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C3a

inflammation

1

opsonization and phagocytosis

C3b

2

inflammation 2nd round

C5a

3

after C5a

Lysis of microbe

4

what consists of several plama proteins that work together to opsonize microbes,
to promote the recruitment of phagocytes to the site of infection,
and in some cases to directly kill the microbes

the complement system

5

What are 3 things that can initiate the complement system?

Classical pathway
Alternative pathway
lectin pathway

6

What is the second step of complement activation?

C3b and formation of C3 convertase

7

What does C3b initiate activation of?

C5 and the formation of C5 convertase

8

What is the last step in the complement activation?

the formation of membrane attack complex, bc it creates holes in the plasma membrane

9

An inactive precursor enzyme called a zymogen is altered to become an active protease that cleaves the next complement protein in the cascasde...

proteolytic cascade

10

What does an enzymatic cascade result in?

A temendous amplification of the amount of proteolytic products that are generated

11

What does the proteolytic products that are generated perform?

vaious effector functions of the complement system

12

What does the complement system work in cooperation with?

Other medically important proteolytic casesed that include
the blood coagulation pathways
the kinin-kallikrein system that regulates vascular permeability

13

How does C3 b bind to a microbe?

covalent binding which forms C5 convertase

14

All three complexes of the complement pathways result in?

sequential recruitment and assembly of additional complement proteins into protease complexes

15

What cleaves the central protein of the complemetn system, C3?

C3 convertase

16

What does C3 convertase cleaving C3 produce?

C3a and C3b

17

What happens to the C3b fragment?

It becomes covalently attached to the microbial surface

18

What serves as an opsonin to promote phagocytosis of the microbes?

C3b

19

When the C3b fragment is realeased, it stimulates?

inflammation by acting as a chemoattractant for neutrophils

20

What do C3b binding to other completment proteins form?

A protease called C5 convertase, that cleaves C5

21

What does C5 convertase cleaving C5 produce?

a released peptide (C5a) and a larger fragment (C5b) that remains attached to the microbial cell membranes

22

C5a has a very important chemoattractant role of?

changing the permeabilliy of blood vessels

23

C5b initiates the formation of what complexes?

the complement proteins C6, C7, C8, and C9, which are assembled into a membrane pore

24

What is the membrane pore of C6, C7, C8, and C9 called?

the membrane attach complex (MAC)

25

What causes lysis of the cells where complement is activated/

MAC

26

What binds to the surface of a microbe, where it functions as an opsonin and as a component of C3 and C5 convertase

C3b

27

What stimulates inflammation?

C3

28

What is a serine protease adn the active enzyme of C3 and C5 conertases?

factor B

29

What is a plasma serine protease that cleaves factor B when it is bound to C3b?

Factor D

30

What stablizes the C3 convertase (C3bBb) on microbial surfaces?

properdin

31

What initiates the classical pathway?

C1 (C1qr2s2)

32

What does C1q bind to?

Fc portion of antibody

33

What are proteases that lead to C4 and C2 activation?

C1r and C1s

34

What does C4a stimulate??

inflmmation

35

What activates C4

C4b covalently binds to surface of microbe or cell where antibody is bound

36

C4b binds to C2 for cleavage by

C1s

37

a serine protease functioning as an active enzyme of C3 and C5 convertases

C2

38

What initiates the lectin pathway?

Mannose beinding lectin (MBL)- it binds to terminal mannose resideus of microbial carbohydrates.

39

What activates C4 and C2

an MBL associated protease

40

How does the classical pathway detect Abs bound to the surface of a microbe or other sturucture?

a plama protein called C1q

41

What happens once C1q binds to the Fc protion of the antibodies?

two associated serine proteases called C1r and C1s become active

42

What initae a proteiolytic cascade involving other complement proteins C2 and C4?

C1r and C1s

43

What does MBL recognize?

terminal mannose residues on microbial glycoproteins and glycolipids, similar to the mannose receptor on phagocyte membranes

44

What family is MBL a member of?

the collectin family

45

The MBL has what strucutre?

a hexamertric structure similar to the C1q component of the ocmplement system

46

What are activated after MBL binds to microbes?

two zymogens MASP1(mannose- associated serine protease 1 or mannan binding lectin associated serine protease) and MASP2 are activated

47

What functions do MAPS1 and 2 have?

Similar to C1r and C1s and initaite downstream proteolytic steps identical to the classical pathway

48

What three homologous hexameric protines can all initate the complement activation?

C1q, MBL and Ficolin

49

What binds to the Fc region of IgM and activates the serine protease activity of C1r and C1s? microbial surface antigetn

C1q

50

MBL binds to?

Mannose on the surface of microbes and acitvates MASP1 and MASP2 assocated with mannose binding lectin

51

What binds to N-acetylglucosamine(bacterial cell wall) on the surface of microbes and activates MASP1 and MASP2

Fibolin

52

What is the collectin family?

