Lesson 5

Question 1

What is the complement?

Answer 1

is a collection of more than 30 inactive proteases present in body fluids.
These proteins are activated by a cut that divide them in 2 fragment (identified by the letter C plus a number): one fragment is smaller, remain in suspension and activate an inflammation process, the bigger remain attached to the pathogen.

Question 2

Which are the pathways for the activation of the complement system (list)

Answer 2

• Classical pathway
• Lectinic pathway
• Alternative pathway

Question 3

Complement sistem: list in the correct order all the proteins involved in the classical pathway

Answer 3

C1q: sensor
complex C1q and C1s+C1r
reclutate C4
C4 and C2 cleaved
C4b and C2a become C3 convertase
C3 is cleaved
C3b+C4b2a become C5
C5 is cleaved

Question 4

Complement sistem: list in the correct order all the proteins involved in the classical pathway

Answer 4

C1q: sensor
complex C1q and C1s+C1r
reclutate C4
C4 and C2 cleaved
C4b and C2a become C3 convertase
C3 is cleaved
C3b+C3b2a become C5
C5 is cleaved

Question 5

Which is the role of C5? (classical pathway of the complement system)

Answer 5

It starts the assembly of the membrane attack comple (MAC) against the pathogen

Question 6

Which are the main proteins necessary for the activation of the lectinic pathway? (complement system)

Answer 6

MBP: it is a large multimeric (3 monomers) protein, where the basic monomer is made by a collagen-like tail linked to a C-lectin head acting as the carbohydrate-.recognition domain.

Ficolins: these are a large family of proteins more abundant than MBP.
Their basic structure is similar to MBP, however, their carbohydrate-recognizing domain is made a fibrinogen-like head.
Microbial sugars recognized by ficolins are different from those recognized by MBP.

Question 7

Describe the process of the lectinic pathway (complement system)

Answer 7

1- MBP and Ficolins interact with microbial sugars
2- They change conformation and activate the MASP (Mannan-Binding Lectin Associated Serin Protease) that adheres to the membrane
3- MASP cleaves C4 into C4a and C4b and C2 into C2a and C2b.
4- These components interact and form the C4b2a complex (C3 convertase) of the lectinic pathway.
5- The pathway then goes on as usual with the cleavage of C3 and C5.

Question 8

Describe the alternative pathway of the complement system

Answer 8

When an infection is present:
1- C3b is stabilized and binds Factor B,
2- The complex is cleaved by Factor D into fragments Ba (which gets eventually released) and Bb
3- The Bb fragment binds the C3b component
4- The Bb-C3b complex acquires a short-lived C3 convertase activity
5- Properdin (molecule made by neutrophils against pathogen) stabilized the C3 convertase
6- The C3 convertase cut C3 in C3a and C3b

Question 9

Which is the common part of the different pathways of the complement system?

Answer 9

After the cleavage of C5 in C5a and C5b there’s a common pathway:
1- C5b recruits C6 and C7 to the membrane.
2- C8 invades the bilayer of microbial sugar
3- At the same time C9 forms a hole through it entirely crossing the surface.

Question 10

Which are the functions of the complement system?

Answer 10

• cell killing
• opsonization: The components of the complement cover the antibodies on the cell surface of many bacteria, virion and infected cells. In this way the cell can be phagocytize by macrophage.
• induction or amplification of a local inflammatory response: thanks to all the soluble complement fragment that get released after the cleavage (anaphylatoxins).
• immunocomplex removal

Question 11

Which are the effects of the anaphylatoxins?

Answer 11

• Mediate a local inflammatory reaction acting on receptors expressed by granulocytes, macrophages and dendritic cells and by receptors expressed by endothelial cells
• Directly, or through mediators released by mast cells, increase the size and permeability of local blood vessels and elicit the recruitment of inflammatory cells.
• Elicit the oxidative burst in phagocytes

Question 12

What are and which are the roles of the immunocomplexes?

Answer 12

immunocomplexes are the complexes formed by antibodies and antigens, which are able to clot and deposit in glomerulocites and thin blood vessels.
These complexes need to be removed before an unnecessary activation of the Complement that can lead to auto-destruction.
This removal process is allowed by the binding of the C3b to the antibody, which can be recognized by the C1r (C1 receptor) on the red blood cell and then carried towards the spleen or the liver (where the phagocytes usually degrade the red blood cells along with the complex).

Question 13

How the complement system is regulated?

Answer 13

It can be regulated in 3 ways by the regulator of the complement activation:
- C1 inhibitor
- MCP, CR1, DAF, C4b binding protein, H factor, I factor
- CD59, S protein

Question 14

regulation of the complement system mediated by the C1 inhibitor: how does it work?

Answer 14

C1 INH it’s a soluble molecule that inhibits C1 activation. It binds C1r and C1s mimicking C4. When this regulator is absent due to a genetic inherited condition or other deficiency, this condition causes an increase in the concentration of C2a in the serum causing the hereditary angioedema, in which endothelial cells are more sensitive and tend to lysis more frequently during the complement activation.

Question 15

Which are the proteins that can limit C3 and C5 activity?

Answer 15

MCP, CR1, DAF, C4b binding protein, H factor, I factor

Question 16

CD59, S protein: what’s their role?

Answer 16

CD59 is a surface protein physiologically present on our cells, while the S protein is a soluble factor. They inhibit the last stage of the formation of the MAP, in particular the formation of the complex made up by C8 and C9, therefore the assembly of the pore structure. The S protein has a similar activity, but it binds the C6 and C7, preventing them from inserting themselves into the membrane.

Question 17

Which are the consequences of a complement deficiency? Which proteins are affected?

Answer 17

The most frequent one is related to C2, deficiency related to C1, C3 and C4 leads to an autoimmune disease to the impossibility to remove the immunocomplexes, causing symptoms comparable to Lupus.
Deficiency in C3b is the most serious one: not only the formation of the pore is impossible, but also no phagocytosis mediated by the complement, no removal of immunocomplexes.