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1

Jules Bordet

nobel prize for his discoveries relating to immunity, 1919

2

definition of complement system

enhances/ complements pathogen destruction by other immune mechanisms

3

how many proteins are made in complement system

over 30

4

where are complement proteins made

in liver

5

proteins in complement system are what type of enzymes

proteolytic enzymes
serine proteases

6

zymogens

complement proteolytic enxymes produced in liver and that are circulating in a healthy individual

7

what triggers the activation of the complement system

infection

8

complement consists of what when activated

protein cleaves and activates next complement protein in the pathway

9

complement activation is similar to

the domino effect

10

what are the three pathways to complement activation

alternative
lectin
classical

11

which complement activation is first to act

alternative

12

which complement activation is last to act

classical

13

what starts alternative pathway

pathogen surface creates local environment conducive to complement activation

14

what starts lectin pathways

mannose- binding lectin binds to pathogen surface

15

what starts classical pathway

c-reactive protein or antibody binds to specific antigen on pathogen surface

16

what pathway is first to respond of immediate innate immune system once barrier has been breached

alternative

17

what is the most important protein in alternative pathway

complement component 3
C3

18

what type of bond in buried in the inactive serine protease

thioester bond

19

a confirmation change of C3 can cause what to thioester bond

can be hydrolyzed

20

when thioester bond is hydrolyzed what happens

new conformational change known as iC3

21

what can now bind to iC3

Factor B

22

what does Factor B do to iC3

allow factor D to attach

23

Factor D does what to Factor B

Factor B cleaves into Bb and Ba

24

what part of factor B stays attached to iC3

Bb, turning into iC3Bb

25

what can iC3Bb do now

cleave C3 molecules into C3a and C3b

26

when C3 molecules are cleaved by iC3Bb what is now exposed

thioester bond, susceptible to nucleophilic attack

27

thioester bond can now attach to what after being cleaved

amino and hydroxyl group of pathogen surface if near it, or attacked by H2O creating inactive soluble C3b

28

what convertase cleaves C3 to C3a and b

C3 convertase

29

complement fixation

when microbe has C3b covalently bound to its surface it is tagged for destruction

30

when C3B is on pathogen surface what can attach to it

Factor B

31

What attaches to Factor B on C3b

Factor D causing cleavage of Factor B

32

what complex is created after Factor D cleaves Factor B on C3b

C3bBb complex

33

C3bBb is also known as

alternative C3 convertase

34

alternative C3 convertse works by

cleaving C3 into a and b exposing thioester bond but since near pathogen surface C3bBb is then attached to surface

35

what is Properdin (factor P) suppose to do

plasma protein that is used to stabilize the C3bBb convertase

36

what is a positive regulator

factor P, create more C3bBb convertase

37

about Factor H

region that binds to sialic residues on eukaryotic host cells
contains region that displaces Bb from the C3bBb convertase complex
cofactor with protease factor I

38

what is involved in negative feedback regulation

Factor H and I
DAF
MCP

39

how does Factor H work

binds to C3b on pathogen surface, cofactor I helps cleave to form iC3b

40

what negative regulation is used for C3bBb

DAF, decay accelerating factor

41

how does DAF work

binds to C3bBb , displaces Bb from convertase rendering it inactive

42

what is another negative regulation used for C3bBb

MCP, membrane cofactor protein

43

how does MCP work

MCP binds to C3bBb kicking off Bb and then cofactor I cleaves molecule and leaves it to iC3b

44

since pathway alternative is not activated by a specific response to a pathogen, there are

host cell regulators of complement activation (RCA proteins) necessary to protect host

45

proteins made up of CCP modules are also called

regulators of complement activation

46

what is a lectin

a protein that can bind a carbohydrate

47

what molecules are not present on mammalian cells

lipoteichoic acid peptidoglycan (gram p)
lipopolysaccharide and peptidoglycan (gram n)

48

yeasts have what type of glycoproteins

terminal mannose residues

49

vertebrates have what type of glycoproteins

terminal sialic acid residues

50

what are PAMPs

pathogen associated molecular patterns

51

what are PRR

pattern recognizing receptors

52

what type of PAMPS

mannose, fucose, and acetylated sugars

53

what type of PRRs

mannose- binding lectin, ficolins
found circulating in blood

54

what are MBL

mannose-binding lectin
c-type lectin bind to mannose containing carb of bacteria, fungi, protozoa and viruses

55

structure of MBL

stalk is a triple helix made from three identical polypeptides
polypeptide provides carbohydrate recognizing domain "flower"

56

individual MBL have what level of affinity to mannose and fucose

very low

57

multimeric MBL has what affinity to mannose and fucose

high affinity
binding strength increase

58

MBL is produced where contains what

liver
consists of carbohydrate recognition domain
(CRD) flower
and a collagen like domain (stalk)
collectin

59

MBL monomer assembles into

trimers

60

2 to 6 trimers of MBL will

oligomerize with oligomers of 3 to 4 trimers
seen in blood

61

when MBL bind to surface of pathogen this triggers

lectin pathway of complement activation

62

Ficolin

consists of collagen like domain and fibronogen like domain, monomers assemble into trimers

63

humans possess 3 ficolins, where are they synthesized

2 synthesized in liver and circulate in blood
other secreted by lung and blood cells

64

in the blood MBL and ficolin oligomers complex with

MASP
MBL- associate serine proteases

65

MASP 1 and 2 are found as

inactive pro enzymes on stalk of MBL or Ficolin

66

step 1 of lectin pathway

MBL with MASP1 and 2 attach to surface of pathogen, conformational change occurs in MASP1, auto activation of MASP1 which then cleaves and activates MASP-2

