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Block 6 Week 1 > Hunter: Complement > Flashcards

Hunter: Complement Flashcards

1
Q

Group of > 30 constitutively expressed serum and cell surface proteins

A

complement

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2
Q

Is complement an innate or adaptive response to pathogens?

A

innate *works with antibodies in the humoral immune response to pathogens

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3
Q

The complement system plays an important part in eliminating (blank)

A

immune complexes

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4
Q

Genetic defects in various complement components can increase the risk for infections with pathogens, especially (blank), and can precipitate (blank)

A

pyogenic bacteria; immune complex diseases

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5
Q

The complement system is similar to which two cascade-like systems?

A

coagulation and kinin systems

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6
Q

In the complement system response, (blank) are cleaved which causes molecules downstream in the pathway to be cleaved as well. This (blank) the response to microbes.

A

zymogens; AMPLIFIES

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7
Q

What are the 4 major functions of the complement system?

A
  1. complement molecules bind directly to pathogens and coat them for phagocytosis
  2. complement molecules cause inflammation and promote chemotaxis and activation of immune cells
  3. some complement molecules help clear immune complexes (antigen-antibody complexes)
  4. some complement molecules form pores in pathogen membranes and directly cause lysis and death
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8
Q

What are the 3 components of the complement system?

A
  1. classical pathway
  2. lectin pathway
  3. alternative pathway
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9
Q

What do all 3 pathways ultimately lead to?

A

activation of C3 convertase and the formation of C3b which binds to complement receptors for destruction of pathogens and removal of immune complexes

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10
Q

What is odd about the order of complement protein activation?

A

C1, C4, C2, C3, C5-9

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11
Q

Which protein in the complement system is typically the “small” fragment, and which is the “large” fragment?

A

small fragment is “a,” while the large fragment is “b” *except in the case of C2, in which the small fragment is C3b

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12
Q

This is a pattern recognition receptor involved in the classical complement pathway that can bind to certain repeat molecular motifs on pathogens (ex: bacterial porins and LPS, as well as IgM, IgG)

A

C1q

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13
Q

Explain the generation of the C3 convertase by the classical pathway.

A
  1. C1q binds to the pathogen surface
    C1s becomes an active serine protease and cleaves C4 into C4a and C4b
  2. C4b binds to the pathogen surface or is quickly hydrolysed, while the small C4a floats away
  3. C1q then cleaves C2 into a small and large fragment, the large fragment (C2a) associates with C4b, the small C2b fragment floats away
  4. C4b2a complex is the C3 convertase and cleaves C3 into C3b which binds to the pathogen and C3a which floats away
  5. Lots of C3b molecules bind to the pathogen
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14
Q

What happens to C3b and C4b to ensure that they do not become highly reactive?

A

they are hydrolyzed rapidly if they don’t bind to pathogen surfaces

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15
Q

What happens once a pathogen is opsonized by C3b?

A

it is endocytosed and killed by phagocytic cells

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16
Q

What is the most important defense against extracellular pathogens?

A

the C3b mediated opsonization and killing of pathogens

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17
Q

Complement activation promotes clearance of (blank)

A

immune complexes

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18
Q

Antigen/antibody complexes form during infections and in some autoimmune diseases. (blank) binds and results in the deposition of C4b and C3b on the complexes. Immune complexes bind to complement receptor 1 on (blank) via C4b and C3b. When the RBCs pass through the spleen and liver, they are stripped and degraded.

A

C1q; RBCs

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19
Q

Antigen/antibody complexes form during infections and in some autoimmune diseases. C1q binds and results in the deposition of (blank) and (blank) on the complexes. Immune complexes bind to (blank) on RBCs via C4b and C3b. When the RBCs pass through the spleen and liver, they are stripped and degraded.

A

C4b; C3b; complement receptor 1 (CR1)

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20
Q

Deficiencies in which complement proteins result in immune complex disease?

A

C1, C4, C2

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21
Q

The lectin pathway is similiar in function to the classical pathway. What is the equivalent to C1q in the lectin pathway? What is the equivalent to C1r/s in the lectin pathway?

A

mannose bindng lectin and ficolins; MASP-1/2

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22
Q

What is the convertase that forms in the mannose binding lectin pathway?

A

C3 convertase *just like the classical pathway

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23
Q

This pathway can amplify both the classical and lectin pathways

A

alternative pathway

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24
Q

What engages the alternative pathway?

A

C3b deposition on the pathogen surface via the classical or lectin pathway

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25
Q

What two molecules are important in the alternative pathway? Also, what is the convertase called?

A

factor B *binds to C3b on pathogen surface then is cleaved to by factor D into Bb (which binds to pathogen) and Ba which floats away
the convertase is C3bBb

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26
Q

What does C3bBb do?

