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IHO Week 2 > Complement -Regal > Flashcards

Complement -Regal Flashcards

1
Q

Sequence of complement rxn:

A

C1, 4, 2, 3, 5, 6, 7, 8, 9,

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2
Q

Functions of Complement:

A
  • Lysis of microorganisms (MAC)
  • Opsonization of antigen
  • Source of mediators of inflammatory response (C3a, C5a)
  • Solubilization and clearance of immune complexes
  • Augments stimulation of B cells (CR2 receptor)
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3
Q

What are C 1, 4, 2, 3, important for?

A

Clearance of immune complexes

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4
Q

C3b importance?

A
  • amplifying adaptive immunity

- Opsonin

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5
Q

C5a importance?

A

Inflammation & T cell regulation

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6
Q

C5, 6, 7, 8, 9 Deficiencies? (they make MAC)

terminal lytic pathway

A
  • think MENINGOCOCCAL infections

- NEISERRIAL infections : need MAC to lyse Neiserria to get rid of it.

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7
Q

Deficiencies in C3 and alternative pathway?

A
  • Glomerulonephritis
  • SLE
  • recurrent infections
  • Neisseria
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8
Q

Deficiencies in C1, 4, 2 or 3 ?

-Classical pathway?

A

High incidence of immune complex diseases like SLE, glomerulonephritis (IC’s are not solubilized and cleared)

  • also role in tissue damage in IC disease like SLE (pathological complement activation)
  • encapsulated bacterial infections or pyogenic infections
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9
Q

MBL deficiency?

A

Serious pyogenic infections

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10
Q

What is complement important for?

Where is it synthesized?

A
  • Lysing bacteria
  • Clearing immune complexes
  • Made by liver hepatocytes and tissue macrophages
  • It is a PLASMA protein system (C3 is 5% of plasma proteins)
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11
Q

What proteins covalently bind to bacteria?

A

C4b and C3b
-via thioester bonds

  • can interact with complement receptors 1-4 on OUR cells
  • Act as opsonins
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12
Q

The proteins get cleaved and for most the B part is active, what protein’s ‘a’ portion is most important?

A

C2a
-think because it is part of C4b2a enzyme!)
(C2b floats off)

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13
Q

C3 convertases?

A

C4b2a (classical, alternative, MBL pathways)

C3bBb (alternative pathway)

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14
Q

C5 convertase?

A

C3bBbC3b (Alternative pathway)

C4b2aC3b (classical)

*C3b at end =think C5 convertase :)

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15
Q

What pathway needs Abs/antigen to activate it?

What antibodies?

A

Classical! - makes C1qrs

IgG or IgM

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16
Q

What activates the MBL pathway?

The alternative pathway?

A

MBL: mannose

Alternative- LPS, carbohydrates, etc

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17
Q

What is common to all pathways?

A

C3

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18
Q

Activation of C1 in classical pathway?

A
  1. C1qr2s2 complex in plasma is usually inactive. but BOOM. it binds two IgG or 1 IgM and makes a conformational change
  2. C1r activates auto-catalytically and activates the second C1r; –> both activate C1s
  3. Active C1 esterase cleaves C4 that is covalently bonded to bacteria.
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19
Q

Activation of C4

A

C1 esterase cleaves it.

C4b covalently bonds with activating surface

C4b can act as opsonin

20
Q

Activation of C2

A

C2 interacts with C4b
C1s cleaves it –> C4b2a is formed on surface

C4b2a == C3 convertase of classical pathway

21
Q

C3 activation

A

C4b2a cleaves C3 –> C3b covalently binds to surface

C3b can be opsonin

22
Q

Mannose Binding Lectin (MBL) pathway

A
  • recognizes mannose/polysaccaride structure
  • MBL, MASP-1, MASP-2 cleave C4 and C2 —> C4b2a =C3 convertase
  • Independent of C1
  • MBL interactions with MASP-1 & 2 are a lot like C1q interactions with C1r and C1s :)
23
Q

Alternative Pathway

Cue Promiscuous Girl by Nelly

A

Trigger: complement recognizes foreign surface structures (LPS) itself. SELF activating pathway

Recognizes antigen/Ab complexes but DONT need specific Ig’s

24
Q

Alternative Pathway–C3 tickover:

A

spontaneous conformational change of C3 –> water hydrolyzes the thioester bond –> C3(H20)

-always doing this

25
Q

Alternative Pathway steps

A
  1. Spontaneous split of C3 by hydrolysis
  2. Factor B binds to C3b
  3. Factor D cleaves FB off –> C3bBb (C3 convertase)
  4. C3b gets bonded to cell surfaces
26
Q

What’s the deal with sialic acid?