A fmaily of trimeric proteins with lectin head

53

What are soluble effector molecules in the innate immune system part of the sollectins?

MBL and pulmonary surfactant proteins (2) SP-A and (3)SP-D

54

what is a soluble PRR that binds carbohydrates with terminal mannose and fucose and enhances phagocytosis of microbes?

MBL

55

What are low MBL levels associated with?

increased susceptibility to a vairety of infections

56

What are collectins with lipophilic properties and their major functions are to maintina the ability of lungs to expand and as mediators of innate immune repsonses

SP-A and SP-d

57

What do SP-A and SP-D bind to?

Various microoganims and act as opsonins, faciciltating phagocytosis by alveolar macrophages

58

What direclty inhibit bacterial growht?

SP-A and SP-D

59

What directly activate macrophages?

SP-A and SP-D

60

What are plama protiens that are strucutally similar to collectins but they have a fibrinogen type carbohydrate recognition domain?

ficolins

61

What are humoral molecules of the innate immune system?

ficolins

62

What are the molecular ligands of the ficolins?

N-acetylglucosamine and the lipoteichoic acid component of the cell walls of gram- POSITIVE bacteria

63

Ficolins have been shown to beind serveral species of....

bacteria, opsonizing them and activating complemetn in a manner simlar to that of MBL

64

How does involement in a opsonin dependent phagocytosis effect?

limits the infection and concurrently orchestrating the subsequent adaptive clonal immune reponse

65

How is the lectin pathway of complemetn activated?

that attached serine proteases MASPs

66

How is the alternative pathway triggered?

when a complement protein called C3 directly recognizes certain microbail surface strucuteres such as bacterial LPS

67

What is constitutively activated in solution at a low level and binds to bacterail surfaces?

C3

68

What is the spontaneous activation amplified on?

microbial surfaces

69

What is the alternative pathway no activated on teh surface of mammalian cells?

the mammals have a regulatory protein that inhibits the activation of alternative pathway

70

What dissociate the complement C3 convertase (C3bBb) from host mammal cells?

decay- accelerating factor DAF), complement receptor 1 (CR1) adn factor I

71

What complex binds to membrane vai C7 in the formation of MAC?

C5b binds C6 and C7 and C5b67 complex

72

What inserts into the cell membrane in MAC?

c8 binds to C5b67 complex

73

What forms a pore in MAC

up to 19 molecules C9 bind and polymerize

74

What is MAC?

It is the cytolitic end complex. Membrane attack complex

75

inflammation

C5a, C3a

76

phagocytosis

C3b

77

lysis of microbe

MAC

78

C3a activation can happen spontaeously, so it has a much lower reaction than

C5a

79

Contraction of smooth muscles
C3a
C4a
C5a

+
(+)
++++

80

increased permeability of blood vessels
C3a
C4a
C5a

+
(+)
++++

81

Degranulation of basophils
C3a
C4a
C5a

+
(+)
+

82

Chomtaxis, release of O2 racials and lysosomal enzymes
C3a
C4a
C5a

-
-
++++

83

What helps kill microbes in phagolysosomes?

ROS, NO, and lysosomal enzymes

84

Microbes may be ingested by .... of phagocytes

different membrane receptors

85

What are microbes internalized into?

phagosomes

86

What fuse with lysosomes to form phagolysosomes?

phagosomes

87

How are the microbes killed?

Reactive Oxygen and Nitrogen species and proteolyitic enzymes

88

What are monocytes actived by?

microbial products such as LPS and by NK cell- derived IFN-gamma

89

What does monocyte activation lead to?

The activation of transcription factors, the trancription of vaious genes, and the synthesis of proteins

90

What are monocytes acvited by?

the stimuli from T lymphocytes such as CD40 ligand and IFN-gamma
- they may alternatively be acitvated by other signals to rpomote tissue repair and fibrosis

91

What lead to inflammation enhanced adaptive immunity?

cytokines TNF, IL-1, IL-6, IL-12

92

What is the principal cell source of tumor necrosis factor (TNF)

macrophages, T cells

93

What is the principal celluarl targets for TNF endothelial cells?

activation (inflammation, coagulation)

94

TNF neutrophils?

activation

95

TNF hypothalaums

fever

96

TNF liver

syntehsis of acute phase proteins

97

TNF mucsle, fat

catabolism (Cachexia)

98

TNF many cell types

apoptosis

99

principle cell source for IL-1

mcarophages, endothelial cells, some epithlieal cells

100

IL-1 endothelia cells

activation (inflammation, coagulation)

