Week 8 Lec: Complement System Flashcards
1
Q
It is a complex series of more than 30 soluble and cell-bound proteins that interact in a very specific way to enhance host defense mechanisms against foreign cells.
A
Complement
2
Q
Complement is a complex series of more than ___ soluble and cell-bound proteins.
A
30
3
Q
Complement systems is also called?
A
complement pathway
4
Q
Complement is a complex series of more than 30 soluble and cell-bound proteins that interact in a very specific way to?
A
enhance host defense mechanisms against foreign cells
5
Q
Complement is a heat-_____ substance.
A
labile
6
Q
A termed “Complement” was given by?
A
Paul Erlich (1980’s)
7
Q
In 1919, __________ was awarded a Noble Prize for elucidating the nature of complement.
A
Jules Bordet
8
Q
In _____, Jules Bordet was awarded a Noble Prize for elucidating the nature of complement.
A
1919
9
Q
Effects of complement activation - Complement activation promotes?
A
- Activation of immune system
- Opsonization (C3b, C4b, C5b) and
- eventually result to LYSIS of Foreign cells and Immune complexes.
10
Q
Chronic Activation of complement system leads to?
A
inflammation and tissue damage
11
Q
Complement pathway plays an essential role as a?
A
pro-inflammatory agent
12
Q
Acute Phase Reactants are produced primarily by __________ within _____ hours in response to an increase in certain intracellular signaling polypeptides called __________.
A
hepatocytes/liver parenchymal cells; 12-24; cytokines
13
Q
2 major acute phase reactants?
A
Serum amyloid A and C-reactive protein
14
Q
C-reactive protein is for?
A
opsonization and for complement activation
15
Q
C-reactive protein response time?
A
6-10 hrs
16
Q
Serum amyloid A is for?
A
removal of cholesterol
17
Q
Acute Phase Reactants increase rapidly by _____ during infection.
A
25%
18
Q
True or false: APRs are normal serum constituents.
A
True
19
Q
Most plasma complement proteins are synthesized in the?
A
liver
20
Q
Most plasma complement proteins are synthesized in the liver, except?
A
C1
21
Q
C1 is produced by?
A
Epithelial cells and Factor D (made in Adipose tissue)
22
Q
Plasma complement proteins are released in inactive precursors called?
A
zymogens
23
Q
Zymogens, when triggered with antigenic stimulation, will convert into active form called?
A
Holoenzymes
24
Q
The complement system can be activated in three different ways?
A
- Classical Pathway
- Alternative pathway
- Lectin Pathway
25
Pillemer and colleagues discovered an antibody-dependent pathway in the 1950s, and this plays a major role as a natural defense system.
Classical Pathway
26
How many proteins does the classical pathway have?
9
27
The Classical Pathway is initiated by?
C1
28
Alternative pathway is formerly known as?
Properdin system
29
True or false: Alternative pathway is antibody-independent.
True
30
Major constituent of Lectin Pathway?
mannose- (or mannan-) binding lectin (MBL)
31
Classical pathway involves proteins that are triggered by ____________ combination.
Antigen-antibody
32
True or false: Classical Pathway/Cascade is antibody-dependent.
True
33
True or false: Not all immunoglobulins are able to activate the Classical Pathway.
True
34
Immunoglobulins that can participate in complement fixation?
IgM and IgG
35
Immunoglobulin most efficient in complement fixation?
IgM, because it has multiple binding sites
36
Which IgG subtypes can participate in complement fixation?
IgG3, IgG1, and IgG2 (in order from most to least efficient)
37
How can the IgG activate complement fixation?
2 IgG molecules should be attached to antigen within 30-40 nanometers
38
Stages of Complement Activation in Classical Pathway?
1. Recognition stage
2. Activation stage
3. Formation of MAC
39
C4, C2 and C3 is known collectively as the?
activation unit
40
In the Recognition Unit, the first complement component to bind is?
C1
41
C1 consists of three subunits?
C1q, C1r, C1s
42
The C1 complex is made up of?
* one Clq subunit
* two each of the C1r and C1s subunits
43
In the Recognition Unit, the _____ and _____ subunits generate enzyme activity to begin the cascade.
C1r and C1s
44
It is composed of six strands that form six globular heads with a collagen-like tail portion.
