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Block 6 - week 1 > Complement - Hunter > Flashcards

Complement - Hunter Flashcards

1
Q

Name the 3 pathways that complement activation. What is their common product?

A

Classical, Lectin and Alternative Pathways. All converge to make C3 convertase.

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2
Q

What is the main product of C3 convertase?

A

C3b molecules.

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3
Q

What is complement?

A

An important component of the immediate innate immune response to pathogens. It also works with antibodies in the adaptive humoral immune response to pathogens. It consists of greater than 30 constitutively expressed serum and cell surface proteins.

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4
Q

What else does complement do?

A

It plays an important role in eliminating immune complexes.

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5
Q

In general, what is the result if there are genetic defects in the various components of complement?

A

The person is at increased risk for infections with pathogens, especially pyogenic or pus forming bacteria and may also be at risk for immune complex disease as a result.

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6
Q

What are the general mechanisms of complement.

A
  1. a signal leads to the cleavage of a zymogen leading to its activation.
  2. the zymogen acquires proteolytic activity and becomes an active enzyme.
  3. One protease cleaves and activates many molecules of the next component
  4. this cascade leads to an amplification of the response to microbes
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7
Q

What are the major functions of complement?

A
  1. opsonization - some complement components bind to pathogens or to antibodies bound to pathogens to promote phagocytosis and killing.
  2. inflammation - some components cause inflammation and promote chemotaxis and activation of immune cells.
  3. clearance of immune complexes.
  4. Death of pathogen - some components form pores in pathogen membranes that cause lysis and death.
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8
Q

Describe the classical pathway.

A
  1. C1q is a PRR that binds to specific molecular motifs on pathogens or binds to IgM, IgG or C-reactive protein deposited on pathogen surfaces.
  2. Upon C1q binding, the C1s subunit becomes an active serine protease that cleaves C4 into a small (C4a) and large (C4b) peptide.
  3. C4b binds covalently to pathogen surface or is hydrolyzed if it doesn’t. C4a floats away.
  4. C1s cleaves C2 into a small (C2b) and a large (C2a) peptide. C2b floats away.
  5. C2a binds to C4b. The C4b2a complex forms a C3 convertase.
  6. C3 convertase cleaves many C3 molecules into a small (C3a) and large (C3b) peptide. C3b binds covalently to pathogen and C3a floats away.
  7. C3b is an opsinin that marks the pathogen for destruction. It also helps form a membrane attack complex with C5-9 in some cases.
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9
Q

What happens to the C3a, C4a and C5a?

A

They are anaphylotoxins that act as peptide mediators of inflammation, and phagocyte recruitment.

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10
Q

What is the order of activation of complement components in the classical pathway?

A

C1, C4, C2, C3, C5-9

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11
Q

In complement, a protein that is cleaves usually has a small fragment labeled ‘a’ and a large fragment labeled ‘b’. What is the exception to this rule?

A

In the classical pathway, C2 is cleaved into a small C2b fragment and a large C2a fragment.

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12
Q

What does the letter ‘i’ before a complement protein indicate?

A

An enzymatically inactive form.

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13
Q

What are the components of the C1 complex in the classical pathway?

A

C1q is the collagen region that acts as a pattern recognition receptor (PRR) that binds to specific motifs on pathogens. C1s and C1r subunits are the activating enzymes.

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14
Q

What happens if C3b does not rapidly bind to pathogen surface?

A

It is hydrolyzed because it has a highly reactive thioester bond within it.

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15
Q

What is the structure of a newly synthesized C3 protein?

A

It consists of an alpha and beta chain joined by a disulfide bond. It has a highly reactive thioester bond within the alpha chain that is protected before it is cleaved by a C3 convertase. This thioester bond is the region that will bind to pathogen surface or become hydrolyzed if it doesn’t bind quickly.

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16
Q

What happens to pathogens that are opsonized by C3b?

A

Macrophages, neutrophils and dendritic cells have receptors that recognize C3 and its breakdown products. Upon binding, the pathogen is phagocytosed and killed.

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17
Q

C3b opsonization and killing of pathogens is the most important innate defense agains what type of pathogen?

A

Extracellular

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18
Q

What happens to C4b if it does not bind rapidly to pathogen surface?

A

It is hydrolyzed.

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19
Q

How does complement lead to clearance of immune complexes?

A
  1. C1q binding results in deposition of C4b and C3b molecules on the complexes.
  2. C3b and C4b bind to complement receptor 1 (CR1) on the surface of RBC’s
  3. Complexes are stripped from RBC’s in the spleen and liver and are degraded.
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20
Q

What are immune complexes?

A

They are antibodies attached to pathogen or pieces of pathogen. They form during infections and in some autoimmune diseases.

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21
Q

Deficiencies in C1, C4 or C2 can result in what?

A

Immune complex diseases such as Systemic Lupus Erythematosis.

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22
Q

Describe the Lectin pathway of complement.

A
  1. Mannose binding lectin (MBL) binds to mannose and other common microbial sugars. OR Ficolins (L,M and H) bind to microbial oligosaccharides.
  2. upon binding to microbe, MASP proteins in the complex become active serine proteases.
  3. C4 is cleaved. C4b binds to the microbe and C4a floats away.
  4. C2 is cleaved. C2a binds to C4b and C2b floats away.
  5. C4b2a forms a C3 convertase.
  6. Many C3 molecules are cleaved. C3b binds to the microbe surface and C3a floats away.
  7. C3b marks the microbe for phagocytosis and killing as well as participating with C5-9 in forming membrane attack complexes in some cases.
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23
Q

What is the difference between the classical and lectin complement pathways?