A

makes 1000+ opsonic C3 molecules which stick to the pathogen surface

27
Q

Why is C3a important?

A

it is a potent anaphylatoxin

28
Q

What stabilizes the C3bBb complex?

A

properdin (factor P)

29
Q

When C5 convertases cleave C5 into a large fragment (C5b) and a small fragment (C5a), what does C5b do? What does C5a do?

A

C5b triggers assembly of the membrane attack complex

C5a is a potent anaphylatoxin

30
Q

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

A

C5a

31
Q

This anaphylatoxin works with C5a to activate mast cells, recruit antibody, complement, and phagocytic cells, and increases fluid in the tissue

A

C3a

32
Q

This is the least active anaphylatoxin

A

C4a

33
Q

What can overexpression of anaphylatoxins cause?

A

systemic anaphylaxis

34
Q

These are peptide mediators of inflammation, they recruit phagocytes

A

C3a, C5a

35
Q

This binds to complement receptors on phagocytes and causes opsonization of pathogens, and removal of immune complexes

A

C3b

36
Q

What do terminal complement components cause?

A

formation of membrane-attack complex and lysis of certain pathogens and cells

37
Q

C5b, C6, C7, 8, 9, 10-16 are all involved in formation of the membrane attack complex. What does this cause? What are the only two microorganisms that are routinely killed through this mechanism?

A

causes a pore to be formed in the microorganism, which disrupts the osmotic integrity and causes cell death; Neisseria meningitidis and Neisseria gonorrheae

38
Q

Deficiencies in this pathway leads to immune-complex disease

A

classical pathway

39
Q

Deficiencies in this pathway leads to bacterial infections, mainly in childhood

A

MBL pathway (mannose binding lectin)

40
Q

Deficiencies in this pathway lead to infection with pyogenic bacteria and Neisseria spp. but no immune complex disease

A

alternative pathway

41
Q

Deficiencies in this molecule lead to infection with pyogenic bacteria and Neisseria spp. and sometimes immune-complex disease.

A

C3

42
Q

Deficiencies in these proteins lead to infection with Neisseria spp. only.

A

C5-C9

43
Q

If complement is depleted in the bloodstream, there are two possible explanations. What are they?

A
  1. deficiency *usu a single component

2. temporary depletion if complement is active *usu multiple component depletion

44
Q

What is the best screening test for deficiencies in the classical or terminal pathways?

A

measuring CH50

45
Q

What is the best screening test for deficiencies in the alternative pathway?

A

measuring AH50

46
Q

What does a low level of CH50 AND AH50 suggest?

A

a deficiency in one of the components shared by both pathways

47
Q

What does a low AH50, but normal CH50 suggest?

A

deficiency in factor B, D, or properdin

48
Q

What is used to demonstrate SPECIFIC complement protein deficiencies?

A

immunoassays

49
Q

What do low C3 and C4 levels suggest? What does low C3 but normal C4 levels suggest?

A

activation of classical pathway; activation of the alternative pathway

50
Q

This is the most common complement deficiency, and is found in up to 50% of certain populations

A

MBL deficiency

51
Q

MLB deficiency increases the risk of (blank), esp in children

A

pyogenic bacterial infections

52
Q

MBL deficiency is 2-3x more common in (blank) patients

A

Lupus

53
Q

MBL deficiency presents with a clinical pattern similar to (blank)

A

agammaglobulnemia

54
Q

This is the second most common complement deficiency, and is usu characterized by recurrent but mild infections in children >1 yo

A

C2 deficiency

55
Q

What does C2 deficiency prevent?

A

the formation of C3 convertase after C1q binds to immune complexes

56
Q

What do recurrent neisserial infections suggest a defect in?

A

a component of the membrane attack complex (C5-C9) OR

factor D and P of the alternative pathway

57
Q

What is the first test performed in a suspected complement deficiency?

A

CH50 *measures total serum hemolytic complement

58
Q

The complement system must be tightly regulated! What can deficiencies in regulation lead to?

A

tissue damage or depletion of critical complement components and increased susceptibility to infections and immune complex disease

59
Q

Name one important complement system regulator protein

A

C1 inhibitor

60
Q

This is caused by a deficiency in the complement regulatory protein C1 inhibitor (C1INH)

A

hereditary angioedema

61
Q

What does C1 inhibitor do?

A

it prevents C1r/C1s overactivation of the classical complement pathway

62
Q

What actually causes the clinical manifestations of hereditary angioedema (HAE)?

A

C1 inhibitor fails to inhibit a protease that generates bradykinin, so you get lots of bradykinin which causes recurrent swelling of skin, intestines, airway

63
Q

How do you diagnose hereditary angioedema?

A

low C1 inhibitor protein
low C4 levels
normal C3 levels
*HAE does not respond to epinephrine like anaphylaxis

Block 6 Week 1 (13 decks)

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