The Complement System Introduction n The complement system
- Slides: 21
The Complement System
Introduction n The complement system consists of a number of small proteins found in the blood, in general synthesized by the liver, and normally circulating as inactive precursors (pro-proteins) n When stimulated ---release cytokines and initiate an amplifying cascade of further cleavages. n The complement system is part of the innate immune response (vs adaptive)
In 1899, Paul Ehrlich named as complement n It is named “complement system” because it was first identified as a heat-labile component of serum that “complemented” antibodies in the killing of bacteria n It is now known that it consists of over 30 proteins and contributes 3 g/L to overall serum protein quantities n
“Classical” Pathway (Specific immune response) n n Begins with antibody binding to a cell surface and ends with the lysis of the cell The proteins in this pathway are named C 1 -C 9 (the order they were discovered and not the order of the reaction) When complement is activated it is split into two parts – a – smaller – B – larger part and usually the active part Remember 3 Key Words – ACTIVATION – AMPLIFICATION – ATTACK
“Classical Pathway” n ACTIVATION – C 1 q portion of C 1 attaches to the Fc portion of an antibody – Only Ig. G and Ig. M can activate complement – Once activated C 1 s is eventually cleaved which activates C 4 and C 2 – C 4 b & C 2 a come together to form the C 4 b 2 a which is the C 3 convertase – C 3 convertase activates C 3 to C 3 a and C 3 b
“Classical Pathway” n ACTIVATION – C 3 a binds to receptors on basophils and mast cells triggering them to release there vasoactive compounds (enhances vasodilation and vasopermeability). – C 3 a is called an anaphylatoxin (a fragment that activate the complement system) – C 3 b serves as an opsonin which facilitates immune complex clearance
“Classical Pathway” n AMPLIFICATION – Each C 1 s creates many C 4 b and C 2 b fragments – Each C 4 b. C 2 a creates many C 3 b (activated C 3) – Each C 3 b goes on to create many Membrane Attack Complexes – Example n 1 C 1 S makes 100 C 4 b. C 2 b n 100 C 4 b. C 2 b makes 10, 000 C 3 b n 10, 000 C 3 b makes 1, 000 MAC
“Classical Pathway” n ATTACK – Most C 3 b serves an opsonin function – Some C 3 b binds to C 4 b. C 2 a to form the C 5 convertase C 4 b. C 2 a. C 3 b – C 5 convertase cleaves C 5 leading to the formation of the Membrane attack Complex (C 5 -C 6 -C 7 -C 8 -C 9) – The MAC (memberane attack cells/Unit) “punches holes” in cell walls resulting in lysis
Co m pl em en t. P at hw ay
“Alternative Pathway” (Non specific immune response) n Properdin (Regulator- complement activation) Pathway n Requires no specific recognition of antigen in order to cause activation
“Alternative Pathway” n ACTIVATION – Spontaneous conversion from C 3 to C 3 b occurs in body – Normally, C 3 b is very short lived and quickly inactivated by proteins on the surface of the body’s own cell walls – However, bacteria or other foreign material may lack these surface proteins allowing C 3 b to bind and stay active
“Alternative Pathway” n AMPLIFICATION – Factor B binds to C 3 b – Factor B is then cleaved by factor D into Ba and Bb – C 3 b. Bb remains which acts as a C 3 convertase (C 3 C 3 a and C 3 b) – C 3 b. Bb. C 3 b is formed which acts as a C 5 convertase
“Alternative Pathway” n ATTACK – C 5 is cleaved to C 5 a and C 5 b – C 5 b then starts the assembly of the Membrane Attack Complex
Alternative Pathway
Lectin pathway Activate mannose-binding lectin n Antibody not involved n The lectin pathway is homologous to the classical pathway but with the opsonin, mannose-binding lectin (MBL), and ficolins, instead of C 1 q n
Lectin pathway n This pathway is activated by binding of MBL to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, and MASP-2 (very similar to C 1 r and C 1 s, respectively), which can then split C 4 into C 4 a and C 4 b and C 2 into C 2 a and C 2 b. C 4 b and C 2 a then bind together to form the classical C 3 convertase, as in the classical pathway.
Lectin pathway n Ficolins are homologous to MBL and function via MASP in a similar way.
Summary - Activation n Complement can be activated by the binding of antibody (Classical) or by the adherance of C 3 b to foreign material (Alternative) n The two pathways converge at the formation of the C 5 convertase (C 4 b 2 a 3 b or C 3 b. Bb. C 3 b) n The final common pathway is the formation of the membrane attack complex
Summary - Function n Opsonization – C 3 b n Chemotaxis – C 5 a (attracts neutrophils) n Increases vasodilation & permeability (Inflammation) of capillary beds via mast cell and basophil activation – C 3 a & C 5 a (Anaphylatoxins) n Cellular Lysis via the MAC (Membrane attack cells )(by rupturing membranes of foreign cells)
- Venn diagram notes
- Bcd subtraction using 1's complement
- Cell lysis complement system
- Complement system
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