Complement

Question 1

What is the function of the complement?

Answer 1

It cooperates with both the innate and adaptive immune systems to eliminate blood and tissue pathogens

Question 2

What is the membrane attack complex?

Answer 2

Following the complement cascade to the activation of the C9, it creates a pore in the microbial membrane, causing irreversible cell death

Question 3

Where are the complement comonents synthesised?

Answer 3

Most of them are synthesised in the liver by the hepatocytes, but some are produced by blood monocytes, tissue macrophages, fibroblasts, and epithelium cells of the GI and genitourinary tracts

Question 4

What are the 3 main complement pathways?

Answer 4

Classical, lectin and alternate

Question 5

The complement can be classified into 7 functional cateogires, one of them is called initiator comlement componenets, what do these do?

Answer 5

The initiate respective component cascades by binding to particular soluble membrane-bound molecules. Once bound to the activating ligand, they undergo conformational alterations resulting in changes to biological activities such as mannose-binding lectin

Question 6

What are the seven different functional categories of the complement?

Answer 6

Initiator complement components, enzymatic mediators, opsonins, inflammation mediators, membrane attack proteins, complement receptor proteins and regulatory complement components

Question 7

What do enzymatic mediators do?

Answer 7

They are proteolytic enzymes that cleave and activate other members of the complement cascade, some are activated by binding to other macromolecules and undergo conformational changes

Question 8

What do opsonins do?

Answer 8

They enhance phagocytosis by binding to microbial cells and serving as binding tags for phagocytic cells bearing receptors for C3b or C4b

Question 9

What do inflammation mediators do?

Answer 9

They enhance the blood supply to the area in which they are released, they do this by binding to endothelial cells lining the small vessels and induce and increase in capillary diameter, they also attract other cells to the site of tissue damage, but excess of these can be damaging, calling them anaphylatoxins

Question 10

What do membrane attack proteins do?

Answer 10

Insert into the cell membrane of invading microorganisms and punch holes that result in lysis of the pathogen

Question 11

What do complement receptor proteins do?

Answer 11

Bind complement proteins and signal specific cell functions such as triggering phagocytosis or triggering neutrophil degranulation and inflammation

Question 12

What do regulatory complement components do?

Answer 12

Protect from unintentional complement-mediated lysis by presence of membrane-bound proteins and soluble regulation proteins

Question 13

What are the 3 complement pathways, and what triggers them?

Answer 13

Classical - Antigen-antibody immune complexes
Lectin - PAMP recognition by lectins
Alternative - Spontaneous hydrolysis or pathogenic surfaces

Question 14

What do the complement pathways all result in?

Answer 14

the generation if an enzyme complex capable of cleaving C3 to C3a and C3b. The classical and lectin pathway use the dimer C4b2a, while the alternative pathway uses C3bBb

Question 15

What are the two C5 convertases?

Answer 15

C5 convertases are made by C3b binding to a C3 convertase, can be either C3bBbC3b or C4b2aC3b

Question 16

What does C5 do when split?

Answer 16

C5a and C5b are both inflammation mediators, they are the initiating factors for MAC

Question 17

Which pathway is considered part of the adaptive immune system?

Answer 17

Classical, as it starts with the formation of antigen-antibody complexes. Only IgM and certain subclasses of IgG are capable of activating the classical pathway

Question 18

Describe the classical pathway initiation? (long answer)

Answer 18

Formation of A-A complexes induces conformational changes in the non-antigen binding portion (Fc) of the antibody molecule, exposing a binding site for C1. C1 is a macromolecular complex made up of C1q, C1r and C1s held together in a calcium stable complex. C1q binds to Ch2 domain of the Fc region and causes a conformational change in one C1r to an active serine protease enzyme, it can then cleave and activate other C1r to cleave and activate both C1s. C1s cleaves 2 substrates, C2 and C4, C4 is activated through the hydrolysis of C4a by C1s. the cleaved C4 and C2 can then bind to become the C3 convertase C4b2a

Question 19

How is the lectin pathway initiated?

Answer 19

The lectin pathway uses lectins (proteins that recognise specific carb compounds) to recognise the microbial threat. Mannose-binding lectin is the first lectin capable of initiating a complement activation, it does this by binding to close-knit arrays on microbial surfaces, Specifically MASP-1 and 2 (mannose-binding protein associated serine protease) to cleave C2 and C4 into the C3 convertase

Question 20

How is the alternative pathway initiated? (long answer)

Answer 20

It can be initiated by 3 ways, First through the tick over pathway, which utilises C3, factor B, factor D and properdin. It can be initiated solely by properdin and can be initiated by proteases such as thrombin and kallikrein. Tickover begins when C3 undergoes spontaneous hydrolysis to C3(H2O), which in the presence of magnesium can bind to factor B and become susceptible to cleavage by factor D. This releases smaller Ba subunits to diffuse away and leave catalytically active Bb subunit that remains bound to C3(H20). This can cleave many molecules of C3 into C3b and C3a. The formation of more C3b molecules builds further C3bBb convertases resulting int he surface deposition of C3b molecules. Another C3b can bind to the C3 convertase resulting in C3bBbC3b, which is a C5 convertase.

Question 21

What has research about properdin shown?

Answer 21

That it can initiate the alternative pathway and not only stabilise it by binding with C3Bb C3 convertase. Patients with properdin deficiency are uniquely susceptible to meningococcal disease induced by Neisseria gonorrhoea, suggesting that it can act as a pattern recognition receptor

Question 22

What do all three of the complement pathways result in? (long answer)

Answer 22

The cleavage of C5 into C5a and C5b. C5b can bind to the surface of the target cell or immune complex and provides binding sites for MAC, C5b is not covalently bound to the membrane and is rapidly inactivated unless stabilised by C6. C5b67 are followed by C8beta to induce a conformational change in C8 dimer so that the hydrophobic domain of C8alphagamma can insert into the membrane, creating a small pore that can lyse RBC but not nucleated cells. Finally, C9 binds and is polymerised into a tubular form leaving a pore diameter of 70-100A leading to a loss of plasma membrane integrity and irreversible cell death