W7L11 - Complement Systems Part 2 Flashcards
Terminal Pathway
Terminal components are common to all pathways
Union of the terminal pathway forms the membrane attack complex (MAC)
C5b, which binds to the pathogen surface, is formed by enzymatic cleavage of C5
One molecule of C5b binds C6 and the C5b6 complex binds one molecule of C7 which causes the complex C5b67 to insert into lipid bilayer
The binding of C8 causes compolex to penetrate deeper into the cell membrane as it is very hydrophobic
C5b8 complex acts as a receptor for C9
Function of the Membrane Attack Complex
Integrates a pore in the cell membrane causing loss of membrane integrity
Causes cell lysis
MAC has a hydrophobic external face allowing association with lipid bilayer and a hydrophilic internal channel
As the pore is formed by the polymerisation of C9, the final structure depends on availability of C9
- if less C9 pores are smaller
It is essential that complement pathways are regulated to prevent what?
Destruction of host cells and tissues
Uncontrolled complement activation rapidly depleting complement components leaving the host unable to remove infectious bacteria
Regulation of Complement Pathways
Complement activation initiated by proteins that bind to the pathogen surface
The enzyme triggered cascade is confined to the pathogen surface
- achieved primarily by the covalent binding of C4b to the pathogen surface
- cleavage of C4 exposes highly reactive thioester bond on C4b allowing binding to proteins and carbs on cell surfaces
- if no binding, hydrolysis rapidly and irreversibly inactivates C4b
C2 is susceptible to cleavage by C1s only when bound to C4b
Activation of C3 occurs at pathogen surface and C3b is rapidly inactivated unless it binds to the pathogen
- therefore opsonises the surface on which activation has taken place
Biological Activities of Complement
In order for the opsonins to work there has to complement receptors on the surface of phagocytes
C3b and C4b are important opsonins
- bacteria coated by these are rapidly taken up and destroyed by phagocytes (macrophages and neutrophils)
Dying cells also activate complement
- deposition of C4b or C3b on their surface
- these opsonins bind to receptors CR1 or CR3 on phagocytic cells causing removal
Biological Activities of Complement - Removal of Immune Complexes
Deposition of C3b on such complexes breaks them up into smaller pieces that can be cleared by macrophages
- C3b deposition allows binding to erythrocytes via CR1
- erythrocytes clear the complexes transporting them to the liver and spleen where macrophages recognise either C3b via CR3 or the antibody by Fc receptors
- recognition by macrophages triggers phagocytosis of the complexes
Biological Activities of Complement - Anaphylatoxins
C3a, C4a and C5a act on specific receptors on cells to produce local inflammatory responses
They:
- activate vascular endothelial cells increasing permeability leading to tissue edema and further recruitment of antibody, complement and phagocytes to site of infection
- act on neutrophils and monocytes to increase the migration of these cells to site of infection
- activate these cells to increase microbicidal activity
Complement Deficiencies - Classical Pathway
Generally a genetic deficiency in a classical pathway component causes an autoimmune disease, increased infections or both
- e.g. lack of C1q, C4 or C2 causes susceptibility to systemic lupus erythematosus because of decreased ability to clear immune complexes
- C1q, C4 or C2 deficient persons may get recurrent pyogenic bacterial infections as GP organisms are generally resistant to MAC lysis
Complement Deficiencies - Alternative Pathway
People lacking alternative pathway have very high risk of recurrent pyogenic bacterial infections
Lack of factor D and properdin is associated with Neisseria infections
Complement Deficiencies - MBL
Deficiencies in MBL are relatively common
- severe pyogenic (fever-inducing) infections in babies and children
- patients with systemic lupus erythematosus have an MBL deficiency or mutation
