q

how must the proteins interact when activated

A

they interact sequentially forming a self-assembling enzymatic cascade and generating biologically active molecules, important for full inflammatory response

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8
Q

where is one of the most important key sites for the activation of the complement

A

is the surface of pathogens

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9
Q

what must happen for the complement to be useful immunologically

A

it has to be activated first

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10
Q

what are the 3 distinct pathways through which complement can be activated

A
  1. Classical pathway
  2. Lectin pathway
  3. Alternative pathway
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11
Q

what is the differences between the 3 different pathways of activation for the complement

A

depend on different types molecules for their initiation

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12
Q

what are the 3 ways in which the complement system protects against pathogens

A
  1. Recruitment of inflammatory and immunocompetent cells
  2. opsonization of pathogens
  3. killing of pathogens
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13
Q

First way of protection: recruitment

A

some components of the complement act as chemoattractants to recruit phagocytic cells to sites of complement activation

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14
Q

Second way of protection: opsonization

A

generation of large amounts of activated complement proteins that bind covalently to the pathogens opsonizing them for phagocytosis

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15
Q

Third way of protection: Killing of pathogens

A

the final components of the complement activation kill (damage) microbes by creating pores in their membranes

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16
Q

how does the complement also activate the adaptive immunity

A
  1. opsonization by complement components allows uptake of microbes by antigen-presenting cells (APC) such as dendritic cells
  2. B cells have complement receptors for certain complement receptors for certain complement proteins which enhance B cell response to complement coated microbes
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17
Q

what letter is designated by the letter C

A

the native components

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18
Q

how were the components numbered

A

not in numerical order but according to the order of discovery

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19
Q

what was the order of discovery of the complement components

A
  1. C1
  2. C4
  3. C2
  4. C3
  5. C5
  6. C6
  7. C7
  8. C8
  9. C9
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20
Q

how are the products of complement cleavage designated

A

the products of complement cleavage are designated by added lower case letter

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21
Q

what is the smaller cleaved fragment designated

A

the smaller cleavage fragment is designated “a”

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22
Q

What is the larger cleavage fragment of the complement components designated

A
  • the larger cleavage fragment is designated “b”
    • i.e. C4 is cleaved to C4a and C4b
      • and C4b is larger fragment
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23
Q

what is the exception to the nomenclature of the products of complement cleavage

A
  • C2
  • the larger fragment is C2a
    • the one with enzymatic activity
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24
Q

what are the complement component of the alternative pathway

A
  • they are designated by different capital letters
    • the cleavage products are designated lower case letters “a or b”
    • larger fragment of factor cleavage is Bb and smaller is Ba
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25
Q

how it the classical pathway initiated

A

the classical pathway is initiated by binding of C1q (first protein of the cascade) to the surface of a pathogen

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26
Q

How does C1q bind to the surface of pathogens in

A
  1. binds directly to the surface of bacterial components
    1. proteins, lipoteichoic acid
  2. Binds to C-reactive protein that initially binds to phosphocholine residues on bacterial polysaccharides
  3. binds to antigen-antibody complex on the pathogen surface
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27
Q

which pathway of C1q binding to the surface of a pathogen is the most effective

A

when it binds to the antibody-antigen complex

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28
Q

how is the lectin pathway initiated

A

by binding of carbohydrate-binding proteins to carbohydrates on the surface of pathogens

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29
Q

the carbohydrate-binding proteins in the lectin pathway include

A
  • Mannose binding lectin (MBL)
  • Ficolins
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30
Q

(MBL) mannose binding lectin:

A

a lectin that binds mannose-containing carbs on microbial surface

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31
Q

Ficolins

A

bind N-acetylglucosamine on the surface of some microbes

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32
Q

how is the alternative pathway of the complement be initiated

A

by binding of spontaneously derived plasma C3b to pathogen surfaces

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33
Q

In each pathway, sequential reactions lead to the generation of a protein complex called________

A

C3 convertase

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34
Q

The C3 convertase remains bound to the surface of the _______

A

pathogen

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35
Q

C3 convertase cleaves C3 to yield large amounts of ______

A
  1. C3b and C3a
    1. C3b: the main effector molecule of the complement system
    2. C3a: a mediator of inflammation
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36
Q

