Innate Immunity (part 2) Flashcards
1
Q
complement system
A
consists of several plasma 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
2
Q
3 complement pathways
A
alternative (spontaneous) pathway
classical pathway
lectin pathway
3
Q
complement pathway early/late steps
A
- formation of C3 convertase complexes that cleave C3 –> C3a (inflammation) and C3b (osponization and phagocytosis of microbes)
- formation of C5 convertase complexes that cleaves C5 –> C5a (inflammation) and C5b (initiates late steps - membrane attack complex)
- late steps results in formation of the membrane attack complexes which form holes in microbial membranes
4
Q
complement activation involves proteolytic cascades in which an inactive precursor enzyme, called a ______ , is altered to become an active _____ that cleaves the next complement protein in the cascade
A
zymogen
protease
5
Q
enzymatic cascades result in tremendous ______ of the amount of proteolytic byproducts that are generated
A
amplification
6
Q
byproducts of complement activation perform various ______ functions of the complement system
A
effector
7
Q
the complement system works in cooperation with other medically important proteolytic cascades including:
A
the blood in coagulation pathways
the kinin-kallikrein system that regulates vascular permeability
8
Q
recognition of microbes by any of the 3 complement pathways results in a sequential recruitment and assembly of additional complement proteins into _____ complexes
A
protease
9
Q
C3 convertase cleaves C3 producing
A
C3a and C3b fragments
10
Q
soluble C3a fragments stimulates ______ by acting as a _______ for ______
A
inflammation
chemoattractant
neutrophils
11
Q
C3b fragment becomes covalently attached to _____ and serves as an opsonin to promote ______ of the microbes
A
microbial surface
phagocytosis
12
Q
C3 convertase binds to ______ to form a protease complex called ______
A
C3b
C5 convertase
13
Q
C5 convertase cleaves C5 producing _____ and _____
A
C5a and C5b
14
Q
soluble C5a is a very potent chemoattractant that also induces changes in
A
the permeability of blood vessels
15
Q
C5b is attached to bacterial membrane that initiates the formation of a complex of ______ called the ______
A
C6, C7, C8, C9 complement proteins
membrane attack complex (MAC)
16
Q
multiples MACs cause
A
bacterial leak and lysis
17
Q
alternative pathway steps
A
- C3 spontaneously cleaves and C3b attaches to pathogen surface
- Factor B binds to C3b –> Factor D cleaves Factor B –> producing Ba and Bb
- C3b and Bb complex is now alternative C3 convertase (C3bBb) which can cleave more C3 molecules generating more C3a and C3b
- properdin binds and stabilizes the formed C3bBb convertase that enhances successive proteolytic steps producing more C3b proteins attaching to pathogen surface
- another C3b binds to properdin-C3bBb complex forming alternative C5 convertase (C3b2Bb)
- alternative C5 convertase (C3b2Bb) cleaves C5 producing C5a and C5b and C5b (along with C6 and C7) intercalates into pathogen membrane surface
- C5b is responsible for MAC formation
18
Q
the alternative pathway can be initiated as an _______ when C3b generated by the classical or lectin pathway binds to microbial surface and interacts with factor B producing C3 convertases of the alternative pathway
A
amplification loop
19
Q
Formation of MAC and lysis of bacteria
A
- C5b binds C6 and C7 and intercalates pathogen membrane
- C8 binds to the C5b67 complex
- C9 binds to the C5b678 complex and polymerize
- 1-16 molecules of C9 bind to form a pore in the membrane
20
Q
classical pathway steps
A
- antibody binds to pathogen surface changing conformation of antibody
- C1q binds to Fc portion of antibody
- C1r activates C1s serine proteases
- C1s activates C2 and C4 producing C2aC4b complex (classical C3 convertase)
- classical C3 convertase (C4bC2a) cleaves C3 into C3a and C3b (C3b attaches to pathogen surface)
- C3b binds to C4bC2a forming classical C5 convertase (C4bC2aC3b)
- classical C5 convertase cleaves C5 into C5a and C5b
- C5b initiates formation of MAC
21
Q
lectin pathway steps
A
- mannose binding lectin (MBL) recognizes terminal mannose residues on microbial glycoproteins and glycolipids (similar to the mannose receptor on phagocytes) and binds to pathogen surface activating MASP-1 and MASP-2
- MASP-1 and MASP-2 cleaves C4 to C4a and C4b and C2 to C2a and C2b
- C4b binds covalently to microbial surface
- C2a binds to C4b (lectin pathway convertase)
- C4b2a (lectin pathway convertase) binds C3 and cleaves into C3a and C3b (C3b remains binded to C3b2a)
- C4b2a3b (lectin pathway C5 convertase)