C1q
45
C1q “recognizes” the ________________ of two adjacent antibody molecules.
fragment crystallizable (FC) region
46
C1q binds to the __________ portion of the antibody.
Fc
47
At least _____________ of C1q must be bound to initiate the classical pathway.
two of the globular heads
48
Recognition Unit process?
1. Fc region is bonded with C1q
2. Activation of C1r
3. Cleaves the thioester bond of C1s
4. Activates C1s
5. End of recognition stage
49
C1q binds to Fc region of the immunoglobulins. This binding occurs specifically at the?
Ch2 region for lgG and at the Ch3 region for IgM
50
End product of Activation Unit is the formation of?
C5 Convertase
51
C4 and C2 must be close enough to _____ for cleavage to occur.
C1s
52
C2 should be at least ___ radius of bound C1s.
60nm
53
C4 should be at least ___ of bound C1s.
40nm
54
____ is the second-most-abundant complement protein.
C4
55
C4 cleaves by C1s to form?
C4a and C4b
56
C4b must bind to protein or carbohydrate within a few seconds, or it will react with water molecules to form ________, which is rapidly degraded.
iC4b
57
In the Activation Unit, the next component to be activated after C4 is?
C2
58
C2 gene is closely associated with the gene for _________ on chromosome ___ in the _______________.
factor B (alternative pathway); chromosome 6; major histocompatibility complex (MHC class III)
59
When combined with C4b in the presence of __________, C2 is cleaved by C1s to form C2a and C2b.
magnesium ions
60
C2a binds to C4b to form?
C3 Convertase
61
C3 Convertase is also known as?
C4b2a
62
True or false: C4b2a (C3 Convertase) is very stable.
False. This complex is not very stable.
63
C4b2a (C3 Convertase) half-life is estimated to be between?
15 seconds to 3 minutes
64
If binding of C4b2a (C3 Convertase) does occur, C3 is cleaved into two parts, namely?
C3a and C3b
65
What is the most significant step in the entire process of complement activation?
cleavage of C3 component to form C3a and C3b
66
Functions of C3b?
* Major function is for the formation of the MAC.
* Another function is that, C3b acts as an opsonin → Macrophages have specific receptors for this complement. Thus, enhance phagocytosis.
67
If C3b is bound within 40 nm of the C4b2a, then this creates a new enzyme known as?
C5 convertase
68
C5 convertase denotes the start of?
MAC
69
C3b is bound within ______ of the C4b2a to create the enzyme C5 convertase.
40 nm
70
These cause increased vascular permeability.
Anaphylatoxins
71
What happens when there is increased permeability due to anaphylatoxins?
* release of histamine from basophils and mast cells
* contraction of smooth muscle
72
Proteins involved in increased permeability?
C3a, C4a, and C5a
73
Cleaving of C5 into C5a and C5b by C5 convertase at another site on the cell membrane constitutes the beginning of the?
membrane attack complex
74
True or false: C5b is extremely labile.
True
75
True or false: C5b is rapidly inactivated when no binding of C6 occurs.
True
76
C6 binds to C5b to form?
C5b6
77
C7 binds to C5b6 to form?
C5b67
78
This forms a trimolecular complex that has a high affinity for lipid constituents of the cell membrane.
C5b67
79
C8 binds to C5b67 to form?
C5b678
80
_____ and _____ interact with the cell membrane to form a small hole in the membrane.
C7 and C8
81
____ is inserted into the lipid bilayer of the cell membrane.
C8
82
What happens after C8 is inserted into the lipid bilayer of the cell membrane?
Pore formation → Lysis of cell starts on this stage → Contents of the cell leaks (potassium, amino acids, ribonucleotides)
83
Pores formed are small and are able to?
lyse RBC but not nucleated cells
84
C9 binds to C5b678 which indicates?
complete lysis of the cell
85
Complete MAC unit?
C5b6789
86
Alternative pathway was originally named for the protein?
properdin
87
Properdin is a constituent of normal serum with a concentration of approximately?
5 to 15 μg/mL
88
Now it is known that properdin does not initiate the alternative pathway but rather?
stabilizes the C3 convertase formed from the activation of other factors
89
In addition to properdin, the serum proteins that are unique to the alternative pathway include?
factor B and factor D
90
C1, C2, and C4, found in the classical pathway, are not used at all in what system?
Alternative Pathway
91
Triggering substances for the alternative pathway include?