The C3b molecule acts as an

A

opsonin - binnds covalently to the pathogen surface

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37
Q

A pathogen opsonized with C3b becomes a

A

target for destruction through phagocytosis

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38
Q

when C3b acts as an opsonin how does it bind to the pathogen

A

it binds covalently to the pathogen surface

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39
Q

after opsonizing a pathogen with C3b what happens to the pathogen

A

it becomes a target for destruction through phagocytosis

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40
Q

C3b binds ______ convertase to produce C5 convertase

A

C3

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41
Q

what happens to C5 convertase after it is formed from C3b binding to C3 convertase

A

C5 convertase is converts C5 into C5a and C5b

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42
Q

what is important about C5a

A

it is an inflammatory peptide

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43
Q

what action does C5b have

A

C5b initiates the last event in the complement system activation

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44
Q

After C5b initiates the last events of activation of the complement system activation the activation culminates in the formation of

A

MAC: membrane attack complex

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45
Q

what is the most potent activators of the classical complement pathway in most domestic species

A

IgM and to a lesser extent IgG

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46
Q

when one IgM or several IgG molecules bind to an antigen, the _______ of the antibody can bind to the complement component ___________

A

Fc portionn

C1 (C1qr2s2)

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47
Q

what is the back bone of C1 made of

A

C1q

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48
Q

how many globular head domains does C1q have that are connected by linear tails

A

six

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49
Q

what are the two proteins that are associated with the tail domains of C1q

A
  • two copies of
    • C1r
    • C1s (serine proteases)
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50
Q

when is C1 activated

A

C1 is activated when two globular heads of C1q bind two adjacent Fc regions of antibodies bound to an antigen

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51
Q

what does the binding of C1q binding to antibodies activate

A
  • C1q binding to antibodies activates the protease activity of C1r
  • C1r then cleaves itself
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52
Q

The active C1r then cleaves the adjacent_____ molecules, which activates the serine protease activity of _____

A

The active C1r then cleaves the adjacent C1s molecules, which activates the serine protease activity of C1s

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53
Q

The activated C1s cleaves the complement protein _______ to _____ and _____

A

The activated C1s cleaves the complement protein C4 to C4a and C4b

54
Q

what does the C4b covalently attach to after it is formed from C1s cleaves C4

A

C4b covalently attaches (through reaction with hydroxyl or amine groups) to the surface of the microbe or Ab-Ag complex

55
Q

what is the next step after C4b is attached to the surface of the microbe

A
  • C1s cleaves C2 into C2b and the larger C2a
  • C4b then binds to C2a forming C2b2a on the surface of the microbe
56
Q

C4b2a is the classical pathway to________

A

C3 convertase

57
Q

what is the function of C3 convertase

A

cleaves C3 into C3a and C3b

58
Q

what is the most abundant complement protein

A

C3

59
Q

what happens to C3b after C3 is cleaved by C3 convertase

A

C3b being the larger fragment attaches to the surface of the microbe

60
Q

what is it called when the C3b from the C3 cleavage by C3 convertase binds to the surface of the microbe

A

opsonisation

61
Q

Since the binding of C3b to the surface opsonisation of the microbe what goal of the complement activation does this achieve

A

it marks the microbe for destruction by phagocytes

62
Q

C3b forms a complex with C3 convertase (C4b2a) to form

A

the classical pathway C5 convertase (C4b2a3b)

63
Q

C5 convertase cleaves C5 into

A

C5a and C5b

64
Q

what piece of the C5 cleavage products remains with the C5 convertase (C4b2a3b) and how is the MAC involved

A
  • C5b stays associated with the C5 convertase (C4b2a3b)
  • this complex that is formed plays a role in the formation of the membrane attack complex MAC
65
Q

what is the activation of the complement through the lectin pathway

A

it is an independent innate immune response

66
Q

what does lectin bind to

A

lectin bind particular carbohydrate (sugar) residues

67
Q

_______ and _______ are found in plasma and can recognize microbial-specific carbohydrates on the surface of microbes

A

MBL and Ficolins are found in plasma and can recognize microbial-specific carbohydrates on the surface of microbes

68
Q

what are the physiological characteristics of MBL

A

MBL is a tetrameric member of the C-type lectin family and has structural similarities with C1q

69
Q

What does MBL recognize on the in the cell walls of bacteria and fungi, as well as on some protozoa and in envelopes of some viruses

A

MBL recognizes Mannose, Fucose, N-acetylgucosamine that are present in the cell walls of bacteria and fungi as well as on some protozoa and in envelopes of some viruses

70
Q

What happens to MBL when it binds to a microbial cell wall

A

conformational changes occur which promote activation of MBL-associated serine proteases (MASPs) via autocatalysis

