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What are the three pathways of complement activation?

The classical pathway which is mediated by antibody
The lectin pathway which is mediated by carbohydrate recognition
The alternate pathway which is activated by direct contact with a surface


What point do the three complement activation pathways converge on?

All pathways converge on the activation of complement C3


What occurs following complement activation?

Opsonisation and phagocytosis
Direct killing
Leukocyte recruitment


What is the classical pathway of complement activation?

An antibody binds to antigen exposing a binding site for C1q
This has 6 globular heads attached to a central body by collagen like strands, if two of these heads bind to antibody then activation can occur (this creates a demand for one IgM or two IgG)
Two C1r and two C1 molecules will then bind to C1q
The C1 (serine proteases) can then cleave C4 into C4a and C4b
C4b then binds to C2 which is cleaved by activated C1s into C2a and C2b
C2a will complex with C4b to produce the C4b2a surface bound C3 convertase


What is the function of C4a?

This is a soluble molecule which diffuses away and has weak vasoactive properties


What is the function of C4b?

This attaches to the surface of the target by a thioester bond and binds C2


What is the function of C2a?

This remains on the target surface and complexes with C4a


What is the function of C2b?

This is a small soluble fragment with no known bioactivity


What is the lectin pathway of complement activation?

Mannose binding lectin is a six headed protein with a similar structure to C1q with mannose binding lectins at ends
This is effective as mannose is not typically a terminal sugar on eukaryotic cells
When this protein binds to mannose and stabilises it interacts with two serine esterases MASP-1 and MASP-2
These lead to activation of C4 leading to stabilised C4b2a


What is the alternative pathway of compliment activation?

C3 is a major plasma protein which is spontaneously activated by surface contact (termed tick over) as it is a highly unstable thioester giving it half-life of milliseconds
C3b will then bind covalently to a surface acting as an opsonin if its inhibitors (CR1, MCP and DAF) are not present
C3b will then bind factor B which is split by factor D to produce Bb
C3Bb will then go on to generate more C3b


How does amplification occur in the complement pathway?

1 C3 convertase molecule is capable of generating 1000 C3b opsonin molecules
Some bacteria may also bind the plasma proteins such as Properdin and factor P which accelerates the alternative pathway by stabilizing the C3bBb complex


What are the features of C3b and C4b covalent binding?

These compounds are able to opsonizes surfaces covalently through a unique bond which becomes exposed in the large fragment after cleavage this results in a highly unstable intermediate being formed which will react with hydroxyl groups on surfaces forming a thioester linkage occuring in milliseconds before water hydrolyses the intermediate


What is the role of C5 convertase and the effector end of complement?

Both surface bound convertases (C4b2a and C3bBb) can cleave more C3 and soluble C5 into C5b which initiates the membrane attack complex and C5a which is a potent anaphylotoxin


What is the membrane attack complex?

This forms when C5b binds to C6 forming a complex which will be joined by C7 to induce a conformational change exposing the hydrophobic domain of C7, inserting it into the target membrane
This is then followed by C8 which causes polymerisation of many C9 molecules
The C9 polymer forms a membrane pore which allows the flow of water and ions leading to osmotic lysis


What is the process of phagocytosis?

Promoting this is an important role of opsonisation which can activate myeloid cells to take up and kill opsonized pathogens
Neutrophils and macrophages actively phagocytose particles rapidly taken into the phagosome which will fuse with the lysozyme forming the phagolysozome
In this structure there are lytic enzymes and oxidation by products such as H2O2, HClO4 and other highly toxic compounds produced with cause terminal damage to the organism


What are anaphylotoxins?

These are the soluble split products of C3,C4 and C5 cleavage
They are extremely potent peptides with C5a being the most potent followed by C4a and C3a
Their receptors are 7-membrane spanning G-protein coupled receptors
They regulate inflammation and anaphylaxis
C4a and C3a have been shown to directly kill bacteria also


What are the functions of C5a?

This binds to the C5a receptor on mast cells and endothelial cells
This induces smooth muscle contraction
This increases adhesion molecule expression such as E-selectin to capture neutrophils
Act on the neutrophils to increases adherence to the endothelium
There is increase of vasodilatation blood flow and vascular permeability- fluid accumulation increases lymphatic drainage
It also causes mas cells to release histamine and TNFalpha
This results in local pain, swelling and tenderness along with activation of phagocytes and being an essential trigger for phagocytosis


What are the features of complement receptors?

These are mostly for C3b and its inactivated products and it stimulates phagocytosis
CR1 is probably the most important on red blood cells hence numerous, it also inhibits C2 binding to prevent complement attack of “self” cells
CR2 on B cells which result in a 100 times increase in sensitivity of B cell to stimulate a specific Ag


What is the role of decay accelerating factor?

This is widely expressed on all cells and it binds to any C4b to stop the binding of C2 and promote cleavage of C4b by factor I protease to accelerate its decay
This destabilizes the C4b2a complex which stops opsonisation of host cells by preventing formation of a C3 convertase


What is the function of the C1 inhibitor (Serpin)?

This is a serine protease inhibitor which inhibits C1s activity regulating the classical pathway of activation of C3 convertase


What is the function of C4BP?

This is C4 binding protein which binds C4 and displaces C2


What is the function of Factor H?

This binds C3b and displaces Bb, and acts as a cofactor for protease factor I which cleaves C3b


What is the function of Factor I?

This cleaves C3b to an inactive form and is activated by Factor H


What is the function of properdin?

This binds to certain bacterial surfaces to stabilize C3 convertase, this previously lead to a pathway called the properidin pathway but it is now believed to be a cofactor for C3 convertase


What is the function of Protectin/CD59?

This is widely expressed on cells and prevents the formation of the membrane attack complex in cells


Other than specific proteins what can lead to control of complement?

Control also stems through natural decay of unstable split products (like C4b and C3b being unstable thioesters which are inactivated by water unless they bind solid surface)
There is also a need of co-localisation of crucial components


Why can the terminology for complement components be confusing?

For most complement proteins the large fragment is named b while the small soluble fragment is the a fragment, however C2 is an exception to this