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Immunology > Complement > Flashcards

Complement Flashcards

1
Q

What does heating serum do to complement?

What does it do to antibodies?

A

The lytic capabilities of complement are heat-labile.

Antibodies are heat-stable

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2
Q

Complement is a series of how many serum and cell-surface proteins?

A

over30

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3
Q

What branch of the immune system is complement a component of?

A

innate immune system- it provides immediate but relatively non-specific protection. It also is an effector of the humoral immune system and works closely with Ab.

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4
Q

What are the three key concepts of complement?

A
  1. Activation
  2. Amplification
  3. Protective/Harmfull effects so it must be turned off
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5
Q

How is complement activated?

A

It circulates as an inactive zymogen in the blood plasma but is activated by:

  1. Undergoing conformational change
  2. Proteolytic cleavage
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6
Q

What are the two things that can happen when the complement is activated?
What does this allow complement to do?

A
  1. It can have new chemical properties
  2. It can gain protease activity

This allows for a complement cascade (one protein can activate enzymes for the next step)

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7
Q

What is the central effect of complement activation?

A

to attach a form of the third component of the complex (C3) to activating surfaces like bacteria or immune complexes

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8
Q

What are the three parallel processes for the deposition of C3?

A
  1. Classic
  2. Alternative
  3. Lectin Pathway
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9
Q

What does the classic pathway rely on to begin activation?

A

the formation of an Ag-Ab complex

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10
Q

What does the alternative pathway rely on to begin activation?

A

It is activated directly by microbial or polysaccharide surfaces (no Ab)

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11
Q

What is necessary to begin the lectin pathway of complement activation?

A

glycoproteins

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12
Q

What are the three major effects of complement activation?

A
  1. opsonization
  2. bacterial lysis
  3. inflammation
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13
Q

When C3 attaches to bacteria, viruses, cells, or proteins, what happens to the activation of complement?

A

It is amplified resulting in rapid generation of local effector molecules.
It requires strict regulation.

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14
Q

What are the 4 major protective functions of complement?

What is the major harmful effect?

A

Benefits:
1. opsonize microbes
2. Lyse bacteria (MAC)
3. Cause inflammation (recruit neutrophils)
4. get rid of harmful Ag-Ab complexes
Harm:
1. If too vigorous or unregulated, can harm host tissue

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15
Q

What does each pathway recognize to initiate the activation of complement?

A

Classic pathway –> Ag-Ab complex
Alternative–> polysaccharides on microbial surfaces
Lectin–> glycoproteins

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16
Q

What are the 3 major steps of activation of complement?

A
  1. Recognition
  2. C3 attachment
  3. generation of effector components
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17
Q

What is the recognition complex called for the classic pathway?
What are the three subunits?

A

C1 and consists of 3 subunits:

C1q, C1s and C1r

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18
Q

How many polypeptide chains is C1q composed of?

A

18 arranged into 3 groups of six each with a collagen-like triple helix and a globular domain.

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19
Q

What are the four activators of the classic pathway?

A

IgM
IgG (3>1>2»4)
Apoptotic cells
oxidized LDL

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20
Q

What part of C1q binds to the Ig?

A

the globular domain binds to the Fc of an Ig that is bound to an antigen

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21
Q

How many IgM does it take to bind to C1q? Why?

A

Just one because it is a pentamer

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22
Q

How many IgG are required to bind to C1q? Why?

A

2 or more because they are just monomers

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23
Q

Which IgG molecule is the worst at binding complement?

A

IgG4

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24
Q

As a rule of thumb, which subunit of complement (alpha or beta) is going to be larger?
What is the notable exception?

A

beta is usually larger except for C2a»C2b

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25
Q

What does the binding of Ig to C1q activate?

A

A serine protease in C1s that cleaves C4 and C2 into alpha and beta fragments

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26
Q

When the C1s serine protease cleave C2 and C4 what does C4b bind to? What does C2a bind to?

A

C4b binds COVALENTLY to the surface of whatever the antibody is bound to, and C2a binds NON-COVALENTLY to C4b.

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27
Q

What function does C2a gain when C2 is cleaved?

A

It gains protease function and is able to cleave C3 into two fragments.

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28
Q

When C2a cleaves C3, what does C3b bind to? What type of interactions?

