Complement

Question 1

What is complement

Answer 1

Heat labile component of normal plasma proteins with the ability to kill bacteria. Important role in inflammation, can kill directly via formation of MAC, or ensure phagocytosis is more effective via opsonisation.

Question 2

Activation general

Answer 2

Normally circulate as zymogens until activated by a series of cleavage reactions, in three possible activation pathways.

Question 3

Alternative pathway of activation

Answer 3

C3b covalently binds to the pathogen surface, pathway binding to factor B and D producing C3bBb which is a C3 convertase.

Question 4

Function of C3

Answer 4

In inactive form then has thioester bond which is stabilised within hydrophobic protein interior. Once cleaved, bond is expose and able to undergo nucleophilic attack by amino and hydroxyl groups on pathogen cells. C3a is a chemoattractant which recruits effector cells like phagocytes.

Question 5

Lectin pathway

Answer 5

Lectin binds to carbohydrates on pathogen surface? -> MBP lectin pathway

Question 6

Classical pathway

Answer 6

Link between adaptive and innate response using a molecule called C1-q/ C1-q binds to antibody-antigen complexes, then associate with C1-q receptors. Which when bound cleave C1 to an active form. C1s cleaves C4 and C2 to release C4b and C2b. C4b2a is a C3 convertase.

Question 7

Regulation of C3b deposition

Answer 7

Various molecules involved in either stabilising or degrading C3b at cell surface.
Factor P stabilises C3bBb on surfaces and prevents its degradation by proteases.
Factor H and I inactivate C3b by converting ot to iC3b. (Lacking factor I leads to depletion of C3 reservoir so inefficient attachment in the case of infection and less effective bacterial clearance.)
Decay accelerating factor = disrupts C3bBb convertase activity so no complement fixation.

Question 8

Complement opsonisation

Answer 8

C3b fragments on pathogen = macrophages can bind via specific receptors.
Complement receptor 1 binds to C3b -> facilitate macrophage engulfment and destruction.
CR3 and 4 bind to iC3b = act as integrins to enable phagocytosis. Receptor distribution differs on different types of cells.

Question 9

MAC complexes

Answer 9

Further reactions lead to enzyme acting on C5 component, production of C5a and b.
C5n initiates formation of membrane attack complex (MAC), with assembly of C6, 7, 8 and 9. Makes holes in membranes of pathogens and eukaryotic cells.

Question 10

Induction of local inflammation

Answer 10

C3a and C5a fragments increase inflammation at site.
Induce contraction of smooth muscle and degranulation of mast ells and basophils.
C5a can also act via a GPCR as a chemoattractant to direct neutrophil migration to sites of complement fixation.