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Immunology Exam 2 > Lecture 16-17 - Complement > Flashcards

Lecture 16-17 - Complement Flashcards

1
Q

Fixation of complement involves forming ___ and ____ from ____

A

C3 –> C3a + C3b

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2
Q

cleavage of C3 exposes ______ which undergoes _____ attack by ______

A

exposes thioester bond

undergoes nucleophilic attack by H20, R-OH or R-NH2

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3
Q

Attack by H20 gives _______

Attack by R-OH or R-NH2 gives _________

A
  • Soluble C3b
  • C3b bound to pathogen surface
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4
Q

Features of the complement pathways (3)

A
  1. Amplification
  2. Factors produced by liver (as zymogens)
  3. Converge onto C3 (the factor with the highest concentration)
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5
Q

What are the three complement pathways?

(and their relative orders, and general schemes)

A
  1. Alternative
    1. Pathogen surface creates a local environment conduction to complement activation
  2. Lectin
    1. Mannose-binding lectin binds to pathogen surface
  3. Classical
    1. CRP (acute phase protein) or antibody binds to specific antigen on pathogen surface
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6
Q

In the alternative pathway, you need to form…

A

C3bBb

= Alternative C3 convertase

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7
Q

Alternative pathway steps (6)

A
  1. H20 exposes C3’s thioester bond (becomes iC3b)
  2. Factor B binds to C3b
  3. Factor D cleaves Factor B —–> Bb + Ba
  4. forms iC3bBb (unstable)
  5. binds another plain C3, which is cleaved into C3a + C3b (starts over…Amplification!)
  6. New C3 leaves, thioester is bound by another ROH/RNH2 = C3bBb = Alt. C3 Convertase
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8
Q

Positive and Negative Regulators of Alt. Pathway

  1. Stabilizer of C3Bb?
  2. Inactivator of C3b on both Pathogen and human cell surface?
A
  1. Stabilizer = Properdin stabilizes C3 convertase C3bBb (active) on a pathogen surface
  2. Pathogen = C3bBb is bound by factor H and then bound to factor I. When this all breaks up, it takes a part of the C3bBb, leaving iC3b (which is inactive)
  3. Human = DAF and MCP inhibit surface bound C3bBb
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9
Q

What are DAF and MCP (function and name)

A

Inhibitors of Human cell surface bound C3bBb

  • DAF = Decay Accelerating Factor
  • CD55 = Membrane cofactor protein
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10
Q

Consequences of Factor I deficiency in Alt pathway

A
  • Unchecked C3 activation
  • C3 depletion (too low to attack when pathogens infect)
  • Chronic *encapsulated *bacterial infection
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11
Q
  1. Factor I deficiency inheritance?
  2. Symptoms?
  3. What will the blood counts look like (lymphocyte, IG)
A
  1. Autosomal Recessive
  2. Recurring infections of URT, ears, skin, UG (PNA, Meningitis, sepsis). Glomerulonephritis with isolated C3 deposits, **RA **or SLE.
  3. Normal lymphocyte ct, nml immunoglobulin concentration
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12
Q

Human cells are covered in ____, which is negative, and it reduces affinity for _____ and increases affinity for ___

A

Sialic acid

C3b

Factor H

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13
Q

C3b binding causes _____ by cells

A

opsonization

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14
Q

C3b on the pathogen binds to ____ on the MQ?

What happens next? (2)

A

C3b binds CR1 on MQ

  1. Endocytosis
  2. vesicle fusion –> phagocytosis
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15
Q

Ligands for CR1, CR2, and CR3/4

A

CR1 and CR2 = C3b

CR3/4 = iC3b

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16
Q

Associated cells for

CR1, CR2, CR3/4

A

CR1 = MQ, PMN, RBC

CR2 = FDC, B cell

CR3/4 = MQ, PMN

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17
Q

Function of CR1, CR2, and CR3/4

A

1 = phagocytosis, clearance of immune complexes

2= Antigen trapping, B cell activation

3/4 = phagocytosis

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18
Q

CR1 reduces the ___________

What happens when RBC’s CR1 recepor binds?

A

amount of Ag-AB complexes in the blood (some are coated with C3b)

–RBC will take the immune complex to the liver/spleen where it is eaten by a MQ

19
Q

Terminal pathway of the Alternative path involves activation of

A

activation of C5

20
Q

What does C5 bind to in the terminal pathway?

What happens next?

A

Binds to C3b(2)Bb

(= the *active *version of C3bBb that had two C3b’s bound to it)

  • The C5 is split into C5b and C5a
  • –> C5b sets off the terminal pathway
21
Q

What is recruited by C5b? What does this result in?