A

It binds COVALENTLY to the activating surface and NON-COVALENTLY to C4bC2a

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29
Q

What is C4bC2a called?

A

C3 convertase

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30
Q

What is C4bC2aC3b called?

A

C5 convertase

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31
Q

Which 3 molecules in the classic pathway have protease function?

A
  1. C1s
  2. C4bC2a
  3. C4bC2aC3b
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32
Q

Which proteins in the classic pathway have a post-translational modification called internal thiolester?

A

C3 and C4

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33
Q

What is an internal thiolester and what does it allow structures to do?

A

it is a bond between cysteine and a glutamic acid that is unstable and high energy.
After proteolysis of C3 and C4 it exposes the thiolester to bind covalently to the activating surface of immune complexes, pathogens and cell surfaces

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34
Q

What is the “central factor” of the Alternative pathway? What is this factors role?

A

It is C3 and it ramps up the activation loop

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35
Q

Which of the three parallel complement pathways is Ab independent?

A

the Alternative pathway- it is activated by polysaccharides and components of bacteria and viruses

Lectin Pathway- activated by proteins that bind carbohydrates (glycoproteins)

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36
Q

What are the 5 activators of the alternative pathway?

A
  1. Repeating polysaccharides
  2. Endotoxins
  3. Virally infected cells
  4. Yeast cell walls
  5. IgA complexes
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37
Q

What is the first step of the alternative pathway?

A

The C3 molecule spontaneously attaches to a pathogen surface

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38
Q

In the Alternative pathway, after C3 binds to the pathogen surface what happens?

A

Factor B binds to C3

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39
Q

What happens to the C3B complex bound to a pathogen surface in the AP?

A

It is cleaved by Factor D to C3Bb

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40
Q

What makes factor D different from complement molecules in terms of circulation?

A

Factor D circulates in active form whereas molecules of complement circulate as zymogen

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41
Q

After cleavage what does the complex become?

A

C3bBb (another form of C3 convertase)

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42
Q

What are the two forms of C3 convertase?

A

C4b2a and C3bBb

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43
Q

What are the two forms of C5 convertase?

A

C4b2a3b and C3bBbC3b

44
Q

Where are the two main areas of the body where you would see the Lectin pathway?

A

Respiratory and GI tract

45
Q

What is the recognition molecule of the Lectin Pathway?

What structure is it structurally similar to?

A

Mannan Binding Lectin- it is structurally similar to C1q of the classic pathway (collagen-like triple helices bound to globular lectin domain)

46
Q

What are the activators of the Lectin pathway?

A
  1. Mannose-containing microbial carbohydrates on yeast/bacteria
  2. Agalactosyl IgG
47
Q

What structures on the MBL are homologous to C1r and C1s?

A

MASPs (Mannose binding lectin Associated Serine Proteases) 1 and 2

48
Q

What do MASPs do>?

A

Cleave C2 and C4 to form C3 convertase and C5 convertase the same way as the classical pathway (C4bC2a and C4bC2aC3b)

49
Q

What are the 4 major effector functions of complement?

A
  1. MAC to lyse bacteria
  2. Opsonization
  3. Clearance of Immune Complexes
  4. Anaphylatoxin
50
Q

What is a MAC?

A

Membrane Attack Complex that forms a channel or pore to disrupt ionic and osmotic gradients to lyse the bacteria or host cell (typically that contains virus or intracellular pathogens)

51
Q

What two bacteria REQUIRE complement for their clearance?

A

Neisseria gonorrhea

Neisseria meningitidis

52
Q

What are the steps in MAC lysis of cells?

A
  1. C5 convertase cleaves C5 into C5a and C5b
  2. C5b binds to C6 and C7
  3. C5b67 has increased affinity for lipids and binds to the lipid bilayer of the cell membrane
  4. C8 binds to C5b67 and starts to perturb the membrane
  5. C5b678 bind C9 and has a conformational change that creates a 100A pore
53
Q

What stage of the MAC complex is able to bind to the lipid bilayer of the cell membrane?

A

C5b67

54
Q

What stage of the MAC complex is able to start perturbation of the cell membrane?

A

C5b678

55
Q

What stage of the MAC complex undergoes a conformational change to self-polymerize and form the pore?

A

C5b6789

56
Q

How many C9 molecules are on the MAC complex? Why?

What does it allow the complex to do?