A

C3b is continuously deposited on surfaces of host cells and pathogenic organisms. Only get activated on right surface.

Low sialic acid =Bacterial surface
Our cells have lots of sialic acid so we are safe :)

27
Q

So C3b is bound to cells…what inactivates it?

A

Factor H and Factor I
===C3bi

*this happens on non-activator surface (aka high sialic acid)

28
Q

Amplification is so awesome:

Where, why, how?

A

-In all 3 pathways!
C3 convertase cleaves a bunch so we get lots of C3b deposits on surfaces

C5 convertase cleaves lots of C5 so we increase the likelihood of forming a complete MAC

29
Q

Properdin?

A

Stabilizes the alternative pathway C3 convertase so it won’t decay as fast!

30
Q

If antibody is activating complement, what C3 convertase is being used?

A

C4bC2a

31
Q

Excessive complement activation in immune complex disease would most likely result in depletion of what components?

A

C4

-keeps getting covalently bound to immune complexes. Happens more quickly thank the making of C4

32
Q

If C5b-9 don’t form a pore, what else than they do?

A

C5b-7 can bind to S protein in fluid phase. No lysis===Keeps it all local/confined.

33
Q

Key points of MAC:

A
  • after C5 cleavage, its just conformational changes

- Lysis can still happen without C9 (slower)

34
Q

How do we control Complement activation?

A
  • Short half life of enzymes
  • our cells have high sialic acid levels
  • Inhibitors:
    • Fluid phase inhibitors
    • Membrane bound inhibitors
35
Q

Fluid phase inhibitors?

A

Fluid: so active fragments don’t go too far

ex: Factor H (inhibitor of C3 convertase) if it sees C3bBb floating around it binds and dissociates the Bb (alternative pathway)

Protein S

36
Q

Membrane bound inhibitors?

A

Membrane: on OUR membranes

-keeps C3b and C4b from attaching and lysing our cells :) thanks so much!

37
Q

C1 Inhibitor Deficiency

A

HAE=Hereditary angioedema
-recurrent episodes of localized edema in skin, GI tract, larynx

Normally, inhibits C1 esterase (and MASP) so C4 doesn’t get cleaved

Uncontrolled activation —> consumption of C4 and C2 so you can’t get rid of immune complexes

38
Q

Secondary Deficiency

A

Using up proteins faster than you can make them.

Kinda a secondary autoimmune diseases b’c you can’t fight other infections

39
Q

C1 Inhibitor Deficiency

Tx:

A
  • Anabolic steroids to increase sythesis of C1 INH
  • purified C1 INH
  • Kallikrein inhibitors and B2 receptor inhibitors
40
Q

Deficiency in DAF (CD55) & CD59

A

-Something is wrong with the anchor that binds these to membrane.
CD55= decays C3 convertases

CD59=stops C9 from inserting on membrane

Increased susceptibility of erythrocytes to MAC mediated lysis

Tx: antibody to C5 (anti C5)

41
Q

What are the inflammatory mediators produced by complement activation?

A

C3a
C5a

Receptors for these on neutrophils, B cells, endothelial cells..

–>anaphylaxis (chemotaxis, smooth muscle contraction, increased vascular perm, degranulation of mast cells)

42
Q

Other functions of complement:

Solubilization/clearance of immune complexes by…..

Augmentation of humoral immunity by…

A

…. CR1 receptor

……..CR2 receptor (CD21) –C3d tags bad things and takes it to lymphocytes to tell them to make antibodies.

43
Q

CR1 (CD35)

A
  • On RBC - makes each RBC a carrier for immune complex –> spleen for degradation
  • Binds C3b, C4b
  • CR1 also blocks formation of C3 convertase
  • Promotes PHAGOCYTOSIS (neutrophils/macs)

Decays acceleration of C3 convertases

44
Q

CR2 (CD21)

A

On B cells -augment stimulation of B cells to increase humoral immune response
-binds C3d, C3dg, iC3b

-CR2 has high affinity for Epstein Barr virus –>allows virus to enter the B cell.

45
Q

CR3 and CR4

A

On WBCs
*Cell adhesion and phagocytosis

Binds IC3b

46
Q

How does complement prevent formation of insoluble immune complexes?

A
  • C3b binding with CR1 interferes with lattice formation and keeps it soluble.

–if allowed to aggregate it could cause damage to organs like kidneys

47
Q

Factor H

A

Makes C3bBb decay faster
-Cofactor to Factor I for C3b inhibition (cleaves Bb off C3bBb so FI can –> C3bi

Works with alternative pathway

IHO Week 2 (14 decks)

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