Lecture 12 - Complement Pathway - ON FINAL Flashcards Preview

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Flashcards in Lecture 12 - Complement Pathway - ON FINAL Deck (40):
1

What is the complement pathway?

System of hepatically synthesized plasma proteins that play a role in innate immunity and inflammation.

membrane attack complex (MAC) defends against gram-negative bacteria

2

Define the components that are required for activation of the following:
1. Classic Pathway
2. Alternative Pathway
3. Lectin Pathway

1. Classic Pathway
- IgM & IgG

2. Alternative Pathway
- endotoxins --> microbe surface molecules

3. Lectin Pathway
- mannose or other sugars on microbe surfaces (MBL)

3

Define the function of the following:

1. C3b
2. C3a, C4a, C5a
3. C5a
4. C5b-9

1. C3b - opsonization
"C3 binds bacteria"

2. C3a, C4a, C5a
- Anaphylaxis

3. C5a - neutrophil chemotaxis

4. C5b-9 - cytolysis by MAC (membrane attack complex)

4

What are the 2 primary opsonins in bacterial defense?

What do they enhance?

1. C3b and IgG

2. Enhance phagocytosis

*C3b also helps clear immune complexes*

5

What are some inhibitors of complement?

1. DAF - decay accelerating factor - CD59 (or CD55?)

2. C1 esterase inhibitor

6

What part of the complement pathway is common to all 3 types?

FINAL COMMON PATHWAY

C5b-9 membrane attack complex

7

When is the Classical pathway formed?

What happens once the antibody binds to antigen? What is exposed?

1. After the immune complex forms

2. C1 recognizes the antigen-antibody complex

3. Conformational change in the antibody constant region induced, this exposes a site on the Fc portion of the antibody molecule
- this can be bound to C1

8

What is C1?

C1 is a macromolecule that consists of C1q (comprised of 6 globular heads and extended tails) in complex with C1r and C1s

- the C1qrs complex

9

When does activation of the C1qrs complex occur?

occurs when at least two of the C1q globular heads are simultaneously bound to antibody

- 2 Fc portions need to be within close molecule proximity of each other on the antigenic surface

10

How is IgM different from IgG in terms of activating complement?

In contrast to IgG, the pentameric nature of IgM allows a single molecule of antigen bound IgM to activate C1.

(IgG needs TWO fc portions in close proximity)

11

What happens once C1q is bound to antibody?

_____ undergoes a conformational change and becomes enzymatically active


______ then cleaves ____ , which is activated by cleavage as well.

C1r undergoes a conformational change and becomes enzymatically active


C1r then cleaves C1s which is activated by cleavage as well.

12

How does activation of the Lectin pathway occur:

1. What initiates the lectin pathway?



1. Initiated by a protein, MBL (Mannan Binding Lectin) or Ficolins, which are homologous to C1q.

13

What are some examples of things MBL binds to?

What are MBL/ficolins associated with that are similar to C1r and C1s?

1. Binds to mannose and other complex carbs on the surface of man microbial pathogens (like Candida albicans - fungus with surface mannose residues)
- Ficolins bind oligosaccharides

2. MASP - 1 and MASP - 2
- become activated when MBL/Ficolins bind to surfaces

14

1. Activated C1qrs, C1s cleave ______. and then the _____ fragment becomes bound to cell surface.

2.____ fragment binds ______.

1. C4

2. C4b binds cell surface

3. C4b binds C2

15

Once C4b bind C2, it is also cleaved forming what complex?

What released C1 in the Lectin Pathway? C1r and C1s?

1. C4b2a complex

-for Lectin Pathway, MBL/ficolins can be substituted for C1 and substitute MASP-1 and MASP-2 for C1r and C1s

16

What is the C3 convertase in the classical pathway?

the C5 convertase? What is its function?

What is the function of C5a and C5b?

1. C4bC2a (orC4b2b) = C3 convertase!

1.C4bC2a3b - cleaves C5 into C5a and C5b

C5a = soluble inflammatory mediator
C5b = complexes with additional complement components

17

What is the function of C3 convertase?

What is C3b, specifically?

1. Amplification point!

2. C3b is the opsonin that enhances uptake of antigenic particles by phagocytes

18

What structure cleaves both C4 and C2?

What is analogous to this in the Lectin pathway?

C1s

MASP-2 associated with MBL or Ficolin --> cleanse C4 and C2

19

What is the final phase of complement activation? What is formed?

Cleavage of C5 into C5b is the final phase
- forms the Membrane Attack Complex

20

True or False

The MAC is different in all pathways of complement activation?

FALSE

21

What is the function of C3a and C5a?

C3a & C5a remain soluble and produce local inflammatory effects

22

How does the MAC form? What is its function? Components?


What kind of bacteria is the MAC restricted to?