A

3-18 but usually around 12.

It forms because of self-polymerization and allows for the formation of the pore

57
Q

How large is the pore formed by the MAC complex?

What does this allow to happen?

A

100 Angstroms- disrupting cell homeostasis letting ions, water, lysozymes across the membrane

58
Q

Which complement components are opsonins? Why?

A

C3b and C4b because they covalently bind to activating surfaces to mark cells microbes and immune complexes for uptake by phagocytes

59
Q

How many receptors are there for the C3 and C4 opsinins?

What are the roles of these receptors?

A

4 -CR1, CR3 and CR4 have the major role of phagocytosis

CR2 is on B cells for amplification of activation

60
Q

In addition to the C3 and C4 opsinins, what other complement molecule can perform opsonization? With what receptor on what cell?

A

C1q with the C1qR on leukocytes, endothelium, epithelium and platelets

61
Q

What is the only C3 and C4 complement receptor that allows for opsonization in RBC as well as PMN, monocytes, Kupffer cells, etc?

A

CR1

62
Q

Which complement receptor is a B-cell activator?

A

CR2

63
Q

Why is the formation of Ag-Ab complexes dangerous in circulation?

A

They can deposit in tissue of the capilllaries, glomeruli, alveoli, or synovium activate complement and cause inflammation and tissue damage

64
Q

How does the body clear immune complexes?

A
  1. C3b and C4b bind covalently to the Ag-Ab complex
  2. RBC with CR1 binds C3b/immune complex
  3. The immune complex is transfered to hepatic FcR in the liver and the bond between the IC and RBC is broken
  4. RBC returns to circulation
65
Q

What complement fragments are anaphylatoxins?

What is their function?

A

C3a, C4a, C5a are potent inflammatory mediators

66
Q

How many AA are C3a, C4a, and C5a?

A

77, 77, 73

67
Q

What do anaphyatoxins bind to?

What 4 things are activated?

A

G protein receptors that activate:

  1. mitogen-associated protein complexes
  2. Phosphatydlinosital kinase
  3. PKC
  4. Calcium flux (intracellular)
68
Q

Which is the most potent anaphylatoxin?

What does it bind to and what is its concentration?

A

C5a binds to C5aR and is less than 5nm in concentration

69
Q

What do C3a and C4a bind to? How much less potent are they than C5a?

A

C3aR

They are 10x less potent than C5a

70
Q

What are the general effects of anaphylatoxins?

A
  1. Chemotaxis to attract myloid lineage cells to site of infection
  2. inflammation
  3. cytokine production
  4. oxidative burst
  5. Vascular permeability etc etc etc
71
Q

Why does there need to be strict regulation of complement activation?

A

because left unchecked, there would be a depletion of complement components in the serum, and excess anaphylatoxin and MAC

72
Q

What is a way the body prevents complement activation on host tissue?

A

The host has regulatory molecules but the microbial surfaces lack regulatory proteins

73
Q

What are the three major ways complement is regulated and controlled?

A
  1. Regulation of C1s
  2. Regulation of C3 convertase by regulators of complement activation (RCA)
  3. Regulation of MAC formation
74
Q

What is the major inhibitor of C1s?

A

C1 esterase inhibitor (C1-INH) which inhibits the serine protease activity of C1s, C1r, kallikrein, and coagulation factors.

75
Q

What does C1-INH inhibit?

A

C1s, C1r protease activity
Kallikrein
Factor XIa, XIIa, and plasmin (coagulation factors)

76
Q

What pathway does C1-INH inhibit?

A

Classic pathway at discrete sites to keep C1s from acting systemically

77
Q

What condition is associated with C1-INH deficiency?

A

Hereditary Angioedema- it acts as autosomal dominant with even a heterozygous deficiency being deleterious

78
Q

The primary control of complement occurs at the level of _____ and _____ because they are common to all three pathways.

A

C3 and C5 convertases

79
Q

What are the two mechanisms by which RCAs work?

A
  1. Cofactors for a serum protease FACTOR I that cleaves C3 to inactive fragments
  2. Bind to C3 to physically disrupt the convertase destroying enzymatic activity
80
Q

What does Factor I do?

A

It works with RCA cofactor to cleave C3 into inactive fragments (C3bi and C3dg that remain attached to the activating surface)

81
Q

RCA is a cofactor with Factor H to regulate which pathway?

