Complement

Question 1

what is complement?

Answer 1

A very complex system of about 50 different proteins found either in serum
or as receptors on white cells

Question 2

what does complement mediate?

Answer 2

wide range of functions

Question 3

what does complement involve?

Answer 3

enzymes cascade

Question 4

Describe enzyme cascades.

Answer 4

• all components circulate as inactive precursors
• comes into contact with appropriate stimulus
• one product of one reaction acts as an enzyme for next reaction and so on

Question 5

what can the compliment system be triggered by?

Answer 5

3 pathways:

• Classical pathway
• Lectin pathway
• alternative pathway

Question 6

What do the 3 pathways have in common?

Answer 6

result in proteolytic cleavage

of C3 to C3b (large fragment) and C3a (small)

Question 7

what is compliment effective at doing?

Answer 7

Getting rid of bacterial infection

Question 8

what is the central protein of the complement system?

Answer 8

C3

Question 9

what does deficient in C3 lead to?

Answer 9

recurrent bacterial infections

Question 10

where is C3b deposited to in all 3 pathways?

Answer 10

surface of micro-organism and marks it out for destruction (lysis/ opsonisation)

Question 11

How does C3b attach to the microorganisms surface?

Answer 11

• C3 comes into close proximity to the membrane of the pathogen
  -thioester bond between Cys and Glu on alpha chain is cleaved
  -Thioester bond becomes exposed and unstable
  Nucleophilic attack by electrons on OH and -NH2 groups
  -covalent bond is formed

Question 12

what is the first component of the classical pathway?

Answer 12

C1q

Question 13

Describe the structure of C1q.

Answer 13

-hexavalent
-“Bunch of tulips” arrangement of 18 polypeptides
-6 collagenous base and arm(stalk) regions
connected to 6 globular heads

Question 14

what is the classical pathway activated by?

Answer 14

IgG and IgM

Question 15

How does IgG activate the classical pathway?

Answer 15

• 2 IgG molecules are adjacent and in close proximity (control measure to prevent innpaorpriate activation)
• C1q binds 2 of the 6 globular head regions to the IgG molecules

Question 16

what is different about IgM?

Answer 16

only one molecule but C1q only binds when it goes through a conformational change

Question 17

what binds to C1q (CP)?

Answer 17

C1r and C1s (2 each)

Question 18

what do C1r and C1s become (CP)?

Answer 18

proteolytic enzymes

Question 19

what is cleaved by C1r and C1s (CP)?

Answer 19

C4 and C2

Question 20

what is formed by classic pathway?

Answer 20

C3 convertase (C4bC2a)
-cleaves  C3 into active products

Question 21

what does proteolyally active C1s cleave C4 into?

Answer 21

C4a and C4b

Question 22

what does C4b bind to and what does it recruit?

Answer 22

microbial surface and recruits C2 protein

Question 23

what else can active C1s enzymes cleave?

Answer 23

C2 into C2a and C2b

Question 24

what is the first component of the lectin pathway?

Answer 24

Mannose binding lectin

Question 25

what is the structure of mannose binding lectin reminiscent of?

Answer 25

C1q

Question 26

what does mannose binding lectin bind?

Answer 26

Binds sugars molecules found in repeating arrays on microbial surfaces

Question 27

Describe lectin pathway activation.

Answer 27

- MBL and MASP-2 together act on C4 and C2 (same classical pathways) - A C3 covertase is formed - C3 is cleaved - C3b fragments bind to surface

Question 28

what is different between the classic pathway and the lectin pathway?

Answer 28

Same outcome from classic pathway- difference is the lectin pathway does not need an antibody i.e its part of the innate system

Question 29

what does the alternative pathway produce?

Answer 29

C3 convertase but uses different proteins

Question 30

what is the alternative pathway directly activated by?

Answer 30

Many types of micro-organism e.g.. bacteria, yeasts , trypanosomes

Question 31

how quickly does the alternative pathway function and what does this mean?

Answer 31

immediately i.e. before Ab response and hence first major line of defence against systemic infection

Question 32

Describe the alternative pathway.

Answer 32

- C3 - spontaneous of hydrolysis of thioester bond - iC3 produced - factor b binds - cleavage of factor B by factor D - C3 converts , some of the C3b formed attach covalently to pathogen surface - C3b attached to pathogen surface binds factor B(cleaves Bb and Ba) - stable C3 convertase formed (C3b, Bb, P) - More C3b becomes attached to pathogen surface

Question 33

In the alternative pathway, what does C3b attached to pathogen surface bind?

Answer 33

factor B

Question 34

Describe the lysis process.

Answer 34

- C3b cleaves C5 to C5b(large) and C5a (small) - C5b binds to surface of micro-organism - four other proteins (C6, C7, C8 and C9) bind - membrane attack complex (MAC) formed - forms funnel-shaped hole in cell membrane

Question 35

what is opsonisation?

Answer 35

Coating of micro-organisms by antibody or complement components

Question 36

what do phagocytes have receptors for?

Answer 36

C3b

Question 37

what effect does opsonisation have?

Answer 37

makes phagocytosis more efficient

Question 38

Describe anaphylaxis.

Answer 38

- C3a and C5a are known as anaphylatoxins - C3a --> binds to receptors on mast cells - histamine release - increased vascular permability - recruitment of other components of inflammatory response to infection site

Question 39

what does anaphylatoxins act directly on?

Answer 39

local blood vessels, increasing blood flow and vascular permeability

Question 40

Describe chemotaxis.

Answer 40

-C5a also triggers phagocyte chemotaxis -C5a binds to C5a receptors on phagocytes: A) Phagocyte migrates up concentration gradient of C5a to infection site B) Phagocyte becomes stickier -Phagocytes stop moving and move through endothelium towards infection in underlying tissues

Question 41

Describe neutrophil transmigration to site of infection in tissues.

Answer 41

- rolling and tethering - adherence - rolling arrest - transmigration - migration into underlying tissues moving towards higher concentrations of C5a

Question 42

what is the classical pathway controlled by?

Answer 42

- C1 inhibitor - Decay accelerating factor (DAF) - Complement receptor 1 (CR1)

Question 43

what is the alternative pathway controlled by?

Answer 43

- Factor I - Factor H - CR1

Question 44

What can some micro-organisms do?

Answer 44

avoid effects of complement

Question 45

what is complement also important in removing?

Answer 45

Immune complexes (IC)

Question 46

What are deficiencies in classical pathway components usually associated with?

Answer 46

``` immune complex (autoimmune) diseases ```

Question 47

Describe the process of complement removing immune complexes.

Answer 47

- IC bind to RBC and phagocytes via complement receptors | - elimination of IC