Bacteria, fungi, viruses, tumor cell lines and some parasites such as Trypanosomes
92
Immunoglobulin that triggers the Alternative Pathway?
IgA
93
Major factor in complement system (alternative and classical pathway)?
C3
94
Alternative Pathway: Factor B is analogous to?
C2
95
Alternative Pathway: Factor B binds to?
activated C3 (C3b)
96
Alternative Pathway: Functions of Factor D?
* Cleaves factor B that are bounded to C3b
* Cleaves factor B to Bb and Ba
* Bb remains attached to C3b, forming C3bBb
97
Alternative Pathway: Functions of C3bBb?
* Cleaves additional C3 into C3a and C3b
* Some C3b attaches to cellular surfaces and acts as a binding site for more Factor B
98
Alternative Pathway: C3bBb is stabilized by ______, which increases its half-life from _____ to _____.
properdin; 90 seconds to several minutes
99
Alternative Pathway: Some C3b binds to C3bBb to form the?
C3bBb3b (C3bBb3bP) complex
100
C3bBb3b (C3bBb3bP) complex has high affinity to?
C5 convertase
101
Alternative Pathway: It cleaves C5 into C5a and C5b.
C3bBb3b (C3bBb3bP) complex
102
Alternative Pathway: _____ is the first part for the formation of the MAC.
C5b
103
MBL is considered an?
acute phase protein
104
MBL is produced in the?
liver
105
MBL is normally present in the?
serum
106
MBL increases during an?
initial inflammatory response
107
Lectins are proteins that bind to?
carbohydrates
108
This pathway provides an additional link between the innate and acquired immune response.
Lectin Pathway
109
Lectin Pathway provides an additional link between the innate and acquired immune response because it involves nonspecific recognition of ________that are common constituents of microbial cell walls and that are distinct from those found on human cell surfaces.
carbohydrates
110
The structure of MBL is similar to that of C1q, and it is associated with three MBL-associated serine proteases (MASPs)?
MASP-1, MASP-2, and MASP-3
111
MASP-1 & 3 function?
still unclear
112
MASP-2 function?
active role in cleaving C4 and C2 with C1s
113
MASP-2 is homologous to?
C1s
114
Lectin Pathway: Once C4 and C2 are cleaved, the rest of the pathway is identical to the?
Classical Pathway
115
It inactivates C1 and MASP-2.
C1 inhibitor or C1INH
116
It is a glycoprotein with a molecular weight of 105,000 that inhibits activation at the first stages of both the classical and lectin pathways.
C1 inhibitor or C1INH
117
C1 inhibitor or C1INH is a glycoprotein with a molecular weight of?
105,000
118
The main role of C1 inhibitor or C1INH is to inactivate C1 by ______________.
binding to the active sites of C1r and C1s; C1r and C1s become instantly and irreversibly dissociated from C1q
119
True or false: After the action of the C1 inhibitor or C1INH, C1q remains bound to antibody, but all enzymatic activity ceases.
True
120
C3 convertase is inhibited by four main regulators?
* C4b-binding protein (C4BP)
* Complement receptor 1 (CR1)
* Membrane cofactor protein (MCP)
* Decay accelerating factor (DAF)
121
Binds to Factor I then inactivates the C4b resulting in the dissociation of C4b from the C4b2a complex, causing the classical pathway to stop and not able to continue the pathway.
C4b-binding protein (C4BP)
122
Also known as CD35; binds to C3b or C4b, then it is degraded by factor I.
Complement receptor 1 (CR1)
123
Main function is it acts as a receptor on platelets and RBCs which helps mediate transport of C3b-coated immune complexes on the liver and spleen.
Complement receptor 1 (CR1)
124
Also known as CD46. Most efficient cofactor for Factor I-mediated cleavage of C3b.
Membrane cofactor protein (MCP)
125
It also serves as cofactor for Factor I in cleaving the C4b; not as efficient as the C4bB (most efficient in inhibiting the activity of the classical pathway).
Membrane cofactor protein (MCP)
126
Also known as CD55. Dissociates the C3 convertase by cleaving the C3b or C4b or both.
Decay accelerating factor (DAF)
127
3rd main receptor and has a wide tissue distribution. Capable of dissociating both classical and alternative pathway C3 convertases.
Decay accelerating factor (DAF)