A

Besides the initial complexes used the only difference is that they ‘see’ slightly different microorganisms.

24
Q

Describe the alternative pathway.

A

The alternative pathway can amplify the classical and lectin pathways.

  1. C3b deposited on the pathogen surface by the classical and lectin pathways can bind Factor B. Upon binding, Factor B is cleaved by Factor D into a small (Ba) and a large (Bb) fragment.
  2. Bb remains bound and Ba floats away.
  3. C3bBb is a C3 convertase that cleaves many more C3 molecules that bind to pathogen surface.
  4. C3bBb is stabilized on the pathogen surface by Factor P (also called properdin).
25
Q

How are membrane attack complexes formed?

A

On the surface of pathogens, C5 convertases can be formed. One of these is the C3(b2)Bb and another is C4b2a3b.

  1. C5 convertases cleave C5 into a small (C5a) and a large (C5b) fragment.
  2. C5b triggers assembly of the membrane attack complex by binding to C6 and C7.
  3. C5b67 binds to pathogen membrane via C7.
  4. C8 binds to the complex and inserts into the cell membrane.
  5. C9 molecules bind to the complex and polymerize. 10-16 molecules of C9 are binding to form a pore in the membrane.
  6. This leads to leakage of microbe products and death or lysing of the cell membrane and microbe death.
26
Q

Do membrane attack complexes form on all microbes?

A

No. The only microorganisms routinely killed this way are Neisseria meningitidis and Neisseria gonorrheae.

27
Q

What do C5a, C3a and C4a have in common?

A

They are all anaphylatoxins - chemoattractants that induce inflammation.

28
Q

What does C5a do?

A

C5a has the highest specific biological activity and is able to act directly on neutrophils and monocytes to speed up the phagocytosis of pathogens.

29
Q

What does C3a do?

A

It works with C5a to activate mast cells, recruit antibody, complement and phagocytic cells and also causes edema.

30
Q

What does C4a do?

A

C4a is the least active anaphylatoxin but it acts as a chemoattractant and induces inflammation.

31
Q

What does over expression of C3,4 and 5a cause?

A

systemic anaphylaxis.

32
Q

Immune complex disease is caused by what?

A

Deficiencies in C1, C2 and C4 of the classical pathway.

33
Q

What does deficiencies in the lectin/MBL pathway cause?

A

Bacterial infections, mainly in childhood.

34
Q

Deficiencies in Factor D and Factor P of the alternative pathway can cause what?

A

Infection with pyogenic bacteria and Neisseria’s but no immune complex disease.

35
Q

Deficiency in C3 causes what?

A

Infection with pyogenic bacteria and Neisseria’s and sometimes immune complex disease. These deficiencies are autosomal recessive.

36
Q

Deficiency in C5-C9 causes what?

A

Infection with the Neisseria’s only.

37
Q

What is complement consumption?

A

When complement is activated by pathogens, multiple components are temporarily depleted.

38
Q

How can you distinguish between consumption and deficiency?

A

In consumption, multiple components are low, in deficiency a single component will be low.

39
Q

What is the best screening test for deficiency of the classical or terminal pathways?

A

The CH50 assay. This assay measures the amounts of the components of the classical and terminal complement pathways.

40
Q

What does AH50 measure?

A

The AH50 assay measures the amounts of the components of the alternative pathway.

41
Q

What does a low CH5O and low AH50 suggest?

A

A deficiency of one of the components shared by both pathways - C3-C9.

42
Q

What does a low AH50 with a normal CH50 suggest?

A

A deficiency in Factor B, Factor D or Factor P.

43
Q

What test is used to demonstrate a s deficiency in a specific complement protein?

A

Immunoassays.

44
Q

What is going on if both C3 and C4 levels are low?

A

Activation of the classical pathway and complement consumption.

45
Q

What is going on if levels of C3 are low and levels of C4 are normal?

A

Activation of the Alternative pathway.

46
Q

What happens if complement is out of control?

A

Major tissue damage. This is why it is tightly controlled.

47
Q

What are complement regulatory proteins?

A

These are proteins that regulate complement. Examples are C1 inhibitor, Factor H, CD59 (also called protectin).

48
Q

What is the result if complement regulatory proteins are deficient?

A

This may result in tissue damage, depletion of critical complement components, and increased susceptibility to infections and immune complex disease. For example a CD59 deficiency can cause Paroxysmal Nocturnal Hemoglobulinemia.

49
Q

What binds to antigen/antibody complexes and pathogen surfaces?

A

C1q

50
Q

What binds to carbohydrate structures on microbial surfaces?

A

C1q, MBL, Ficolins, Factor P

51
Q

What are the activating enzymes of complement?

A

C1r, C1s, C2a, Bb, Factor D and Masp-2.

52
Q

What are the membrane binding proteins and opsonins of complement?

A

C4b and C3b

53
Q

What act as peptide mediators of inflammation?

A

C3a, C5a, and C4a

54
Q

What are the membrane attack proteins?

A

C5b, C6-C9

55
Q

What are the complement receptors on phagocytic cells?

A

CR1-4, and CRIg

Block 6 - week 1 (11 decks)

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