Abs and Complement Flashcards
What is the complement system?
System of neutral proteinases secreted into the plasma by the liver and macrophages which form an enzyme cascade
What are the physiological consequences of the complement system?
Inflammatory cell recruitment
Opsonisation and subsequent phagocytosis
Formation of membrane attack complex
Explain how the complement system leads to inflammatory cell recruitment
- cascade generates C5a, known as an anaphylotoxin
- acts through G-protein coupled receptor on endothelial cells (increased adhesion and vascular permeability), smooth muscle cells (contraction), mast cells (degranulation/histamine release) and phagocytes (here acting as a chemoattractant)
Explain how the complement system leads to opsonisation and subsequent phagocytosis
- cascade generates C3b and C4b, which are both opsonins (mark out antigens/dead cells for phagocytosis)
- Opsonins are recognised by compliment receptors, which are found on cells like B lymphocytes
Explain how the complement system leads to formation of membrane attack complex
- C5b, C6 and C7 form a complex called C5b67, which binds to pathogen membrane
- C8 complexes with C5b67, inserting it into membrane
- C9 binds to C5b678 and polymerises within the membrane, opening up a pore in the membrane, damaging the cell.
Which three pathways activate the complement system?
Classical
Alternative
Mannose binding Lectin
Describe the classical pathway
IgG or IgM forms complex with antigen
Binds the C1 complex, which acts as a C4 and C2 convertase, forming C4a and b and C2a and b.
C4b and 2b form C4b-2b complex, the C3 convertase enzyme on the microbial surface
C3 cleaved to C3a and C3b
C3b joins with C4b2b to form C5 convertase enzyme
C5 converted to C5a and C5b
C5a is a anaphylotoxin and chemotaxant like C3a
C5b forms MAC
Describe the alternative pathway
Continuously active at low level
Spontaneous breaking of C3 into C3a and C3b, but without presence of pathogen is rapidly inactivated by factor H
When pathogen present, C3b covalently binds and cannot be inactivated by factor H
Instead, factor B binds to form C3bB
Factor D then cleaves complex to C3bBb and Ba
C3bBb is the C3 convertase enzyme
Positive feedback, generating many C3b molecules (opsonisation and acute local inflammation enabling)
Describe the mannose binding lectin pathway
Similar to classical pathway, though instead of C1 complex you get lectin binding to mannose on the pathogen surface
This activates proteases to cleave C4 and C2 to C4a and b and C2a and b.
C4b-2b is the C3 convertase which forms C3a and C3b from C3
Why don’t host cells accumulate cell surface C3b?
Because they express complement regulatory proteins
Describe IgG structure
Two heavy and two light chains
Two regions - Fab and Fc
Fab is fragment antigen binding and Fc is fragment crystallisable
There are two Fab regions made from one light chain and part of the heavy chain, and they are joined by a cysteine di-sulphide bridge
Fab as a variable region called complementarity determining regions
What are the main classes of Igs? How many binding sites do they each have?
IgG - 2 IgA - 4 IgE - 2 IgM - 10 (but can only bind 5 antigens at any one time) IgD - 2
What are the functions of the Fc region of an antibody? Give examples
Complement activation via classical pathway
Binding to FcR (Fc- receptor) on immune cells
High affinity FcR always have an Ig bound e.g. on mast cell binds to IgE - when IgE encounters allergen, mast cell degranulates
Low affinity FcR only binds Igs that have formed an Ig-antigen complex - FcRs on macrophages bind antibody-antigen complex, causing phagocytosis
