Lecture 16 Flashcards
1
Q
Innate Proteins
A
- 50 serum proteins
- Mainly hepatocyte synthesization
- Catalytic Casades
2
Q
Catalytic Cascades
A
Amplify the response
3
Q
Complement System
A
- Directly eliminates some pathogens
- Opsonize bacteria
Eliminate apoptotic cells
4
Q
Jules Bordet
A
- Sheep antiserum to Vibrio cholera LYSED the bacterium
- Fresh Ab-free antiserum to heat-treated antiserum restored the LYSIS capability
5
Q
Bacteriolysis requirements
A
- Heat-stable antibodies
- Heat-labile lytic agent
6
Q
Identifying the Lytic agent
A
- Developed Av-s vs RBCs
- Purified serum fractions
- Assay fractions for RBC lysis
7
Q
Paul Ehrlich
A
The activity of blood serum that completes the action of antibodies
8
Q
Complement System Categories
A
- Initiators
- Convertase Activators
- Opsonin s
- Anaphylatoxins
- Membrane Attack Complex
- Complement Receptors
- Regulatory Proteins
9
Q
Initiator Pathways
A
- Classical Pathway
- Lectin Pathway
- Alternative Pathway
10
Q
Classical Pathway
A
- C1q recognition of Antigen-Antibody complexes
- Crossover with ADAPTIVE system
11
Q
Lectin Pathway
A
- Lectin recognition of PAMPs
- INNATE Immunity
12
Q
Alternative Pathway
A
- Spontaneous hydrolysis
- Pathogenic surfaces
- INNATE Immunity
13
Q
Convertases
A
Complexes of proteolytic proteins
14
Q
Zymogen
A
Protein whose activity is turned on by proteolytic cleavage
15
Q
Whole Protein
A
- C2
- C3
- C4
- C5
16
Q
Small Fragment
A
- C2b#
- C3a
- C4a
- C5a
17
Q
Large Fragment
A
- C2a
- C3b
- C4b
- C5b
18
Q
C4b2a
A
Dimer of large subunit of C4 and a large subunit C2
19
Q
C1 Macromolecular Complex
A
- One C1a complex
- Two C1r
- Two C1s
20
Q
Classical Pathway: Step 1
A
- C1qr2s2 recognizes antigen-bound antibodies
- Binding activates r1 serine protease activity
r1 cleaves and activates r2, s1, and s2
21
Q
Classical Pathway: Step 2
A
- C1s cleaves C4 into C4a and C4b
- C4b binds to the adjacent surface
– C4b binds C2
– C1s1 cleaves C2 into C2b and C2a - C4b2a = C3 convertase
22
Q
C2b
A
NO known activity
23
Q
Classical Pathway: Step 3
A
- (C4b2a) C3 convertase catalyzes the proteolysis of many C3
- C3a: anaphylatoxin
- C3b binds to the pathogen surface - C3b binds to C4b2a to form C5 Convertase
- C3b diffuses into extracellular space
24
Q
Classical Pathway: Step 4
A
- C5 convertase cleaves C5
- C5a (anaphylatoxin, chemoattractant) - C5b initiates MAC formation
- Membrane Attack Complex
25
Lectin Pathway
1. C3 Convertase
2. Does NOT rely on antibodies
3. utilizes lectins to bind specific carbohydrate residues on microbial surfaces
26
High-Affinity Binding: Bacteria
1. Salmonella
2. Listeria
3. Neisseria
27
High-Affinity Binding: Fungi
1. Cryptococcus neoformans
2. Candida Albicans
28
High-Affinity Binding: Viruses
1. HIV
2. Respiratory Syncitial Virus
29
Mannose-binding Lectin: MBL
1. Soluble PRR
2. Collectin family
3. Resembles C1q
4. Lectin Pathway initiatiors
30
Lectin Pathway Initiators
1. L-Ficolin
2. H-Ficolin
3. M-Ficolin
31
MASP2
1. Structurally: C1s serine protease
2. Cleaves C4
- Cleaves C2
- C4b2a: C3 Convertase
3. NO antibody-antigen recognition
32
Alternative Pathway
1. Does not utilize antibodies
2. C3bBb C3 Convertase
- C3bBb3b C5 Convertase
33
Alternative Pathways
1. Tickover Pathway
2. Properdin-Activated Pathway
3. Protease-Activated Pathway
34
Tickover: Fluid Phase
1. Spontaneous hydrolysis
- C3(H2O)
2. C3(H2O) binds factor B
3. Factor B is cleaved by factor D
35
Tickover Result
Leaves catalytically-active C3(H2O)Bb
36
Membrane-Bound C3 Convertase
1. Fluid phase C3 convertase (C3(H2O)Bb) proteolyzes C3 to C3a + C3b
2. C3b binds to the pathogen surface
3. Bound C3b binds factor B
4. Factor B is cleaved by Factor D
37
NO Infection; NO Pathogen Surface
1. Fluid phase C3 convertase spontaneously generates C3b
2. Fluid phase C3 degrades rapidly
38
YES Infection; YES Pathogen Surface
1. Fluid phase C3 convertase spontaneously generates C2b
2. Capable of thioester bonding to the pathogen surface
3. Surface-bound C3 anchors the formation of membrane-bound C3 convertase
39
Stabilization of C3 Convertase
1. Factor P binding stabilizes C3bBb
- creates C3bPBb3b; C5 Convertase
40
Properdin-Activated
1. Properdin binds specific microbial surfaces
- acts as a PRR
- Bound properdin can bind and stabilize C3b and factor B
2. Factor D cleaves Factor B
41
Properdin-Activated
1. Innate Source of C2b
2. Specificity vs. PAMPS
42
Protease-Activated
1. Coagulation Cascade proteases can cleave both C3 and C5
2. C3a and C5a increase inflammatory response
43
C5 Convertase:
C4b2a3b or C3bBb3b
1. C5a
2. C5b
44
C5a
1. Anaphalotoxin
2. Potent chemoattractant
45
C5b
1. Initiates MAC formation
46
Membrane Attack Complex
1. 10-19 C9 residues form the pore
2. Pore diameter: 7 to 10 nm
3. Pore permits free exchange of water and ions
4. Generally results in irreversible cell death
47
Initiation
C1qr2s2 complex binds antigen-Ab complexes
48
Convertase Activation
C4b2a=C3 Convertase
C4b2a3b=C5 Convertase
49
Opsonins
Bound C1qr2s2 complex; bound C3b
50
Anaphylatoxin
C4a
C3a
C5a
51
Three Key Functions of C3b
1. Binds covalently to pathogen surfaces
2. Binds to membrane-bound C4b2a to C5 convertase
3. C3b attaches to the Fc portion of Soluble Ab-Antigen complexes
