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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
What are three unique traits of the Classical Pathway in the complement system?
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
What is the first step in the Mannose-Binding Lectin (MBL) Pathway in the complement system?
* MBL binds to sugar residues on membrane of microbe * conformational change of MBL → activates MASP-1/MASP-2 (NO antibody required for activation!)
27
How is the C4b2a complex formed in the Mannose-Binding Lectin Pathway in the complement system?
* 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
What are two unique traits of the Mannose-Binding Lectin (MBL) Pathway?
* Does not require specific antibody for activation. * Most recently discovered of the complement pathways.
29
What is the first step in the Alternative Pathway of the complement system?
* Spontaneous conformational change of C3 molecule leads to hydrolysis of C3 * C3 + H20 → C3(H20) * called "C3 take over"
30
How does C3bBb first form?
* Factor B binds to C3(H20) → * becomes C3(H20)B * Factor D binds and cleaves Factor B → * becomes C3bBb = Alternate Pathway C3 Convertase
31
What does C3bBb do?
* 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
What determines if C3b will undergo Amplification or Decay once it becomes covalently bound to the membrane surface?
* 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
What protein or component of the Alternative Pathway acts to stabilize or prevent decay of C3bBb (the alternative pathway C3 convertase)?
Properdin
34
How is C5 convertase formed?
* After C3 is cleaved, C3b binds to a C3 convertase * C4b2a3b (classical) * C3bBbC3b (alternative)
35
How is C5 activated?
* Cleaved by either: * Classical Pathway C5 convertase (C4b2aC3b) * Alternative Pathway C5 convertase (C3bBbC3b)
36
What happens to active C5a and C5b?
* C5a: floats away * C5b: initiates membrane attack complex * attracts C6 and C7
37
How does Membrane Attack Complex initially insert into the membrane?
* C7 has transmembrane properties and is able to insert into the membrane * C5,C6, & C7 bind together and C7 inserts
38
How does the the Membrane Attack Complex initiate lysis?
* 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
What can C5b-7 bind to in the fluid phase that prevents membrane insertion and MAC formation?
S-protein
40
Can lysis occur in the absence of C9?
Yes, but it is slower
41
What are two possibilities if C9 binding to C5?
* 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
What other unique function do covalently bound C3b and C4b have besides progressing into the Terminal Lytic Pathway?
Interact with complement receptors 1-4 (CR1-4) to perform other biological effects.
43
What are the three main things that limit complement activation?
* 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
What is Factor H?
* Fluid phase inhibitor of C3 convertase * decay acceleration of the convertase * if it sees C3bBb floating around, it binds and dissociates the Bb
45
How does Factor I limit complement activation?
* degrades C3b * with Factor H as a cofactor (FH displaces the Bb)
46
What two things result if you lack control of the complement system?
* Uncontrolled activation of the complement system: * Consequences of activation = lysis * Consumption of the complement components leading to the consequences of secondary complement deficiency
47
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?
* C1 Inhibitor * inhibits C1s esterase
48
What is the main treatment for Hereditary Angioedema?
Anabolic Steroids - increase synthesis of C1 inhibitor - most people have the machinery to make it because they are heterozygous
49
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?
Deficiency in Decay Accelerating Factor (CD55 - decays convertases) (CD59 - stops C9)
50
What two complement proteins are Anaphylatoxins and can mimic the symptoms of inflammation and anaphylaxis?
C3a (C3a receptor) C5a (C5a receptor)
51
What complement receptor binds C3b & C4b ligands, blocks formation of C3 convertase, and helps RBCs transport immune complexes?
CR1 (CD35)
52
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?
CR2 (CD21)
53
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?
CR3 (CD11b/CD18) CR4 (CD11c/CD18)
54
What are further degradation products of C3 and C4 important for?
Interacting with Complement Receptors to elicit important biological responses in inflammation and host defense.

IHO Week 2 - WLB (10 decks)

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