Lecture 16 Flashcards

1
Q

Innate Proteins

A
  1. 50 serum proteins
  2. Mainly hepatocyte synthesization
  3. Catalytic Casades
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2
Q

Catalytic Cascades

A

Amplify the response

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3
Q

Complement System

A
  1. Directly eliminates some pathogens
  2. Opsonize bacteria
    Eliminate apoptotic cells
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4
Q

Jules Bordet

A
  1. Sheep antiserum to Vibrio cholera LYSED the bacterium
  2. Fresh Ab-free antiserum to heat-treated antiserum restored the LYSIS capability
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5
Q

Bacteriolysis requirements

A
  1. Heat-stable antibodies
  2. Heat-labile lytic agent
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6
Q

Identifying the Lytic agent

A
  1. Developed Av-s vs RBCs
  2. Purified serum fractions
  3. Assay fractions for RBC lysis
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7
Q

Paul Ehrlich

A

The activity of blood serum that completes the action of antibodies

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8
Q

Complement System Categories

A
  1. Initiators
  2. Convertase Activators
  3. Opsonin s
  4. Anaphylatoxins
  5. Membrane Attack Complex
  6. Complement Receptors
  7. Regulatory Proteins
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9
Q

Initiator Pathways

A
  1. Classical Pathway
  2. Lectin Pathway
  3. Alternative Pathway
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10
Q

Classical Pathway

A
  1. C1q recognition of Antigen-Antibody complexes
  2. Crossover with ADAPTIVE system
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11
Q

Lectin Pathway

A
  1. Lectin recognition of PAMPs
  2. INNATE Immunity
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12
Q

Alternative Pathway

A
  1. Spontaneous hydrolysis
  2. Pathogenic surfaces
  3. INNATE Immunity
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13
Q

Convertases

A

Complexes of proteolytic proteins

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14
Q

Zymogen

A

Protein whose activity is turned on by proteolytic cleavage

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15
Q

Whole Protein

A
  1. C2
  2. C3
  3. C4
  4. C5
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16
Q

Small Fragment

A
  1. C2b#
  2. C3a
  3. C4a
  4. C5a
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17
Q

Large Fragment

A
  1. C2a
  2. C3b
  3. C4b
  4. C5b
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18
Q

C4b2a

A

Dimer of large subunit of C4 and a large subunit C2

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19
Q

C1 Macromolecular Complex

A
  1. One C1a complex
  2. Two C1r
  3. Two C1s
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20
Q

Classical Pathway: Step 1

A
  1. C1qr2s2 recognizes antigen-bound antibodies
  2. Binding activates r1 serine protease activity
    r1 cleaves and activates r2, s1, and s2
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21
Q

Classical Pathway: Step 2

A
  1. C1s cleaves C4 into C4a and C4b
  2. C4b binds to the adjacent surface
    – C4b binds C2
    – C1s1 cleaves C2 into C2b and C2a
  3. C4b2a = C3 convertase
22
Q

C2b

A

NO known activity

23
Q

Classical Pathway: Step 3

A
  1. (C4b2a) C3 convertase catalyzes the proteolysis of many C3
  2. C3a: anaphylatoxin
    - C3b binds to the pathogen surface
  3. C3b binds to C4b2a to form C5 Convertase
  4. C3b diffuses into extracellular space
24
Q

Classical Pathway: Step 4

A
  1. C5 convertase cleaves C5
    - C5a (anaphylatoxin, chemoattractant)
  2. C5b initiates MAC formation
    - Membrane Attack Complex
25
Q

Lectin Pathway

A
  1. C3 Convertase
  2. Does NOT rely on antibodies
  3. utilizes lectins to bind specific carbohydrate residues on microbial surfaces
26
Q

High-Affinity Binding: Bacteria

A
  1. Salmonella
  2. Listeria
  3. Neisseria
27
Q

High-Affinity Binding: Fungi

A
  1. Cryptococcus neoformans
  2. Candida Albicans
28
Q

High-Affinity Binding: Viruses

A
  1. HIV
  2. Respiratory Syncitial Virus
29
Q

Mannose-binding Lectin: MBL

A
  1. Soluble PRR
  2. Collectin family
  3. Resembles C1q
  4. Lectin Pathway initiatiors
30
Q

Lectin Pathway Initiators

A
  1. L-Ficolin
  2. H-Ficolin
  3. M-Ficolin
31
Q

MASP2

A
  1. Structurally: C1s serine protease
  2. Cleaves C4
    • Cleaves C2
    • C4b2a: C3 Convertase
  3. NO antibody-antigen recognition
32
Q

Alternative Pathway

A
  1. Does not utilize antibodies
  2. C3bBb C3 Convertase
    - C3bBb3b C5 Convertase
33
Q

Alternative Pathways

A
  1. Tickover Pathway
  2. Properdin-Activated Pathway
  3. Protease-Activated Pathway
34
Q

Tickover: Fluid Phase

A
  1. Spontaneous hydrolysis
    • C3(H2O)
  2. C3(H2O) binds factor B
  3. Factor B is cleaved by factor D
35
Q

Tickover Result

A

Leaves catalytically-active C3(H2O)Bb

36
Q

Membrane-Bound C3 Convertase

A
  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
Q

NO Infection; NO Pathogen Surface

A
  1. Fluid phase C3 convertase spontaneously generates C3b
  2. Fluid phase C3 degrades rapidly
38
Q

YES Infection; YES Pathogen Surface

A
  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
Q

Stabilization of C3 Convertase

A
  1. Factor P binding stabilizes C3bBb
    - creates C3bPBb3b; C5 Convertase
40
Q

Properdin-Activated

A
  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
Q

Properdin-Activated

A
  1. Innate Source of C2b
  2. Specificity vs. PAMPS
42
Q

Protease-Activated

A
  1. Coagulation Cascade proteases can cleave both C3 and C5
  2. C3a and C5a increase inflammatory response
43
Q

C5 Convertase:

A

C4b2a3b or C3bBb3b
1. C5a
2. C5b

44
Q

C5a

A
  1. Anaphalotoxin
  2. Potent chemoattractant
45
Q

C5b

A
  1. Initiates MAC formation
46
Q

Membrane Attack Complex

A
  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
Q

Initiation

A

C1qr2s2 complex binds antigen-Ab complexes

48
Q

Convertase Activation

A

C4b2a=C3 Convertase
C4b2a3b=C5 Convertase

49
Q

Opsonins

A

Bound C1qr2s2 complex; bound C3b

50
Q

Anaphylatoxin

A

C4a
C3a
C5a

51
Q

Three Key Functions of C3b

A
  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