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IHO Week 2 - WLB > Complement - Regal > Flashcards

Complement - Regal Flashcards

1
Q

What is the basic order of each numbered complement?

A

C: 142356789

(memorize this!)

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2
Q

What is the importance of the complement system in host defense and inflammation?

A
  • Part of the innate immune system that creates bridge to adaptive immune system (humoral response)
    • major effector system for humoral immunity
  • Primitive surveillance system for microbes
    • independent of T-cells and antibodies
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3
Q

What is the general function of the complement system?

A
  • A group of plasma proteins that acts as an auxiliary system in immunity, both on its own and in conjunction with humoral immunity.
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4
Q

What are the five specific functions of the complement system?

A
  • Lysis
  • Opsonization
  • Mediators of the inflammatory response
  • Solubilization and clearance of immune complexes
  • Augments stimulation of the B-cell
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5
Q

What pathway in the complement system is important for clearing immune complexes and apoptotic cells?

A

Classical Pathway

(C1q, C1r, C1s, C4, C2)

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6
Q

What infections/diseases are associated with deficiencies in the Classical Pathway (C1q, C1r, C1s, C4, C2)?

A
  • encapsulated bacterial infections
    • pyogenic infections (fever)
  • Systemic lupus erythematosus (SLE)
  • glomerulonephritis
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7
Q

What infections/diseases are associated with deficiencies in the Lectin Pathway (Mannose-Binding Lectin, C4, C2)?

A
  • Increased susceptibility to bacterial infection
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8
Q

What infections/diseases are associated with deficiencies in the Alternative Pathway (C3, FB, FD, FH, FI)?

A
  • Neisserial infections
  • Meningococcal infections
  • Recurrent infections
  • SLE
  • glomerulonephritis
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9
Q

What infections/diseases are associated with deficiencies in the Membrane Attack Complex (C5, C6, C7, C8, C9)?

A
  • Meningococcal infections
  • Recurrent Neiserrial infections
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10
Q

What two things is complement good for?

A
  1. Lysing bacteria
  2. Clearing immune complexes (so they don’t cause disease)
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11
Q

Where is complement located?

A
  • Plasma
  • Interstitial secretions (bronchoalveolar lavage fluid)
  • Portals of entry
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12
Q

Where is complement synthesized primarily? Secondarily?

A
  • Primarily: Liver hepatocytes
  • Secondarily: tissue macrophages, epithelial cells, fibroblasts, & monocytes
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13
Q

What activates the Classical Pathway of the complement system?

A

Antigen-Antibody Complexes

-triggered by antigen binding to IgG or IgM

(causes a cascade of proteolytic steps)

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14
Q

What activates the Mannose-Binding Lectin (MBL) Pathway of the complement system?

A

Mannose

(polysaccharides on microbes- fungi, Salmonella, Listeria, Neiserria, Candida)

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15
Q

What activates the Alternative Pathway in the complement system?

A
  • LPS (endotoxin from gram negative bacteria)
  • Carbohydrates
  • Human IgA, IgG, and IgE complexes
  • Fungal and yeast cell walls (zymosan)
  • Human IgA, IgG, and IgE complexes
  • Teichoic acid from gram positive cell walls
  • Some Parasites
  • Some tumor cells
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16
Q

What important enzyme type performs the proteolytic steps in the Classical Pathway?

A

Serine esterases

C1 esterase

C1s

C4b2a

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17
Q

What is the first step in the Classical Pathway of the complement system?

A
  • Activation of C1:
    • C1qr2s2 binds antigen-bound antibody
    • Conformational change in C1q → activates C1r & C1s (esterase)
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18
Q

How does C4 become activated?

A

C1s cleaves inactive C4 → becomes active

C4a + C4b

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19
Q

What happens to activated C4a & C4b?

A
  • C4a: floats away
  • C4b: covalently bonds to membrane surface
    • or act as opsonin
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20
Q

How does C2 become activated?

A
  • Binds to C4b
  • Cleaved by C1s into → C2a + C2b
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21
Q

What happens to activated C2a and C2b?

A
  • C2b: floats away
  • C2a: binds to activated C4b forming a C4b2a complex on the membrane surface
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22
Q

What is another name/title for the C4b2a complex?

A

Classical Pathway C3 Convertase

23
Q

How does C3 become activated?

A
  • Binds to C4b2a complex
  • C4b2a complex cleaves it into → active C3a + C3b
24
Q

What happens to active C3a and C3b?

A
  • C3a: floats away
  • C3b: covalently binds to membrane surface
25
Q

What are three unique traits of the Classical Pathway in the complement system?

A
  1. Activation in conjunction with specific antibody
  2. C3b and C4b covalently bind via labile thioester bonds
  3. Enzymatic cleavage of proteins with amplification
26
Q

What is the first step in the Mannose-Binding Lectin (MBL) Pathway in the complement system?

A
  • MBL binds to sugar residues on membrane of microbe
    • conformational change of MBL → activates MASP-1/MASP-2

(NO antibody required for activation!)

27
Q

How is the C4b2a complex formed in the Mannose-Binding Lectin Pathway in the complement system?

A
  • MASP-1/MASP-2 cleaves C4
    • C4a floats away
    • C4b covalently binds membrane
  • MASP-1/MASP-2 cleaves C2
    • C2b floats away
    • C2a binds to activated C4a forming the classical pathway C3 convertase (without C1 involvement)
28
Q

What are two unique traits of the Mannose-Binding Lectin (MBL) Pathway?

A
  • Does not require specific antibody for activation.
  • Most recently discovered of the complement pathways.
29
Q

What is the first step in the Alternative Pathway of the complement system?

