Complement

Question 1

innate immunity definition

Answer 1

immunity that is naturally present and is not due to prior sensitisation to an antigen from infection or vaccination.

generally non specific

Question 2

when does innate defence begin?

Answer 2

as soon as the pathogen penetrates the epithelial barrier and begins to live in the human tissue

Question 3

what is the complement system?

Answer 3

part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the organism, promote inflammation and attach the pathogen’s cell membrane

can be recruited by antibodies

Question 4

what does the complement system consist of?

Answer 4

31 small proteins that are synthesised by the liver and macrophages and circulate in the blood as inactive precursors (zymogens)

Question 5

what are the three steps to achieve complement activation?

Answer 5

1. generation of C3 splitting enzymes- convertases
2. the cleavage of complement protein C3
3. terminal lytic events- MAC attack

Question 6

Three main complement pathways + what they all have in common

Answer 6

classical, MBP lectin, alternative

all lead to the cleavage of C3 to form C3b and C3a

Question 7

three main outcomes

Answer 7

recruitment of inflammatory cells

opsonisation

killing pathogens

Question 8

What is the most important stage of complement activation?

Answer 8

The cleavage of the protein C3 to form C3a and C3b

Question 9

function of C3b

Answer 9

binds to pathogens, which tags the pathogen for destruction by the phagocytes

known as complement fixation

Question 10

function of C3a

Answer 10

the C3a molecule is smaller, and more soluble

acts as a chemoattractant to recruit effector cells from blood, such as phagocytes

Question 11

Important feature of C3b explained

Answer 11

high-energy thioester bond within the glycoprotein

when C3 is made and enters circulation, the zymogen is stabilised by sequestering the thioester

when C3 is cleaved, the bond is exposed and becomes subject to nucleophilic attack by carbohydrates on the pathogen, which binds C3b to it

Question 12

Determine whether each pathway is innate or adaptive

Answer 12

alternative- completely innate

MBP lectin- innate, however require inflammation

classical- innate and adaptive- requires an antibody-antigen complex to activate it

Question 13

stages of alternative pathway

Answer 13

1. C3 is hydrolysed by water molecules to form iC3
2. iC3 binds to inactive complement factor , making factor B susceptible to cleavage by protease factor D
3. protease factor D cleaves factor B. This produces a small factor Ba which is released and a large factor Bb which remains bound to iC3
4. Bb has protease activity. The iC3bBb complex efficiently cleaves C3 into C3a and C3b respectively
5. iC3bBb diffuses away, C3b becomes bound

Question 14

how is the alternative pathway able to take place?

Answer 14

the pathogen surface creates local environments that are conducive to complement activation-

it increases the rate at which C3 is hydrolysed to iC3- known as tickover

Question 15

what is iC3bBb an example of?

Answer 15

a soluble C3 converts

Question 16

lectin definition

Answer 16

a group of cell-surface receptors and plasma proteins that recognise carbohydrates

Question 17

What is MBL?

Answer 17

Mannose binding lectin, a C type lectin that binds to mannose containing carbohydrates of bacteria, protozoa, fungi and viruses

Question 18

What is the MBL structure + significance?

Answer 18

resembles a bouquet of flowers

triple helix formed of three identical polypeptides contributes a carbohydrate recognition domain- around 5 or 6 of these so have either 15 or 18 potential binding sites

even though the individual binding is very weak, the large number increases the strength

Question 19

lectin pathway of complement activation stages

Answer 19

1. mannose of pathogen binds to MBL, which circulates in the plasma as a complex with two serine protease zymogens: MASP 1 and 2- 2 molecules of each in complex
2. once the MBL complex binds to the mannose in the pathogen, one molecule of MASP 2 is induced to become enzymatically active and cut itself
3. the MASP 2 then cuts the other MASP 2
4. the activated MASP 2 proteases cleaves C4 molecules into C4b and C4a
5. the cleavage exposes a thioester bond of C4b which fixes some C4b fragments onto the pathogen surface. C4a acts as an anaphylatoxin and weakly recruits leukocytes
6. C2 interacts with an activated MASP 2, which is cleaved into a larger fragment C2a and smaller inactive C2b.
7. the C2a binds to C4b on the pathogen surface. The complex C4bC2a is a C3 convertase

Question 20

What antibodies are the most effective at initiating the classical pathway?

Answer 20

IgM and IgG

Question 21

Important protein in the classical pathway + structure

Answer 21

C1- bouquet of 6 flowers, formed of 18 C1q polypeptides and 2 molecules each or C1r and C1s which are inactive serine proteases.

Question 22

classical pathway stages

Answer 22

1. C reactive proteins bind to the C1q stalks
2. this causes C1r to cut itself, the other C1r and the C1s
3. C1s becomes the active protease and cleaves C4, leaving the covalent attachment of C4b
4. C1s cleaves C2
5. C2a binds to C4b, forming the C4bC2a C3 convertase

Question 23

how can IgM activate this process?

Answer 23

binds to the surface of a pathogen and undergoes a conformational change to a staple form, which enables the binding to C1q on the Fc part of each antibody

Question 24

How can IgG activate the process?

Answer 24

C1q crosslinks two IgG molecules bound to antigens on the pathogen’s surface.

C1 is then activated and the classical pathway proceeds

Question 25

what is a major consequence of the innate immune response + why?

Answer 25

inflammation

cleaved C proteins produce smaller soluble C3a and C5a fragments which may induce an anaphylactic shock

C5a- via a GPCR induce the contraction of smooth muscle add degranulation of mast cells and basophils, releasing histamine and other vasoactive substances

increase the permeability of blood vessels, enabling plasma proteins and cells to passs out of blood to the site of infection

Question 26

What are C3b and C4b?

Answer 26

Opsonins

Question 27

function of opsonins

Answer 27

coat the surface of the pathogens so that they are more efficiently ingested by phagocytes, which have receptors for the Fc regions of some antibodies and complement proteins

Question 28

Explain the formation of the membrane-attack complex

Answer 28

1. C3b binds to the alternative C3 convertase to produce an enzyme that works on C5, called the alternative C5 convertase
2. this cleaves C5 to form C5b and C5a
3. C5b initiates the formation of the membrane-attack- complex which leads to holes in the membrane of bacterial and eukaryotic cells forming.
4. C5b binds to C6 and C7
5. C7 then binds the complex to the membrane of the pathogen
6. C8 binds to the complex and inserts into the bilayer
7. C9 binds to C8 and builds up a pore from around 16 molecules by polymerisation

Question 29

Diseases associated with complement

Answer 29

SLE- lupus