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Molecular & Cellular Immunology > Lecture 5: Complement > Flashcards

Lecture 5: Complement Flashcards

1
Q

What is complement?

A

A series of over 20 proteins circulating in the blood and tissue fluids

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2
Q

What causes complement proteins to become activated?

A

Become sequentially activated in an enzyme cascade in response to the recognition of molecular components

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3
Q

What is the function of complement?

A
  • opsonise or cause direct killing of the target
  • signalling to promote inflammation or chemotaxis
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4
Q

What are the 3 different complement pathways?

A

Classical, lectin, and alternative

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5
Q

What is a zymogen?

A

An inactive substance which is converted into an enzyme when activated by another enzyme

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6
Q

What is the specific initiating steps in the lectin pathway?

A

Mannose binding lectin (MBL) and ficolins recognise and bind carbohydrates on the pathogen surface

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7
Q

What is the specific initiating steps in the classical pathway?

A

C1q interacts with the pathogen surface or with antibodies bound to the surface

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8
Q

What is the specific initiating steps in the alternative pathway?

A

C3 undergoes spontaneous hydrolysis to C3(H2O) to initiate eventual deposition of C3 convertase on microbial surfaces

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9
Q

What is similar about all pathways?

A

All pathways produce a C3 convertase, which cleaves C3. C3b is left bound to microbial surface, while C3a is released

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10
Q

What are the 3 outcomes from complement pathways?

A

Inflammation, phagocytosis, and membrane disruption

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11
Q

How does complement induce inflammation?

A

C3a and C5a recruit phagocytic cells to the infection site and promote inflammation

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12
Q

How does complement induce phagocytosis?

A

Phagocytes with receptors for C3b engulf and destroy the pathogen

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13
Q

How does complement induce membrane disruption?

A

All pathogens generate a C5 convertase that leads to formation of the membrane attack complex (MAC), which disrupts the cell membrane

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14
Q

What is TED?

A

A thioester domain found in the alpha chain of C3

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15
Q

How is TED involved and affected by C3 cleavage?

A
  • before cleavage, the thioester bond within TED is protected from reacting
  • cleavage releases C3a, and a conformational change of C3b allows the thioester bond to react with a chemical group on the pathogen surface
  • can be inactivated by hydrolysis
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16
Q

What are the different C3 convertases in each pathway?

A

Lectin & classical : C4b2a
Alternative : C3bBb

17
Q

What are the different C5 convertases in each pathway?

A

Lectin & classical : C4b2a3b
Alternative : C3b2Bb

18
Q

What is the function of ficolins and MBL?

A

Recognise differences in oligosaccharides between different species

Eg. Yeast: terminal mannose residues, vertebrates: terminal sialic acid residues

19
Q

What does MBL do?

A

MBL monomers form trimeric clusters of carbohydrate recognition domains, which bind with high avidity to mannose and ficolin residues

20
Q

What does ficolin do?

A

Similar structures to MBL but have different carbohydrate binding domains (bind to oligosaccharides containing acetylation sugars)

21
Q

What is the process of C3 convertase?

A
  • activated MASP-2 (MBL or ficolin associated) cleaves C4, where C4b binds to the microbial surface
  • C4b bind C2, which is cleaved by MASP-2
  • C2a and C4b bind to form the C4b2a complex
  • C4b2a is an active C3 convertase which cleaves C3, where C3b binds to either the microbial surface or the convertase itself
22
Q

How are IgG involved in the classical pathway?

A
  • Multiple IgG are needed for activation, as they bind to C1q
  • Movement of Fc domain opens up C1q binding sites
  • Number and position of IgG determines opening and strength of the pathway
23
Q

Why are structural changes of C1q needed for the classical pathway?

A
  • Structural changes from IgG are needed for activation of C1r and C1a
  • C1q will rotate inwards which leads to opening of the CLR stalk
  • C1rC1s will pass from an inactive 8 to an active S shape confirmation
24
Q

What does the enzyme C1s do?

A

Cleaves C4 to C4a and C4b, as well as C2

25
Q

What is the dominant complement pathway in plasma during normal haematopoiesis?

A

Alternative pathway

26
Q

What is the concept of tick over?

A

There is constant low level activation of the alternative pathway, through spontaneous hydrolysis of the TED domain which exposes binding site of TED domain with help of cofactor B

27
Q

What control measures are involved with tick over of the alternative pathway?

A
  • half life of C3b is 60 seconds
  • must bind to a surface in 60nm
  • rapidly inactivated on host cells
28
Q

How does factor B help make for C3 convertase?

A
  • C3b is deposited by classical or lectin pathway C3 convertase
  • C3b binds factor B, while MASP-3 cleaves pro-factor D
  • bound factor B is cleaved by plasma protease factor D, resulting in Ba and Bb
  • C3bBb complex is a C3 convertase, cleaving many C3 molecules to C3a and C3b
29
Q

How does C3 hydrolyse in the plasma to give C3(H20)?

A
  • C3 undergoes spontaneous hydrolysis to C3(H20), which binds to factor B allowing it to be cleaved into factor D
  • The C3(H20)Bb complex is a C3 convertase, cleaving more C3 into C3a and C3b
    C3b is rapidly inactivated unless it binds to a cell surface
  • Factor B binds noncovelantly to C3b on a cell surface and is cleaved to Bb by factor D
30
Q

What is properdin?

A

A glycoprotein in the plasma that is mainly produced by leukocytes and can positively regulate AP activity by stabilising C3

30
Q

How does properdin stabilise the alternative pathway?

A
  • pathogens lack complementary regulatory proteins
  • binding of properdin stabilises C3bBb complex
  • C3bBb complex cleaves C3 and deposits many C3b molecules on the pathogen surface
  • results in opsonisation
31
Q
A

Molecular & Cellular Immunology (14 decks)

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