Complement

Question 1

What is complement?

Answer 1

A very complex system of about 50 different proteins found either in serum or as receptors on white cells

• mediates a wide range of functions
• involves an enzyme cascade

Question 2

Describe the enzyme cascade:

Answer 2

All components circulate as inactive precursors

Precursor A is activated by appropriate contact with stimulus which cleaves proteolytic enzyme A, which activates precursor B to proteolytic enzyme B and so on

Question 3

Name the three pathways that result in complement:

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Answer 3

• Classical pathway
• Lectin pathway
• Alternative pathway

Question 4

What do all three pathways result in?

Answer 4

The formation of an enzymatic activity capable of cleaving C3 (central component of complement)

Question 5

What can C3b do?

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What is C3a involved in?

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Answer 5

C3b:

• Feedback into alternative pathway
• Opsonisation
• Immune complex solubilisation
• Undergo an activity to cleave the next component (C5)

C3a:

• Anaphylaxis

Question 6

What does C5 go on to produce?

What do each of these components bring about?

Answer 6

C5 ——> C5b + C5a

C5a:

• Chemotaxis

C5b:

• comes together with late components (C6-C9) and forms a complex which results in Lysis

Question 7

What is the central protein of complement?

A deficiency in this protein can lead to:

What do all three pathways result in?

What does C3b do?

Answer 7

C3 is the central protein of complement systems

C3 deficiency leads to reccurent bacterial infections

All three pathways rsult in proteolytic cleavage of C3 to C3b and C3a

C3b is deposited onto the surface of micro-organism and marks it out for destruction by lysis or opsonisation

Question 8

How does C3b become attached to the membrane of a pathogen?

Answer 8

• C3 has a thioester bond between cys and glu on alpha chain
• C3 convertase enzyme cleaves C3 so C3a breaks off, leaving C3b
• C3b thioester bond becomes exposed and unstable, so nucleophilic attack by electrons on -OH and -NH₂ groups
• After nucleophilic attack, covalent bond is formed and C3b is attached to membrane of pathogen

Question 9

In what way does the classical pathway differ to both the lectin and alternative pathways?

Answer 9

Involvement of immunoglobulins to recognise the micro-organism in the classical pathway, whereas the lectin and alternative pathways are directly activated by the micro-organism itself

Question 10

Name the first component of the classical pathway

What can this molecule be described as?

What binds to the globular heads?

Answer 10

C1q is the first component of the classical pathway

It is hexavalent and can be described as a ‘bunch of tulips’

The globular heads bind to Fc of IgG or IgM

Question 11

Explain the classical pathway and its components:

Answer 11

• Once Fc regions of IgG or IgM bind to globular heads of C1q, complement is activated
• The next components are C1r and C1s which bind to C1q
• C1r and C1s become proteolytic enzymes, which cleave C4 and C2 allowing C3 convertase to form

Question 12

What does C1r and C1s cleave?

What is C2 cleaved into?

What components associate with each other to form C3 convertase enzyme?

Answer 12

• C1r and C1s become capable of cleaving C4 into C4b (attaches to membrane) and C4a
• C2 is cleaved to generate C2b and C2a
• C2a associates with C4b and together form C3 convertase

Question 13

Answer 13

Question 14

Answer 14

Question 15

Answer 15

Question 16

Name the first component of the lectin pathway and what it interacs with:

Describe the pathway:

Answer 16

The first component of the lectin pathway is the mannose binding lectin (MBL)

• bouquet-like structure
• binds to sugar molecules found in repeating arrays on microbial surfaces

MBL binds to microbial surface with sugars, MASP-2 comes into play and structure is capable of cleaving C4, C4 and C2 are cleaved and form C4b2a (same as classical pathway) and C3 convertase cleaves C3 into C3b + C3a

Question 17

Describe how the alternative pathway is activated:

Answer 17

Question 18

Answer 18

Question 19

What is opsonisation?

What happens to the survival rate of antigens if they are opsonised?

Why does this occur?

Answer 19

Opsonisation is the coating of micro-organisms by antibody or complement components

Antigens survival rate decreases rapidly as phagocytes have specific receptors for C3b and can uptake cells much more quickly

Question 20

What components are known as anaphylatoxins?

How does anaphylaxis and chemotaxis work?

Answer 20

C3a and C5a are known as anaphylatoxins

C3a binds to receptors on mast cells

• histamine is released
• increased vascular permeability
• recruitment of other components of inflammatory response to infection site

In addition, anaphylatoxins act directly on local blood vessels and increase blood flow and vascular permeability

Question 21

What mediates chemotaxis?

What does this involve?

Answer 21

• C5a triggers phagocyte chemotaxis

C5a binds to C5a receptors on phagocytes

• phagocytes migrate up concentration gradient of C5a to infection site
• phagocyte becomes more sticky and slows down

Phagocytes stop moving and move through endothelium towards infection in underlying tissues and bring about phagocytosis

Question 22

Neutrophil transmigration (extravasation) to site of infection in tissues:

Answer 22

Question 23

Which components control the classical pathway?

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Alternative pathway:

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Answer 23

Classical pathway:

• C1 inhibitor
• decay accelerating factor (DAF)
• complement receptor 1 (CR1)

Alternative pathway:

• Factor I
• Factor H
• CR1