A

combines with C6, 7, 8, 9 to make the Membrane attack complex

*The pore is lined with C9, so many are recruited per C5b

22
Q

Functions of C7 and C8 in MAC formation?

A

Both expose hydrophobic regions

C7 allows attachment to membrane

C8 allows insertion into membrane

23
Q

Why doesnt the MAC get formed in all cells that have C3b2Bb?

A

CD9 can’t bind in human cells because C5b678 is bound by** CD59**

(CD59 = CI factor 5)

24
Q

PNH?

  1. Main feature/ pathophysiology
  2. Defective expression of ____ and ____
  3. Somatic mutation in _____ gene
A

Paroxysomal Nocturnal hemoglobinuria

  1. Intermittent intravascular hemolysis
  2. No CD55 (DAF) or CD59
  3. Mutation of PIGA gene (X-linked)
25
Q

PNH path:

DAF defect causes ______

CD59 defect causes ______

A

DAF = extravascular hemolysis

CD59 = intravascular hemolysis –> Free Hb –> NO scavenging = fatigue, esophageal spasms, thrombosis

**both result in anemia

26
Q

PNH treatments

A
  1. Bone marrow transplantation
  2. Eculizumab
    1. (Soliris, a humanized anti-C5 antibody)
    2. prevents C5 activation by C5 convertase (C3b(2)Bb)
27
Q

Anaphylatoxins

  • potencies
  • act on ____ to increase_____
  • also causes migration of…
A

C5a > C3a > C4a

act on vessels to increase vascular permeability

MQ and PMN into tissue from bloodstream

28
Q

Two types of C3 convertase

A

ALt = C3bBb

Classical = C2aC4b

29
Q

Classical C3 pathway steps (4)

A
  1. Immune complex’s Fc receptor recruits C1q,r,s
  2. C4 and C2 are cleaved, giving C4b2a (C4a and C2b leave…mediate inflammation)
  3. C4b2a (= C3 convertase) cleaves C3 into C3b (C3a leaves, also mediates inflamm.)
  4. Forms C4b2aC3b = C5 convertase (classical)
30
Q

Classical pathway can be activated by…

How?

A

antibodies and CRP

  • If CRP binds to phosphocholine on the pathogen surface, it can recruit C1 in the same way as IgM
31
Q

Initiation of the classical pathway involves binding of _____

A

Binding of IgM to antigen on a pathogen surface

32
Q

IgM binds in ___ conformation to bacterial cell surface

A

staple

(soluble form is planar)

33
Q

Can IgG activate complement classical pathway?

A

Yes. Multiple IgG are required for activation

  • IgG binds to surface antigen –> C1q binds to two or more IgG and initiates complement

OR

  • IgG binds to soluble multivalent antigen –> C1q binds to soluble immune complex and initiates complement activation
34
Q

Amplification by _______

Steps?

A

Alt. C3 convertase

  1. C1 binds to immune complex
  2. Deposition of C4b (by C1)
  3. Deposition of C3b (by C4b2a and C3bBb)
35
Q

Ability of isotypes to activate complement (rank)

A
  1. IgM best
  2. then IgG 3 > 1 > 2
  3. Then IgA 1+2

“So M31212”

36
Q

C4 haplotype - people can have ______ genes (and what are the combos)

Absence of C4A =

Absence of C4B =

A

People can have 1, 2, or 3 genes. (A/B, AA/BB/AB, AAB/ABB)

C4A = SLE susceptibility

C4B = increased infections

37
Q

C1 r + s (in classical pathway) are ____

A

serine proteases

38
Q

Lectin pathway steps

A
  1. MBP binds bacterial surface
  2. MASP1 and 2 are recruited
  3. C4 activated
  4. C2 activated
  5. C4b2a is formed (as in the classical pathway
39
Q

What are MASP1/2?

A

MBP-associated serine proteases

40
Q

Hereditary angioedema lab tests

A

C1 inhibitor deficiency

Low serum C4

Normal C3

41
Q
  • Hereditary angioneurotic edema = deficiency of _____
  • Genetics
  • Increase of ____, decrease of ___ and ___
A
  • Low functional C1-INH
  • Autosomal dominant
  • increaed bradykinin, decreased C4 + C2
42
Q

HAE Sx

Why do these patients NOT have increased susceptibility to infectious disease?

A

Recurrent edema of Skin, GI, UG, larynx

Abdomal/pelvic pain, suffocation

*Because C3 is still active = Alternative pathway still intact and you still have antibodies doing their thing

43
Q

C1 inhibitor inhibits activation of ___ and ___ (among severeal other steps)

A

kallikrein and plasminogen

44
Q

C2 Kinin =

A

a vasoactive peptide generated by C2b cleavage from plasmin

*results in edema

Immunology Exam 2 (11 decks)

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