Formed when C5 cleaved into C5b
- binds to C6 and C7
- C5b67 bind to membrane via C7
- C8 binds into complex & inserts into cell membrane
- C9 molecule binds to the complex and polymerizes

ONLY GRAM NEGATIVE --> gram positive has a very thick peptidoglycan layer

23

How is the Alternate Complement pathway activated?

Hydrolyzed _____ binds ____ and the resulting ____ complex is a C3 convertase that generates additional molecules of C3b.

Depends on the slow hydrolysis of C3
- which spontaneously occurs in plasma

1. C3 can bind Factor B (in plasma)
2. resulting C3(H20)Bb complex is a C3 convertase that generates additional molecules of C3b

24

What happens to C3b if it is not attacked to pathogen surfaces?

If it is attached:
Crb binds ______ and it is cleaved by _____ forming what?

1. Degraded

2. binds Factor B --> Factor B is cleaved by Factor D --> forming bond C3bBb

25

What is the C3 convertase in the Alternate Pathway?

The C5 convertase?

1. when stabilized by factor P --> C3bBb complex acts as C3 convertase

- analogous to C4b2a of classical pathway

2.C3bBbC3b
- analogous to C4b2a3b

26

What is the biological consequence of the MAC complex?

What type of bacteria does MAC lyse? Example?

1. Cell lysis and viral neutralization

- MAC (C5b-9) creates a pore in the cell membrane and disrupts cell homeostasis by cellular lysis --> gram negative bacteria

ex: Neisseria

* certain viruses with a membrane coat can also be lysed in this manner

27

Define how C3b works as an OPSONANT (in opsonization).

What is the function of C3b and when?

What else enhances phagocytosis by stimulating phagocytic cells to ingest C3b coated antigens?

1. Phagocytic leukocytes including neutrophils and macrophages carry receptors for C3b (CR1)

2. When an antigenic particle is coated with C3b, C3b (and C4b) assists in adherence and ultimate ingestion of the particle by the phagocytic cell

3. C5a fragment also enhances phagocytosis by stimulating phagocytic cells to ingest C3b coated antigens

28

Removal of antigen- antibody complexes from the circulation depend upon what?

Where are the coated complexes stripped off? This relies on what?

1. C3b
- clear immune complexes

a) Ag-Antibody complexes bind complement receptors on RBCs via C3b

b) as RBCs pass through the spleen & liver, the coated complexes are stripped off of the RBCs by resident phagocytes
- relies on receptor CR1 on RBC's bound to C3b (of immune complex)

29

What soluble fragment produced during complement activation is a Chemotaxis?

What does it assist in?

C5a!!!

- an important chemoattractant for neutrophils, eosinophils, basophils, and monocytes


--> development of a C5a gradient at sites of complement activation assists in the recruitment of leukocytes to the area of antigenic challenge

30

Which fragments are capable of binding to specific receptors on mast cells and basophils thereby triggering granule release?

What does this ultimately result in?

What are these fragments called?

1. C3a, C4a, C5a

2. Release of histamine --> vascular changes including increased vascular permeability

3. Anaphylatoxins

31

What is the regulator protein for C1?

How does it work?

1. C1 inhibitor (C1INH)
- inhibits C1 by dissociating C1r and C1s from the C1 complex

32

What are the inhibitors of C3 Convertase? (5)

1. Decay Accelerating Factor (DAF)
2. C4- Binding Protein (C4BP)
3. Complement Receptor 1 (CR1)
4. Membrane Cofactor Protein (MCP)
5. Factor I (I)

33

What are the inhibitors of C5 convertase? (3)

1. Factor I (I)
2. Factor H (H)
3. Complement Receptor 1 (CR1)

34

What prevents the assembly of the Membrane Attack Complex?

CD59

35

Deficiency in the following leads to what?
C1, C2, C4

Which pathway is this associated with?

Immune Complex Disease

2. Classical Pathway

36

Deficiency in the Following leads to what?
MBL
MASP1
MASP2
C2
C4
Which pathway is this associated with?

1. Deficiency of MBL leads to bacterial infections
- mainly in childhood

2. Lectin Pathway

37

Deficiency in the following lead to what?
Factor D & Factor P

Which pathway is this associated with?

Infection with pyogenic bacteria & Neisseria
** NO IMMUNE COMPLEX DISEASE**

2. Alternative Pathway

38

Define the result of deficiency in the following:

1. C3

2. C5,C6,C7,C8,C9

1. C3 - infection with pyogenic bacteria & Neisseria
- sometimes immune complex disease!

2. Deficiency leads to infection with Neissera only!

39

What is deficient in the following diseases:

1. Hereditary Angioneurotic Edema

2. Paroxysmal Nocturnal Hemoglobinurea

1. C1 INH deficiency - failure to regulate C1 resulting in fluid accumulation, epiglottal swelling

2. CD59 fails to function

- lack of complement regulation leads to RBC lysis

40

What makes the complement components?

LIVER