Complement

Question 1

What is a complement?

Answer 1

Soluble component proteins of the immune system
There are over 20 serum proteins floating around in the blood
They destroy organisms or target them for phagocytosis
There are three major pathways of the complement: classical, lectin and alternative

Question 2

What are some proteins, factors and receptors of complements?

Answer 2

Complement proteins [C] C1; C2; C3; C4; C5; C6; C7; C8;C9
Complement factors: Factor B; Factor D; Properdin
Mannose binding protein [MBP], ficollins. CRP
Complement receptors [CR] CR1; CR2; CR3

Question 3

How are the three different pathways activated?

Answer 3

Classical - antigen-antibody complexes
Alternative and lectin - microorganisms (innate)

They all result in an activation cascade, activating enzymes etc…
They all converge to form an overall attack from all the proteins coming together to form a pore in the membrane of pathogens

Question 4

What is the initial stage of the complement pathway?

Answer 4

Inactive protein in the serum is activated by chopping it in half to form two different fragments (one small and one large)
Small fragment - mediator of inflammation
Large fragment - binding to surface of antigen

Question 5

What is the end result of the classical pathway?

Answer 5

There is a build up of soluble proteins on the membrane = a membrane attack complex (MAC)
This will form a pore in the pathogen
Hundreds of MACs are deposited in the lipid bilayer

Question 6

What are the main features of the classical complement pathway?

Answer 6

Trigger - anitbodies (IgG/M)
Main molecules involved - First C1r and C2s and later C1Q and C3B
Outcome - membrane attack complex (MAC)

Question 7

What is gram positive and gram negative bacteria?

Answer 7

Gram positive bacteria - thick cell wall of polypeptidoglycan

Gram negative bacteria - thin cell wall of polpeptidoglycan

Question 8

What does the classical complement pathway affect?

Answer 8

It kills gram-negative bacteria, enveloped viruses and some protozoan parasites

For gram positive bacteria there is no cell lysis - as they can protect themselves with a thicker polypeptidoglycan cell wall
Fungi also protect themselves with a thick chitin cell wall

Question 9

What is a lectin?

Answer 9

A carbohydrate binding protein

They mediate attachment and binding of bacteria and viruses to their intended targets

Question 10

What initiates the lectin binding pathway?

Answer 10

Mannose-binding lectin

This is bound to microbial surfaces
Present in serum at low concentrations and increased in acute phase response (liver-derived proteins upregulated during inflammation)

And collectins - SpA and Sp-D

Question 11

What is involved in the lectin binding pathway?

Answer 11

Associated serine proteases - MASP-1 and MASP-2

Theses enzyme complexes cleave C4 and C2

Question 12

What is the outcome of the lectin binding pathway?

Answer 12

Either Membrane attack complex (MAC) or Terminal complement complex (TCC)

Question 13

What is the alternative pathway?

Answer 13

It is constantly being activated but continually being switched off by host control mechanisms
Molecules will bind to everything and are very reactive
There is a C3b dependent positive feedback loop (amplification loop)

Question 14

What does the alternative pathway involve?

Answer 14

Factors B and D
Initiated when C3 is spontaneously hydrolysed
C3b - binds to a microbe

Question 15

What is the outcome of the alternative pathway?

Answer 15

Membrane attack complex or terminal complement complex

Question 16

What are some other biological effects of the complement proteins?

Answer 16

Phagocytes and macrophages have regions that can bind to complement proteins which act as chemoattractants

C3a and C5a are “anaphylatoxins” they activate mast cells
The receptors on mast cells bind to C3a/C5a and digest them (overactivation leads to allergies)
C3a and C5a are chemotaxins. They attract phagocytes (neutrophils and mononuclear phagocytes)
C3b is an opsonin; it enables phagocytes to recognise and bind to antigens (due to C3b receptor) and phagocytose them

Question 17

What are some control mechanisms of the complement proteins?

Answer 17

Factor I (co-factor H)
Anaphylatoxin inactivator
Cell surface proteins

Question 18

How does Factor I, help give control?

Answer 18

Factor I is a highly specific serine proteinase which is concerned with the regulation of the C3 convertase of the alternative (C3bBb) pathways
With the help of the cofactor H ; Factor I splits the alpha chain of C3b
This destroys the C3 convertase activity

Question 19

How does the anaphylatoxin inactivator help control?

Answer 19

The anaphylatoxins C3a and C5a are inactivatated by this, not allowing the C3/C5 convertase to split these proteins

Question 20

What are some cell surface proteins that help in regulation?

Answer 20

Cr1
Membrane cofactor protein
Delat accelerating factor
Homologous restriction factor
Vitronectin

Question 21

What are some complement deficiencies?

Answer 21

Factor I deficiency - inability to deal properly with pyogenic microorganisms
C3/MBL deficiencies causes increases to a variety of infections
Deficiencies in immune complex clearance may lead to systemic lupus
or glomerulonephritis
Inflammatory thrombotic conditions- uncontrolled C5a in antiphospholipid syndrome

Question 22

What is the overall pathway to take away?

Answer 22

Initiation - opsonization - cell lysis - signalling

Question 23

What can happen to evade the complement pathway?

Answer 23

If viruses have similar homologs to the complement protein it may be able to evade an immune response (blocking the complement pathway)