71
Q

what is the function of MASPs

A
  • it cleaves C4
    • into C4a and C4b
  • it also cleaves C2
    • into C2a and C2b
72
Q

after MASPs cleaves C4 and C2 what happens to the larger portions

A

C4b complexes with C2a to create C3 convertase (C4b2a), which is assembled on the surface of the microbe

73
Q

In the lectin pathway what is the function of the C3 convertase (C4b2a)

A

C3 convertase cleaves C3 into C3a and C3b leading to deposition of C3b on the surface of microbes

74
Q

in the lectin pathway C4b2a complexes with C3b to create ______, a _______ convertase, which initiates the terminal membrane attack pathway

A

in the lectin pathway C4b2a complexes with C3b to create C4b2a, a a C5 convertase, which initiates the terminal membrane attack pathway

75
Q

How does the activation of the complement through the alternative pathway differ from the other pathways

A
  • it does not require recognition of a microbial surface by antibodies or lectin
  • it utilizes the nonspecific, low-level hydrolysis of C3
76
Q

why is C3 important to the activation of the complement

A
  • it is the most abundant complement protein
  • also a key player in all pathways
77
Q

how does the complement activation begin in the alternative pathway

A
  • spontaneous cleavage of C3
    • this produces C3a and C3b components
78
Q

in the alternative pathway what happens to the C3b from the spontaneous cleavage of C3

A

C3b binds to a microbial surface or is degraded

79
Q

What happens in the alternative pathway if a C3b binds to a healthy host cell membrane

A

it is rapidly degraded to prevent any further complement activation

80
Q

how is C3b degraded when it binds to a healthy cell membrane in the alternative pathway

A

-Sialic acid residues on cell membranes promote binding of C3b to factor H (a negative regulator of complement activation)

81
Q

What is the function of factor H and I

A

inactivate and degrade inappropriately bound C3b

82
Q

why is it that when C3b binds to a microbe membranes and cell walls it is not degraded

A
  • Microbial membranes and cell walls are typically rich in Polysaccharides that do not contain sialic acid
  • additionally C3b bound to a microbial surface cannot be degraded by factor H and I
83
Q

what is the next step in the alternative complement pathway after C3b binds to the microbial surface

A

C3b binds Factor B to form C3bB complez

84
Q

what happens to C3bB after it is formed in the alternative complement pathway

A

C3bB complex is then cleaved by factor D

85
Q

what are the two products of the C3bB complex cleavage by factor D in the alternative complement pathway

A
  • Ba is released
  • active C3bBb remains
86
Q

what is C3bBb in the alternative complement pathway

A

C3bBb is the alternative C3 convertase

87
Q

what is the purpose of this alternative C3 convertase in the alternative complement pathway

A
  • Alternative C3 convertase can efficiently cleave plasma C3 and create more C3b that gets deposited onto microbial surfaces
    • this is also known as an amplification loop
88
Q

The alternative C3 convertase is unstable in the alternative complement pathway what is used to stabilize it

A

Factor P (properdin)

89
Q

What happens after the Alternative C3 convertase cleaves C3 in the alternative complement pathway

A

C3b complexes C3bBb to form C3bBb3b

90
Q

In the alternative complement pathway the formation of C3bBb3b is the:

A

alternative C5 convertase

91
Q

What is the function of the alternative C5 convertase in the alternative complement pathway

A

Alternative C5 convertase cleaves C5 producing C5b initiating the terminal MAC formation

92
Q

What is the goal of the Terminal membrane attack pathway

A

the goal of the terminal membrane attack pathway is to construct a protein complex that makes a hole in the target membrane and thus can directly lyse and kill the microbe

93
Q

what protein is formed in the Terminal membrane attack pathway

A

the Membrane attack complex (MAC)

94
Q

What product from each pathway initiates the formation of the MAC

A
  • Classical: C5 convertase (C4b2a3b)
  • Lectin pathway: C5 convertase (C4b2a3b)
  • Alternative pathway: Alternative C5 convertase (C3bBb3b)
95
Q

what is the first step in the MAC formation

A

C5b recruits C6 and C& to the target membrane forming the C5b67 complex

96
Q

In the MAC formation what happens after C5b67 complex is formed

A

C8 binds to the C5b67 complex unfolding a hydrophobic region that wedges into the target membranes

97
Q

In the MAC formation what happens after the C8 binds to C5b67 and inserts itself into the cell membrane

A

the complex recruits 10-16 copies of C9 into the membrane to create a cylindrical pore

98
Q

In the MAC formation, what is the result after the cylindrical pore is formed

A
  • Mac breaches the cell membrane of the microbe allowing water to rush into the cell
  • Osmotic lysis of the microbe by sufficient number of MAC on the membrane
99
Q