101

IL-1 hypothalmus

Fever

102

IL-1 liver

synthesis of acute phase protines

103

IL-1 T cells

Th17 differentiation

104

principal cell source for chemokines

macrophages, dendritic cells, endothelial cells, T lymphoctes, fibroblasts, platelets

105

chmokines leukoytes

increased integrin affinity, chemotaxis, activation

106

Principal cells for IL-12

dendritic cells, macrophages

107

IL-12 NK cells and T cells

IFN-gamma production, increased cytotoxic activity

108

IL-12 T cells

Th1 differentiation

109

IFN-a/b principal cell sources

IFN alpha- Dendritic cells, and macrophages
IFN-beta- fibroblast

110

IFN gama princiapl cell source

NK cells and T lymphocytes

111

Target of IFN gamma

activation of macrophages
stimulatioin of some antibody responses

112

IFN a/b targets

all cells; antiviral state, increased class I MHC expression
NK cells activation

113

IL-10 principal cell source

macrophages, dendirtic cells, T cells

114

IL10 macrophages, dendritic cells

inhibition of IL12 production, reduced expression of costimulators and class II MHC molecules

115

IL6 principal cell source

macrophages, endothelial cells, T cells

116

IL-6 liver

synthesis of acute phase proteins

117

IL6 B cells

proliferation of antibody producing cells

118

IL15 principal cell source

macrophages and others

119

IL15 NK cells

porliferation

120

IL15 T cells

proliferation

121

IL18 principal cells source

macrophages

122

IL18 NK cells and T cells

IFN gamma synthesis

123

TGF beta principal cell source

many cell types

124

TGF beta inhibition of inflmmation T cells

differentiation of TH17, regulatory T cells

125

Local inflammation in endothelia cells

TNF, IL-1 act on adhsion molecule TNF increase permability and give off IL-1 chemokines

126

Local inflmmation of leukocytes

TNF, IL1 activation... gives IL1 IL6 chemokines

127

systemic protective effects of the brain

TNF, IL1, IL6 give fever

128

ststemic protective effects of the liver

IL1, IL6 give actue phase protiens

129

ststemic protective effect of bone marrow

TNF, IL1, IL6 produce leukocyte production

130

Systemic pahtologic effects on heart

TNF... low output

131

systemic pahtologic effects on endothlial cells/ blood vessel

TNF becasue of thrombus gives increased permablity

132

systemic pathologic effects on multiple tissues

TNF on skeletel muscles insulin resisitance

133

What have multiple local and systemic inflammatory effects?

TNF, IL1, IL6

134

what act locally on leukocytes and endothleium to induce acute inflmation/

TNF and IL1

135

TNF and IL1 induce?

the expression of IL6 from leukocytes and other cell types

136

What mediate protective systemic effects of inflmmation?

IL1, IL6 and TNF

137

What induce fever, acute phase protein synthesis by liver, and increased production of leukocytes by bone marrow?

TNF IL1 MAIN, IL6

138

TNF can cause septic shock, what are 3 pahtologic abnormalities?

decreased cardiac function
thrombosis and capillary leak
metabolic abnormalitites due to insulin resistance

139

several plama protines that recognize microbial structrue and partcipate in innate immunity belong to the

pentraxin family

140

What are acute phase protines from the pentraxin

C reactive protein (CRP) and serum amyloidP (SAP)

141

What can activate complement by binding C1q and intiaitng the classical pathway?

CRP and SAP

142

What do CRP and SAP recognize?

phosphorylcholine and phosphatidylethanolamine respectively, which are found on bacteria and apoptotic cells

143

Plasma concentrations of CRP and SAP are very low in helathy individuals but can?

Increase up to 1000-fold during infections and in response to other inflammatory stimuli

144

What does the increased levels of CRP and SAP result in?

An increased synthesis by the liver induced by cytokines IL6 and IL1, which are produced by phagocytes as part of the innate immune repsone

145

What are acute phase protines from the pentraxin family

C-reactive protien (CRP) and serum amyloid P (SAP)

146

opsonize

make more susceptible to phagocytosis

147

Acute phase reactant Dramatic increase in concentration...
C-reactive protine
mannose biding lectin
alpha 1- acid glycoprotein
serum amyloid P component

fixes complement, opsonizes
fixes complement, opsonizes
transport protein
amyloid component precursor

148

What are produced by virus infected cells?

Type 1 interferons (IFNalpha and IFNbeta)

149

What is the production of IFNa and IFNb triggered by?

response to intracellular TLR signaling and other sensors of viral RNA

150

What do IFNalpha and IFN beta bind to?

receptors on neighboring unifected cells and activate JAK STAT signaling pathways

151

What does the activation of the JAK STAT pathyway induce?

genes whoe products interfer with viral replication

152

IFNA and IFNb bind to receptors on infected cells and?

induce expression of genes whoe products enhance the cell's susceptibility to CTL medicated killing