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Fundamental Immunology MCQ #1 > LECTURE 8 > Flashcards

LECTURE 8 Flashcards

1
Q

At what stage in infection is complement activated?

A

early on in infection

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2
Q

how was complement discovered?

A

found heat labile substance in serum that had non-specific antimicrobial activity

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3
Q

describe complement proteins in general

A

ZYMOGENS: released from liver as inactive proteins, then activated via enzymes at infection site

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4
Q

Describe classical complement pathway up to C3 convertase

A
  1. C1q/C1s/C1r complex cleave C4
  2. C4b binds pathogen
  3. C4b binds C2, allowing cleavage by C1s
  4. C2a+C4b = C3 convertase
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5
Q

Describe MBL pathway up to C3 convertase

A
  1. MBL binds mannose on pathogen
  2. MASP1/MASP2 activate
  3. C2 and C4 cleaved
  4. C2a+C4b = C3 convertase
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6
Q

describe classical/MBL complement pathway after C3 convertase

A
  1. C3a leaves as inflammatory mediator
  2. C3b coats pathogen as serine protease and binds C4b and C2b
  3. C3b + C4b + C2b = C5 convertase
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7
Q

describe alternative complement pathway up to C5 convertase

A
  1. C3 spontaneously hydrolyzed
  2. C3(H2O) binds factor B
  3. Factor D cleaves B
  4. Bb cleaves C3(H2O)
  5. Bb+C3b = C3 convertase
  6. C3b+C3b+Bb = C5 convertase
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8
Q

where do the complement pathways converge?

A

classical and MBL converge at C3 convertase, and then converge with alternative once C5 convertase has cleaved C5

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9
Q

complement pathway after C5 is cleaved

A
  1. C5b binds C6 and C7
  2. C7 undergoes conformational change and inserts into bacterial membrane
  3. C8 and C9 bind and polymerize
  4. form MAC
  5. disrupt homeostasis, lose H+ gradient, pathogen dies
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10
Q

which complement proteins induce inflammation? how?

A

C3a, C4a, and C5a

induce smooth muscle contraction which causes vasodilation and vascular permeability

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11
Q

complement-induced inflammation by mast cells

A

C3a and C5a trigger histamine + TNFa

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12
Q

complement-induced inflammation by endothelial cells

A

C3a and C5a induce expression of adhesion molecules

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13
Q

complement-induced migration of immune cells

A

C5a attracts neutrophils and monocytes to site of infection

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14
Q

which complement molecule is involved in opsonization?

how?

A

C3b

binds CR1, CR3, CR4 on macrophages
binds CR2 on B cells

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15
Q

what is iC3b?

A

inhibits C3 convertase BUT stimulates phagocytosis

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16
Q

why do complement proteins need to be regulated?

A

prevent spont. activation on host cells

17
Q

6 methods of negative regulation

A
  1. C3b and C4b that don’t bind will react with water to be inactivated
  2. C1 inhibitor removes C1q from C1 complex
  3. CR1 and DAF/CD55 displace Bb in C3 convertase
  4. Factor I cleaves C3b to iC3b
  5. Factor H competes with Bb for C3b binding
  6. CD59/protectin prevents C9 binding
18
Q

1 method of positive regulation

A

Factor P/properdin stabilizes C3 convertase on pathogen surface

19
Q

intracellular sensing of C3 for viruses and bacteria

A

virus targeted to proteasome

virus and bacteria targeted to MAVS-dependent signaling to induce IRF3/5/7, NFkB, and AP1 (pro-inflammatory)

20
Q

complement system and B cells

A

opsonized Ag and immune complexes taken up by CR2 on B cells so they can migrate to T/B cell boundary to activate and proliferate

binding to CR1 inhibits TLR9-mediated activation of B cells

21
Q

complement system and T cells

A

complement is necessary for T cell function

TCR induces:
- C3
- C5
- factor B
- factor D
- C3aR –> mTOR, ROS, cell survival

C3b binding to CD46 = Treg

22
Q

2 types of diseases

A
  1. deficiency in component –> recurrent infection
  2. excessive activation –> inflammatory, autoimmune, etc. diseases
23
Q

2 tests for complement diseases

A
  1. CH50 assay –> ability of patient serum to lyse sheep RBCs with rabbit anti-sheep Ab
  2. ELISA –> measure quantities of components
24
Q

hereditary angioneurotic edema

A

C1 inhibitor deficiency
- spont. C1 activation
- makes C2 kinin –> vasoactive peptide
- causes edema

  • treat with C1 inhibitor from human plasma (Cinryze)
25
Q

factor I deficiency

A

cannot make iC3b
- genetic
- uncontrolled activation
- causes cerebral inflammation and complement depletion –> infection

26
Q

factor H deficiency

A

cannot regulate alternative pathway
- defective causes Macular Degeneration –> deposits in retina, treat with Compstatin
- deficiency causes Atypical Hemolytic Uremic syndrome, schizophrenia, stroke

27
Q

paroxysmal nocturnal hemoglobinuria

A

PIGA deficiency –> DAF/CD55 and CD59 not active
- RBCs and leukocytes vulnerable to complement-mediated lysis
- causes reduced hematopoietis, venus thrombosis, intravascular hemolysis, Hb in urine

  • treat with BM transplant or anti-C5 Ab (eculizumab/Soliris or ravulizumab)
28
Q

complement deficiency

A

mostly undiagnosed bc redundancy
- recurring infection
- autoimmunity
- glomerulonephritis
- joint and lung issues
- angioedema
- dermatomyositis
- vasculitis

29
Q

heart attack and stroke

A

inflammation seen in stroke and heart attack is due to complement

30
Q

transplant rejection

A

C5a triggers inflammatory response to make MAC on all cells of transplant organ

31
Q

AD

A

C3 and C1q bind amyloid-B to cause neuron lysis

32
Q

schizophrenia

A

C4 binds neurons

33
Q

asthma

A

environmental factors, like smoke, induce C3a and C5a in bronchoalveolar lavage fluid to cause inflammation

34
Q

SLE –> double edged sword

A

complement deficiency = can’t clear immune complexes

complement activation = inflammation

35
Q

COVID

A

a) Env binds and activates MBL and C1q (complement)
b) Nucleocapsid activates MASP1/MASP2 (complement, coagulation)
c) blocks factor H
d) infected epithelial cells make C5

36
Q

cancer

A

tumour cells normally removed by ADCC or complement-dependent cytotoxicity BUT they express the complement regulatory proteins normally expressed by host cells to evade complement

37
Q

anti-complement immunotherapy

A
  1. eculizumab (soliris) against C5
  2. compstatin prevents C3 cleavage
  3. PMX-53 is C5aR antagonist for SLE and sepsis
38
Q

4 methods of complement evasion by bacteria

A
  1. complement inhibitor –> SSL7 inhibits C5
  2. inhibitor of complement inhibitor –> Borrelia makes CRASP that binds factor H
  3. regulatory proteins –> Borrelia makes CD59-like protein that binds C3 to block C3 convertase
  4. bacterial protease –> pseudomonas elastase cleaves C3
39
Q

3 methods of complement evasion by viruses

A
  1. variola/small pox makes inhibitor SPICE
  2. vaccinia makes inhibitor VCP
  3. HCV makes C3 and C9 inhibitor

Fundamental Immunology MCQ #1 (6 decks)

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