- lectin pathway C5 convertase (C4b2a3b) cleaves C5 into C5a and C5b
- C5b initiates formation of MAC
22
Q
classical complement pathway:
C3 convertase
C5 convertase
A
C3: C4bC2a
C5: C4bC2aC3b
23
Q
lectin complement pathway
C3 convertase
C5 convertase
A
C3: C4bC2a
C5: C4bC2aC3b
24
Q
alternative complement pathway
C3 convertase
C5 convertase
A
C3: C3bBb
C5: C3bBbC3b
25
classical pathway requires
IgM or IgG
CI
26
in alternative pathway, C3 undergoes ______ hydrolysis
spontaneous
27
alternative pathways requries
Factors B and D
28
complement is not activated on the surface of mammalian cells because they express ______ that inhibit, disassemble, or cleave the convertases
complement regulatory proteins
29
DAF complement regulatory proteins
blocks C4b and C2a
30
DAF or CR1
dissociate C3 convertase (C4bC2a)
31
CR1 and Factor I
C3b/C4b inactivator
Factor I cleaves C4b/C3b preventing the assembly of the C3 and C5 convertase
(CR1 is cofactor for Factor I)
32
complement pathways produce soluble C3a and C5a which act as recruiters and activation of ______ resulting in _______
leukocytes
inflammation
33
bound C3b to pathogen surface results in
recognition of bound C3b by phagocyte resulting in phagocytosis
34
C3a and C5a stimulate mast cells and basophils to secrete ______ resulting in ______
vasoactive substances
inflammation
35
C3a and C5a stimulate neutrophils to secrete _____ resulting in _____
chemokines, prostaglandins, ROS, and RNS
inflammation
36
C3a and C5a stimulate monocyte and macrophage to secrete _____ resulting in _____
IL-1, IL-6, prostaglandins, ROS, RNS
inflammation
37
there are no receptors for
C4a
38
which is more potent stimulator of inflammation, C3a or C5a
C5a
39
how does C3a and C5a result in inflammation
contraction of smooth muscles
increases permeability of blood vessels
degranulation of basophils
chemotaxis, release of O2 radicals and lysosomal enzymes
40
complement-mediated phagocytosis and killing steps
1. complement activation leads to deposition of C3b on the bacterial cell surface
2. CR1 (complementary receptor 1) on macrophage binds to C3b on bacterium
3. endocytosis of the bacterium by the macrophage
4. macrophage membrane fuse creating a membrane-bounded vesicle called a phagosome
5. lysosomes fuse with the phagosomes forming the phagolysosome and killing by ROS, RNS, NO, and lysosomal enzymes
41
some bacteria can survive in phagolysosome because they express
catalase
42
microbes may be ingested by different membrane receptors of
phagocytes
43
collectins and ficolins are enhancers of
phagocytosis
44
collectins are a family of soluble _____ with lectin head which serve as effector molecules of the innate immune system
PRRs
45
mannose binding lectin (MBL) and pulmonary surfactant proteins ____ are members of the collectins family
SP-A and SP-D
Surfactant Protein (SP)
46
MBL is a soluble PRR that binds to carbohydrates with terminal _____ and enhance phagocytosis of microbes
mannose
47
low MBL levels are associated with increased susceptibility to a variety of
infections
48
SP-A (surfactant protein A) and SP-D have ______ properties and their major functions are to maintain the ability of lungs to expand and as mediators of innate immune responses
lipophilic
49
SP-A and SP-D bind to various microorganisms and act as _____ , facilitating phagocytosis by ______ macrophages
opsonins
alveolar
50
SP-A and SP-D can also directly inhibit ______ growth and directly activate______
bacterial
macrophages
51
ficolins are a family of
PRRs
52
ficolins are plasma proteins (humoral molecules) that are structurally similar to collectins but they have a fibrinogen-type ______ recognition domains
carbohydrate
53
ficolins recognize ______ and ______ on the surface of microbes and activates _____ complement pathway through activation of MASP1 and MASP2
N-acetylglucosamine
lipoteichoic acid
lectin
54
ficolins limit ongoing ______ growth
bacterial
55
collectins and ficolins are ______ molecules (PRRs) which recognize pathogen surface proteins
humoral
56
C1q binds to the Fc regions of _____ and activates _____ and _____ which initiates ______ complement pathway
IgM
C1r
C1s
classical
57
MBL (collectin) binds _____ on the surface of pathogens and activates _____ complement pathway by activation of MASP1 and MASP2
mannose
lectin
58
cytokine: Tumor Necrosis Factor (TNF)
produced by:
cellular target and effect:
macrophages* ; T-cells
endothelial cells: activation (inflammation, coagulation)***
neutrophils: activation
hypothalamus: fever
liver: synthesis of acute-phase proteins
muscle, fat: catabolism
many cell types: apoptosis
59
cytokine: IL-1
produced by:
cellular target and effect:
macrophages** ; DCs, endothelial cells, T cells, fibroblasts, platelets
endothelial cells: activation (inflammation and coagulatioon)
hypothalamus: fever***
liver: synthesis of acute phase proteins
60
cytokine: chemokines
produced by:
cellular target and effect:
macrophage*** ; DCs, endothelial cells, T cells, fibroblasts, platelets
leukocytes: increased integrin affinity, chemotaxis, activation
61
cytokine: IL-12
produced by:
cellular target and effect:
macrophages*** ; DCs
NK cells and T cells: IFN-gamma production
62
cytokine: IFN-gamma
produced by:
cellular target and effect:
NK cells and T cells
activation of macrophages --> production of cytokines
63
cytokine: Type 1 IFNs (alpha and beta)
produced by:
cellular target and effect:
IFN-a: macrophages*** ; DCs
IFN-b: fibroblasts
all cells: antiviral***, increased class I MHC expression
NK cells: activation
64
cytokine: IL-10
produced by:
cellular target and effect:
macrophages*** ; DCs, T cells
macrophages, DCs: inhibition of IL-12 production, reduced expression of costimulators and class II MHC molecules
65
cytokine: IL-6
produced by:
cellular target and effect:
macrophages*** ; endothelial cells, T cells
liver: synthesis of acute-phase proteins***
B cells: proliferation of plasma cells
66
cytokine: IL-15
produced by:
cellular target and effect:
macrophages***
NK cells: proliferation
T cells: proliferation
67
cytokine: IL-18
produced by:
cellular target and effect:
macrophages
NK cells and T cells: IFN-gamma synthesis***
68
cytokine: TGF-beta (transforming growth factor)
produced by:
cellular target and effect:
macrophages and many others
inhibition of inflammation
69
first sign of systemic inflammatory response is
fever
70
sickness cytokine (what makes you feel miserable)
TNF
71
TNF and IL-1 act locally on leukocytes and endothelium to induce acute _______ and induce expression of cytokine ______
inflammation
IL-6
72
TNF, IL-1, and IL-6 mediate protective systemic effects of inflammation, by inducing ______, _______ synthesis by the liver, and _______
fever
acute-phase protein
leukoctyosis (increased production of leukocytes by the bone marrow )
73
systemic TNF can cause the pathologic abnormalities that lead to septic shock, including:
decreased ______ function
thrombosis and ______ leak
metabolic abnormalities due to ______ resistance
cardiac
capillary
insulin
74
two major acute phase proteins
C-reactive protein (CRP)
serum amyloid P (SAP)
75
C-reactive protein (CRP) and serum amyloid P (SAP) are acute phase proteins from the ______ family
pentraxin
76
plasma concentrations of CRP and SAP are very low in healthy individuals but can increase up to ______ - fold during infections
1000
77
what is responsible for increased levels of CRP and SAP?
tissue damage/infection --> phagocytes produce IL-1 and IL-6 --> liver increases synthesis of CRP and SAP
78
CRP and SAP recognize ______ (found on bacteria) and _______ (found on apoptotic cells)
phosphorycholine
phosphatidylethanolamine
79
CRP and SAP can activate complement by binding _____ and initiating the ______ pathway
C1q
classical
80
C1q binds to CRP in the same way as C1q binds to ______ in classical complement pathway
IgM
81
upon viral infection, viral nucleic acids and proteins are recognized by several
cellular TLRs
82
TLR-mediated signaling activates transcription factors [the IRF (interferon regulatory factors) proteins] that stimulate the production of
Type I Interferons (IFN-alpha and IFN-beta)
83
once virally infected cells secrete IFN-alpha and IFN-beta, they bind to receptors on infected cells inducing the expression of genes whose products enhance the cell's susceptibility to
CTL-mediated killing
84
IFN-alpha and IFN-beta produced by virus-infected cells can bind to membrane receptors on neighboring uninfected cells and activate ______ pathway that induces expression of genes whose products ______ with viral replication by the following ways:
1. inhibition of viral protein synthesis
2. degradation of viral RNA
3. inhibition of viral gene expression and virion assembly
JAK-STAT signaling
interfere
85
pathogen recognition through PRRs is an important bridge between
innate and adaptive immunity
86
pathogen recognition through PRRs causes activation and maturation of
antigen-presenting cells (APCs)
87
secreted cytokines (e.g. cytokine ______ ) assisted with development and maturation of T cell
IL-12
| in absence of IL-12 --> humoral-mediated immunity???
88
2 ways B cells are activated
1. antigen recognition by B cell leads to activation
2. molecules induced by innate immune responses to microbes (costimulator, complement fragment, etc.) leads to activation
