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PATH 402 > Complement and Disease > Flashcards

Complement and Disease Flashcards

1
Q

What are the major protective mechanism afforded by complement?

A

Anaphylatoxins – C3a, C4a, C5a
Inflammatory mediators
Recruit inflammatory/immune cells (leukocytes)

Opsonization – C3b, iC3b, C3d/g and C4b
Tag pathogens for immune destruction (phagocytosis)

Membrane Attack Complex (MAC)
Damages and form pores in pathogen membranes

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2
Q

What are the 3 pathways the complement can be activated?

A

Classical Pathway (CP)
Lectin Pathway (LP)
Alternative Pathway (AP)

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3
Q

How is the classical pathway activated?

A
  1. Initiated by the binding of Ag-Ab complexes to the C1q protein
  2. This leads to conformational changes and the activation of the serine protease C1r
  3. Activated C1r cleaves and activates the serine protease C1s
  4. Activated C1s cleaves C4 into C4a and C4b
  5. C2a and C4b forms C4bC2a (C3-convertase)
  6. C3-convertase cleaves C3 into C3a (smaller fragment) and C3b
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4
Q

How is the lectin pathway activated?

A
  1. MBL forms a complex with MASP
  2. When MBL binds to mannose residues on the surface of a pathogen, MASP are activated to cleave complement components C4 and C2 into C4a, C4b, C2a and C2b
  3. C2a and C4b combine to form C3 convertase
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5
Q

How is the alternative pathway activated?

A
  1. Triggered when C3b protein directly binds microbe, or triggered by foreign materials and damaged tissue
  2. C3 changes into C3.H2O by spontaneous hydrolysis
  3. Plasma protein factor B (FB) is cleaved by factor D (FD) into Ba and Bb
  4. Bb binds to C3b to form C3bBb → a.k.a fluid-phase C3-convertase
  5. C3bBb binds to C3 to form (C3b)2Bb → a.k.a C5 convertase
  6. C5 convertase cleaves C5 into C5a and C5b
  7. C5b binds sequentially to C6, C7, C8 and C9 to form membrane attack complex (MAC)
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6
Q

What are the complement control proteins that ensure host cell protection found in the blood plasma?

A

Factor H
Factor I
C4BP
Clusterin
Vitronectin

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7
Q

What is complement factor B activated by?

A

Factor D

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8
Q

What is the function of complement factor H? What is the structure of CFH?

A

Blocks formation of C3 convertase.

20 ~60 aa residues, short consensus repeats (SCR)
~150 kDa, circulates as dimer

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9
Q

What are the mutations (loss of function) associated with complement factor H?

A

More than 80 mutations associated with Factor H
1. Associated with atypical hemolytic uremic syndrome (SCR 19 & 20)
- mutation in SCR 19 and 20 can lead to
1. decr in binding to host endothelial cells
2. decreased CFI-inactivated of C3b

  1. Assoc w/ macular degeneration
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10
Q

What is the function of CD55?

A

inactivate C3 convertases by dissociating them into their constituent proteins as well as preventing their assembly

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11
Q

What is the function of the soluble inhibitors clusterin and vitronectin?

A
  1. Binds to C7, C8
  2. Prevents MAC assembly
  3. Prevents membrane insertion
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12
Q

What is the function of the membrane bound inhibitors CD59? (EXAM)

A
  1. Prevents C9 insertion into membrane
  2. Prevents addition of more C9s
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13
Q

What are the three clinical disorders that can cause excess complement activation?

A
  1. Hemolytic uremic syndrome
    - atypical Hemolytic Uremic Syndrome
  2. Paroxysmal Nocturnal Hemoglobinuria
  3. COVID-19 and Age-related macular degeneration
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14
Q

What is the pathology of hemolytic uremic syndrome?

A
  1. Capillary thrombi
  2. Leukocyte accumulation
  3. Thickened and swollen capillary & arteriolar endothelial cells
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15
Q

What are the signs of atypical Hemolytic Uremic Syndrome?

A
  1. Low serum C3 & normal C4
  2. Prominent C3 and C9 deposits in glomeruli
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16
Q

What is the etiology of aHUS?

A

50-60% with mutations in complement proteins
- Loss of function: CFH, CFI, MCP, clusterin
- Gain of function: FB, C3

17
Q

What is the treatment of aHUS? (EXAM)

A

Eculizumab

18
Q

What is Paroxysmal Nocturnal Hemoglobinuria (PNH)? and what are the clinical manifestations? (EXAM)

A

Rare acquired clonal disorder of hematopoietic cells

  1. Loss of GPI anchor for CD55, CD59
  2. Increased C3/C5 convertase activity***
  3. Associated with thrombosis***
19
Q

What is the treatment for PNH? (EXAM)

A

Eculizumab

20
Q

What is the pathophysiology of COVID-19?

A

Induces activation via all 3 pathways
1. IgM and IgG anti-SARS-CoV-2 Ab activate CP
2. S-protein → glycosylated; binds to MBL and activates LP
3. N-protein → released from infected cells and enhances MASP2
4. S-protein interferes with FH allowing activation of AP

21
Q

What causes age-related macular degeneration?

A
  1. > 5% associated with FH mutations
  2. Excess complement activation on retinal cells

PATH 402 (7 decks)

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