What is the function of the complement control proteins

A

the complement control proteins act to prevent the complement innate defense system from acting inappropriate targets and also from acting in perpetuity

100
Q

what type of proteins can downregulate or stop the classical, lectin, and alternative pathways at key points

A

soluble or membrane-associated complement control proteins

101
Q

how do the complement control proteins function

A
  • Inhibit the protease activities
  • or facilitate the degradation of activated complement complexes or convertases
102
Q

Complement control protein “C1 inhibiter” is located

A
  • in the plasma
  • large amounts are in the serum
103
Q

Complement control protein “C1 inhibitor” regulates which pathway

A

classical and lectin

104
Q

Complement control protein “C1 inhibiter” action

A
  • inactivates
    • C1r
    • C1s
    • MASPs
105
Q

Complement control protein “C4b-binding protein” is located

A

in the plasma and serum

106
Q

Complement control protein “C4b-binding protein” regulated these pathways

A

classical and lectin

107
Q

Complement control protein “C4b-binding protein” regulatory action

A
  • Binds C4b
    • accelerates the decay of the classical and lectin C3 convertase (C4b2a)
108
Q

Complement control protein “Factor H and I” location

A

plasma and serum

109
Q

Complement control protein “Factor H and I” regulates which pathway

A

Alternative complement pathway

110
Q

Complement control protein “Factor H and I” action

A
  • Binds C3b and accelerates decay
111
Q

Complement control protein Decay-accelerating factor (CD55): location

A

cell membrane of erythrocytes, neutrophils, lymphocytes, monocytes, platelets, and endothelial cells

112
Q

Complement control protein Decay-accelerating factor (CD55): pathway regulation

A

alternative

113
Q

Complement control protein Decay-accelerating factor (CD55): action

A

accelerates decay of C3 convertase (C3bBb)

114
Q

Complement control protein Complement receptor I (CD35): location

A

Cell membrane of erythrocytes (primates), neutrophils, lymphocytes, monocytes, and macrophages

115
Q

Complement control protein Complement receptor I (CD35): pathway regulation

A

classical, lectin, and alternative

116
Q

Complement control protein Complement receptor I (CD35): action

A

Binds C3b and C4b and inhibits alternative and classical/lectin C3 convertase

117
Q

Complement control protein membrane cofactor protein (CD46): location

A

widely expressed on cell membrane of host cells

118
Q

Complement control protein membrane cofactor protein (CD46): Pathway regulated

A

classical, lectin, and alternative

119
Q

Complement control protein membrane cofactor protein (CD46): Action

A

Binds C3b and C4a and inhibits alternative and classical/lectin C3 Convertases

120
Q

Complement control protein protectin (CD59): location

A

predominantly expressed on cell membrane of erythrocytes, leukocytes, and vascular endothelium

121
Q

Complement control protein protectin (CD59): pathway regulated

A

terminal membrane attack

122
Q

Complement control protein protectin (CD59): Action

A

Binds to C5b678 and prevents C9 recruitment and MAC formation

123
Q

what is the outcome from the complement product MAC

A
  • Direct target lysis
  • Osmodysregulation and lysis of target cells
124
Q

what is the outcome from the complement product C3a and C5a tissue inflammation

A
  • Tissue inflammation
    • Activation of mast-cell degranulation leadinng to release of vasoactive amines (histamine and serotonin)
125
Q

what is the outcome from the complement product C3a and C5a Endothelial activation

A
  • Endothelial activation
    • increased expression of adhesion molecules
126
Q

what is the outcome from the complement product C3a and C5a chemotaxis

A
  • Promotes migration of neutrophils, eosinophils, and macrophages toward the site of complement activation
127
Q

what is the outcome from the complement productC5a (C3a and C4a) leukocyte activation

A

upregulation of adhesion molecules, phagocytic receptors, and antimicrobial effectors by neutrophils and monocytes

128
Q

what is the outcome from the complement product C3b and iC3b Opsonization

A
  • enhancement of particle phagocytosis by macrophages and nneutrophils
129
Q

what is the outcome from the complement product C3dg promotion of humoral responses

A

Enhanced B-cell activation, retention of antigen complexes in B-cell follicles

130
Q

what is the outcome from the complement product C3b (and iC3b) immune complex clearance

A

Blocking of growth and facilitation of dissociation of immune complexes, immobilization and clearance of immune complexes through interaction with CR1 on erythrocytes

131
Q
A