A

the alternative pathway- fluid phase

82
Q

RCA is a cofactor with C4bp to regulate which pathway? What phase is it?

A

classical - fluid phase

83
Q

RCA is a cofactor with Membrane cofactor protein (MCP, CD46) where and in what pathway?

A

On the cell surface in all pathways

84
Q

RCA is a cofactor for CR1 (CD35) where and in what phase?

A

The cell surface in all pathways as an opsinin receptor

85
Q

RCA is a cofactor for what five things?

Which ones are pathway specific?

A
  1. Factor I
  2. Factor H- alternative
  3. MCP, CD46)
  4. CRI (CD35)
  5. CD4bp- classical
86
Q

What 5 ways can RCA accelerate decay?

A
  1. Disrupts non-covalent C3b with C2a and Bb
  2. Factor H- alternative
  3. C4bp- classical
  4. CR1 (CD35) - cell surface all pathways, opsinin receptor
  5. Decay Accelerating Factor (DAF. CD55)
87
Q

Where does DAF operate and in what complement pathway?

A

Cell surface in all pathways

88
Q

Which RCA cofactors operate in the fluid phase (plasma)

A

Factor H, CD4bp

89
Q

What RCA cofactors operate on the cell surface?

A

CR1 (CD35), DAF (decay), MCP (cofactor)

90
Q

What are the three regulators of MAC formation?

A
  1. Vitronectin- binds C5b-7 trimer and makes it hydrophilic instead of lipophilic (cant attach to membrane)
  2. Clusterin- prevents C5b-9 that forms in the serum from binding to cells
  3. CD59- binds to C8 in the C5b-8 complex and prevents the subsequent incorporation and binding of C9
91
Q

Where are CD59 molecules located?

A

Attached to the RBCs, leukocytes, endothelial cells, neuronal cells by glycophosphotidyl-inositol anchor

92
Q

What does CD59 do?

A

Prevents MAC from forming by binding to C8 and not allowing C9 to bind to C5b-8

93
Q

What is clusterin and what does it do?

A

It prevents MAC formation by binding to C5b-9 in serum and not allowing it to attach to cells

94
Q

What is vitronectin and what does it do?

A

It prevents MAC formation by binding C5b-7 and making it hydrophilic so it can’t attach to cell membranes

95
Q

Almost all forms of _______________ and _____________ have been associated with complement activation.

A

Tissue damage, inflammation

96
Q

What does a defect in C3 or anything earlier in the classical pathway (C1,C2,C4) or alternative pathway (B, D) cause?

A

Recurrent infections especially in the respiratory and GI tract

97
Q

People with defects later in the complement pathway (C5-C9) present with what?

A

recurrent infections from neisseria bacteria if they are HOMOZYGOUS only.
Heterozygous people have half the level of complement which is enough to give 100% protection

98
Q

What would a defect in Factor H or Factor I lead to?

A

Uncontrolled activation of complement.

glomerulonephritis- because complement gathers in the kidney

99
Q

What syndrome is associated with a deficiency in factor H?

A

Hemolytic uremic syndrome

100
Q

What is autoimmune hemolytic anemia?

A

when IgG or IgM antibodies on RBCs activate complement and lead to hemolysis.

Happens with transfusions or autoantibodies

101
Q

What 2 lab tests can detect if C3 is bound to RBC or if Ig is attached?

A

Coombs or DAT (Direct Anti-globulin Test)

102
Q

What is immune complex disease?

A

When soluble Ag in the blood binds Ab that overwhelm complements ability to clear it and they deposit in capillaries, alveoli, glomeruli, activate complement and cause inflammation and tissue damage in these sites

103
Q

What is sub-lytic MAC deposition?

A

When MAC deposits on host tissue in amounts higher than normal but not enough to lyse.
Causes intracellular signalling to activate neutrophils and platelets.

104
Q

What do endothelial cells release when there is sub-lytic MAC deposition?

A

IL-1, vWF and TF which causes cell adhesion to blood vessels and thrombosis

105
Q

What is the major cause of excessive anaphylatoxin productions?

What is the major result?

A

sepsis where there is massive amount of complement due to massive amounts of bacteria and there is a lot of C3a and C5a .which cause hypotension, thrombosis and edema

Immunology (25 decks)

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