A
  • Spontaneous conformational change of C3 molecule leads to hydrolysis of C3
    • C3 + H20 → C3(H20)
    • called “C3 take over”
30
Q

How does C3bBb first form?

A
  • Factor B binds to C3(H20) →
    • becomes C3(H20)B
  • Factor D binds and cleaves Factor B →
    • becomes C3bBb = Alternate Pathway C3 Convertase
31
Q

What does C3bBb do?

A
  • Forms positive feedback loop
    • Cleaves C3 into → C3a + C3b
    • C3b binds to factor B and is cleaved by factor D to produce more C3bBb
  • Covalently binds to membrane surface
    • where it will undergo amplification with more Factor B
    • or decay with Factor H & Factor I (becomes inactive = C3bi)
32
Q

What determines if C3b will undergo Amplification or Decay once it becomes covalently bound to the membrane surface?

A
  • If Sialic Acid is present or not:
    • absent = activator surface
      • factor B binds C3b and gets cleaved by factor D → make more C3bBb
      • bacteria deficient in sialic acid
    • present = non-activator surface
      • factor H and factor I inactivate C3b → form C3bi
      • human cells have sialic acid
33
Q

What protein or component of the Alternative Pathway acts to stabilize or prevent decay of C3bBb (the alternative pathway C3 convertase)?

A

Properdin

34
Q

How is C5 convertase formed?

A
  • After C3 is cleaved, C3b binds to a C3 convertase
    • C4b2a3b (classical)
    • C3bBbC3b (alternative)
35
Q

How is C5 activated?

A
  • Cleaved by either:
    • Classical Pathway C5 convertase (C4b2aC3b)
    • Alternative Pathway C5 convertase (C3bBbC3b)
36
Q

What happens to active C5a and C5b?

A
  • C5a: floats away
  • C5b: initiates membrane attack complex
    • attracts C6 and C7
37
Q

How does Membrane Attack Complex initially insert into the membrane?

A
  • C7 has transmembrane properties and is able to insert into the membrane
    • C5,C6, & C7 bind together and C7 inserts
38
Q

How does the the Membrane Attack Complex initiate lysis?

A
  • Membrane-bound C5,C6,C7 attract C8
    • C8 also inserts into the membrane
  • They attract many C9 molecules
    • form pore spanning the membrane
    • disrupts osmotic balance across membrane
    • KILLS CELL!
39
Q

What can C5b-7 bind to in the fluid phase that prevents membrane insertion and MAC formation?

A

S-protein

40
Q

Can lysis occur in the absence of C9?

A

Yes, but it is slower

41
Q

What are two possibilities if C9 binding to C5?

A
  • If the interaction with C5b and C9 occurs in proximity to a membrane
    • MAC assemble occurs in the membrane
    • lysis occurs
  • Alternatively, C5b & C9 can float away together
    • form soluble C5b-9 (sC5b-9)
42
Q

What other unique function do covalently bound C3b and C4b have besides progressing into the Terminal Lytic Pathway?

A

Interact with complement receptors 1-4 (CR1-4) to perform other biological effects.

43
Q

What are the three main things that limit complement activation?

A
  • Short half-life of the enzymes formed
    • they decay quickly
  • Properties of non-activator surfaces
    • e.g. sialic acid
  • Inhibitors
    • Fluid phase inhibitors (so active fragments don’t go too far)
    • Membrane bound inhibitors (on our own membranes, so that C3b and C4b don’t attache or lead to lysis of our own cells)
44
Q

What is Factor H?

A
  • Fluid phase inhibitor of C3 convertase
    • decay acceleration of the convertase
      • if it sees C3bBb floating around, it binds and dissociates the Bb
45
Q

How does Factor I limit complement activation?

A
  • degrades C3b
    • with Factor H as a cofactor (FH displaces the Bb)
46
Q

What two things result if you lack control of the complement system?

A
  • Uncontrolled activation of the complement system:
    • Consequences of activation = lysis
    • Consumption of the complement components leading to the consequences of secondary complement deficiency
47
Q

Due to uncontrolled complement activation leading to the consumption of C4 and C2, hereditary angioedema results in recurrent episodes of localized edema in the skin, GI, and larynx because of a deficiency in what complement component?

A
  • C1 Inhibitor
    • inhibits C1s esterase
48
Q

What is the main treatment for Hereditary Angioedema?

A

Anabolic Steroids

  • increase synthesis of C1 inhibitor
  • most people have the machinery to make it because they are heterozygous
49
Q

What deficiency causes increased susceptibility of erythrocytes to MAC-mediated lysis, complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria, and results in defects in a post-translational modification of the peptide anchors that bind the proteins to the cell membrane?

A

Deficiency in Decay Accelerating Factor

(CD55 - decays convertases)

(CD59 - stops C9)

50
Q

What two complement proteins are Anaphylatoxins and can mimic the symptoms of inflammation and anaphylaxis?

A

C3a (C3a receptor)

C5a (C5a receptor)

51
Q

What complement receptor binds C3b & C4b ligands, blocks formation of C3 convertase, and helps RBCs transport immune complexes?

A

CR1 (CD35)

52
Q

What complement receptor helps augment stimulation of the B-cell to increase antibody response (humoral immunity) and has a high affinity for binding to Epstein Barr virus?

A

CR2 (CD21)

53
Q

What complement receptor binds iC3b, is present on a variety of cells (Monocytes, macrophages, PMNs, NK cells, T-cells) making them “sticky”, and is important for cell adhesion?

A

CR3 (CD11b/CD18)

CR4 (CD11c/CD18)

54
Q

What are further degradation products of C3 and C4 important for?

A

Interacting with Complement Receptors to elicit important biological responses in inflammation and host defense.

IHO Week 2 - WLB (10 decks)

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