67

difference between C4 and C3

thioester bond hidden further in C4

68

complement component of C2

a serine protease zymogen that is similar to factor B

69

step 2 of lectin pathway

active MASP2 cleaves C4 into C4 a and b

70

C4b can either attach to

water and become inactive or attach to pathogen surface and become active

71

step 3 of lectin pathway

C4b bind covalently bond to pathogen surface

72

step 4 of lectin pathway

active MASP2 cleaves c2 fragment into a and b

73

step 5 of lectin pathway

c2a is an active serine protease that binds to C4b on microbe surface and produces
C4bC2a

74

C4bC2a is the what like in alternative pathway

C3 convertase

75

Step 6 of lectin pathway

C4bC2a can cleave C3 molecules into C3b and a, allowing C3b to covalently bond to pathogen surface

76

lectin pathway is initiated by

activation of a specific PAMP and PRR interaction

77

what is the pathogen sensor of the classical pathway

C1 complex

78

what is the C1 complex made up of

C1q: collagen like domain and globular domain
monomers into timers
C1R and C1s (like MASP) are inactive serine proteases zymogens, two molecules of each protease assamble as a complex associated with C1q,

79

how can globular heads of C1q attach to pathogen surface

1. directly binding to certain bacterial cell wall structure such as lipteichoic acid
2. binding to c-reactive proteins that have adhered to surface of bacterium
3. bind to antibodies that have already bound to surface of pathogen

80

what are C reactive proteins (CRP)

pentraxin family of proteins
pattern recognition receptor
binds to phosphochoiline
cannot bind to that on mammals

81

classical pathway step 1a

C1 complex binds and if 2 or globular heads interact with ligand conformational change in C1r:c1s complex

82

classical pathway step 1b

conformational change in c1r:c1s complex causes autoactivatoin of C1r and active C1r able to cleave and activate c1s

83

Active C1s can cleave what substrates

C4 (similar to C3) and C2 (serine protease zymogen similar to factor B)

84

Step 2 of classical pathway

active c1s cleaves C4 to produce c4a and b

85

Step 3 of classical pathway

C4b molecule bind to surface of pathogen

86

c4a molecule becomes

mediator of inflammation

87

Step 4 of classical pathway

active c1s cleaves c2 into c2a and b, which is precursor to vasoactive c2kinin

88

step 5 of classical pathway

c2a is an active serine protease that binds to c4b on the microbe surface producing c4b2a (c3 convertase of classical pathway)

89

step 6 of classical pathway

one molecule of c4bc2a can cleave c3 into c3a and b. C3b can covalently bond to pathogen surface

90

what regulates CRP activation

recognition of a specific microbial signal/patter but both c1 complex, MBL and Ficolins can activate spontaneously

91

regulators of classical

DAF competes with face 2a for binding to c4b
MCP can associate with c4b2a convertase and displace 2a fragment, with help from cofactor I protease, cleaves c4b to inactive for iC4b

92

C1 inhibitor function

causes dissociation of either c1s/c1r from c1 complex and MASPs from MBL or ficolins

93

molecules involved with alternative pathway

C3, factor b, factor d and properdin
c3 convertase: ic2Bb and C3bBb

94

molecules involved with lectin pathway

MBL, ficolin, MASP1-2, C4 and C2
c3 convertase: C4b2a

95

molecules involved in classical pathway

C1q, C1r, C1s, C4 and C2
c3 convertase: C4b2a

96

all pathways lead to release of

C3a and binding of c3b to pathogen marking it for destruction

97

when C3b molecule combined with C3bB2 or C4bC2a it generates

a new enzyme called c5 convertase

98

what different about c5

two protein chains but no thioester bond

99

c5 binds to c3b in

c5 convertase complex

100

what happens to c5 convertase complex when c5 binds

conformation of complex change allowing Bb or the C2a serine proteases to cleave c5

101

c5b initiates

membrane attack

102

opsonization

coating the surface of a pathogen so that it is more readily ingested by phagocytosis

103

macrophages have what receptor that binds to C3b

CR1

104

macrophages have what receptor that binds to c5a

C5aR

105

C3b coated pathogen will bind to CR1 but is that enough for phagocytosis

no

106

C5a binding on C5aR will help do what to CR1

help phagocytos

107

c3a and c5a bind to

receptors on phagocytes, mast cells and endothelial cells and induce changes in the functions of these cells and alter the secretion of mulecules from the cells

108

what do C3a and C5a do to endothelial cells

increase blood flow and vascular permeability, leading to leakage of fluid from blood vessels and other complement and plasma proteins

109

C3a and c5a act also as what to recruit more phagocytes to site of injury

chemoattractants

110

C3a and 5a increase expression of complement receptors on

phagocytes

111

C3a and C5a cause what cell to degranualte and release histamine

mast cells

112

how does C5 initiate membrane attack

C5b binds to c6 (c5b6), then c5b6 complex binds to c7 (c5b67), causing conformational change of complex exposing hydrophobic site of c7 that inserts into lipid bilayer, c8 binds to c5b67 complex, another conformational change happens exposing hydrophobinc regiojn of c8 that inserts into bilayer, multiple c9 molecules bind to c5b678 complex until membrane spanning channel forms

113

what is MAC

membrane attack complex creates pore damages to lipid bilayer resulting in disruption of proton gradient, penetration of host cell enzymes like lysoyzome and eventual death of pathogen

114

how to prevent MAC on human cell

S proteins, clusterins, and Factor I prevent C5b from associating with c6 and 7,
human cell surface protein CD59 inhibits binding of C9 to complex