Lecture 4: Complement Systems

Question 1

how many mechanisms and pathways in complement?

Answer 1

4 mechanisms and 3 pathways

Question 2

what complement protein is the most abundant

Answer 2

c3

Question 3

proteins in complement and triggers

Answer 3

9 proteins named C1, C2, C3, C4, C5, C6, C7, C8 and C9
Plus subgroups for example C1r and C1r and C1s
◦ Factors for example B, D and P and DAF

These proteins are present in the plasma and other body fluids in an inactive form
◦ Certain triggers activate the proteins in a sequence

Triggers include:
◦ Micro-organisms (specifically sugars in their cell walls) ◦ Antibodies (specifically immunogloblins G, M)

Question 4

how does complement cascade occur?
Role of each fragment

Answer 4

Complement proteins are enzymatic catalysts
Each protein exists as an inactive precursor.

Once activated, it splits into 2 fragments; small (a) and large (b)

The large fragment has 2 biologically active sites;
◦ attachment site for binding to bacterial cell walls
◦ enzyme site for cleavage of the next protein in the cascade

The small fragment acts a mediator of inflammation and a chemical alarm

Question 5

what are the 4 mechanisms and 3 pathways

Answer 5

3 mechanisms to fight pathogens:
Crippling
Chemical Alarm
Opsonization
Lysis

3 pathways for the complement cascade: Classical
Alternative
Lectin

Question 6

Describe the mechanisms

Answer 6

1. CRIPPLING: Bacteria are covered with C3b proteins; which cripples or slows their movement
2. CHEMICAL ALARM: The small fragment C3a travels through the circulation. Cells of the immune system recognise it with receptors and travel to the site of the infection and aid with inflammatory response
3. OPSONIZATION: Bacterial cells with C3b on their surface are more easily engulfed by phagocytes. Complement is an opsonin for phagocytes
4. LYSIS: bacterial cells with MAC on their surface burst and die

Question 7

Describe classical pathway:
Triggers
What protein does it start from?
Effective against what
Process

Answer 7

Triggers: Antibodies of immunoglobulin class IgM or IgG

Sequence of events beginning from C1 Very effective against many viruses

Antibody binds to a target antigen. This produces a shape change in the Fc portion of the antibody, revealing a site that can bind C1q complement protein

Question 8

Why is complement acivation more likely to occur with IgM antibodies than IgG

Answer 8

Complement activation requires a shape change
in the complement protein C1.

• C1 consists of three sub-units; C1q, C1r, and C1s.
• The shape change in C1 can only be effected by
  two antibody Fc fragments binding to one or
  more C1q sub-unit.

+ Therefore complement activation is more likely
to occur with antibodies of the subclass IgM
than IgG, because IgM have pentameric
structure and contain 5 Fc fragments.

• 1G antibodies need to be present in higher
  concentrations to activate C1
• Free calcium ions are required for C1 activation

Following C1 activation it is a stepwise process where each newly activated complement protein acts like a catalyst for the activation of the next protein in sequence

Question 9

Describe alternative pathway:
Triggers
What protein does it start from?
Effective against what

General process

Answer 9

Triggers: Bacterial cell walls and toxins
Sequence of events beginning from C3
Very effective against many bacteria

Cleavage of C3 is happening continuously and spontaneously, generating C3b. C3b is very unstable; it must find a target cell within microseconds, or decay.
If it lands on a surface, it uses factors D and B to activate the next protein in the cascade.

Question 10

Describe lectin pathway:
Triggers
What protein does it start from?
Effective against what

Answer 10

Triggers: Mannose binding lectin (MBL) in our plasma binds to mannose on bacterial cell walls
Sequence of events beginning from C3
Very effective against many bacteria and viruses
Binding of MBL associated serine protease (MASP) activates the next protein in the cascade.

Question 11

Factors on complement system

Example of dysregualtion

Answer 11

Factors influence the dynamics of the reaction and consequent
complex stability
- concentration of complement proteins
-pH
-ionic strength of the environment

Complement inhibitors
1. Classical pathway
- C1 esterase inhibitor
-C4 binding protein

2. Alternative pathway
   - Decay Accelerating Factor (DAF)
   - Complement Receptor 1 (CR1)
   - Factor H
   - Membrane Cofactor Protein (MCP)

Question 12

why is C3 the gateway?

Answer 12

many complement regulators modify/destroy C3b hence C3 is the gateway to cessiation or cascade progression in all 3 pathways

Question 13

Hereditary Angioedema (HAE) due to

Answer 13

An inherited lack of C1 esterase inhibitor
Uncontrolled classical pathway complement activation