Lecture 4 block 4 Flashcards


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1

review start of alternative path

  • positive feedback loop rapidly opsonize pathogen for phagocytosis
  • amplification of C3b by C3 convertase would kill our cells w/o negative regulation
  • C3b recognized by phagocytic cellsd
  • *** C3 is cleaved to C3b and C3a by C3bBb (the C3 convertase of the alternative path)
    • C3bBb and C3b covalently bound to bacterial cell surface
2

review

  • properdin - positive regulator on bacteria help make more C3 to opsonize
  • Factor I and H - no more binding to B by iC3b
  • DAF + MCP - protect host cells from this
3

NEW - iC3b = major opsonin

...

4

Q: C3bBb convertase

A) controlled by factor H and I on bacterial surface

B) May be self amplifying by positive feedback

C) convert C3 -> C3b if not controlled

D) All of above

ANSWER: D

5

reminder:

  • alternative pathway of complement activation - start w/ C3 -> spontaneous hydrolysis
  • Lectin pathway - start by binding PAMPs (like mannose)
  • classical pathway - start w/ Ag/Ab complexes on pathogen surface -> bind w/ C1

ALL = C3b -> deposit on bacterium + C5a/C3a/C4a recruit phagocytes + inflammatory

-phagocytes = major bacterial removal

6

Q: What makes alternative different from other 2?

A) initiated at a low level by spontaneous hydrolysis of C3 all the time

B) dos not require PAMP recognition

C) uses C3bBb as convertase

D) All of above

ANSWER: D

7

reminder: how C5a activated by alternative C5 convertase

C3b2Bb cleave C5 =

  • C5a - anaphylatoxin (most potent one)
    • activates phagocytosis
    • enhances phagocytosis of opsonized microorganisms
  • C5b - initiates assembly of MAC
    • does not form the pore (C9 does)
8

reminder - MBL binding to bacteria -> C3b on bacteria bind to CR1 on macrophage

  • ***if only C3b bind to CR1 = bacteria not phagocytosed
    • C5a activates phagocytosis (REMEMBER THIS)
9

iC3b - major opsonin

card image
  • facilitates phagocytosis of pathogens by phages/leukocytes + binds to several complement receptors
  • bind to several complement receptors
    • CR3, CR4, CR2
  • iC3b made when cleaved by factor I
10

Q: which complement component (in addition to C3b) is needed to promote activation of macrophages to phagocytose?

A) C1

B) C4b

C) C5a

D) C9

ANSWER: C

11

reminder:

slide abt phagocytes having both CR1 and FCR to recognize C3b + Ag/Ab complexes

12

Reminder: IC removal

...

13

Q: Some complement receptors

A) detect C9 fragments

B) recognize antibodies

C) Mediate phagocytosis of opsonized bacteria

D) Protect bacteria from innate immunity

E) all incorrect

ANSWER: C

14

Q: C3a, C4a, C5a, produced by activation of complement

A) opsonization of parasites by macrophages that express CD33 receptors

B) NK killing of tumor cells targets b/c C3b interacts w/ FCyR molecules

C) CD8T helper cell expression of IL-4 to assist IgG...

D) inflammation + phagocyte recruitment

ANSWER: D bc theyre anaphylatoxins

15

reminder: DAF slide

ADDED/NEW:

  • DAF also recognize C4b in classical/lectin pathway + block C2 -> C2b = prevent formation of C4b2b C3 convertase
  • genetic deficiency in deactivation pathway (DAF/MCP) for our own cells = destruction of RBC and autoimmune disorder
  • DAF inactivate C3b by cleaving off Bb
16

Complement deficiencies cause chronic/lethal susceptibility to bacterial infections

  • Deficiency in classical - C1,C2,C4= immune complex disease
  • MBL - bacterial infections (esp childhood)
  • Alternative - infection w/ pyrogenic bacteria(pus-causing) but no immune complex disease
  • deficiency in C3b deposition = diminished opsonization + phagocytosis - infection w/ pyrogenic bacteria (more severe than MAC)
  • deficiency in MAC = lack of pore formation + diminished complement killing
17

LECTIN PATH - collectins / pentraxins

  • MBL - collectin
  • CRP - pentraxin
  • BOTH - acute phase proteins in blood = made soon after infection
18

Lectin

Lectins - proteins w/ carbohydrate binding sites

  • diff sugars in carbs require lectins w/ diff binding sites
    • part that binds to the carb on pathogens (binds to the PAMPs)
    • = lectin = a PRR
  • use vanderwaals forces for binding
  • lectins = specific for certain sugars
    • bacteria, viruses, etc, have diff sugars on surface from mammals
  • many binding sites needed bc vanderwaals = weak forces
19

collectin

collectins - collagen-containing C-type lectin

  • calcium dependent
  • collagen like region attached to lectin like region w/ binding site
  • in plasma + mucosal surfaces - molecules of innate system
  • = family of calcium-dependent lectins that recognize PAMPs
  • = soluble PRRs
20

MBL structure (mannose binding lectin)

  • this is the lectin
card image
  • 6 binding sites
  • acute phase protein
  • binds to mannose - containing carbs
  • spheres on it - MASPS (mannose-binding lectin associated serine proteases)
    • cut C4 + C2 (C4a = anaphylatoxin)
21

kinetics of acuse phase proteins in blood/acute phase response

CRP (c reactive protein) - pentraxin - 5 regions

  • measured clinically to see if have infection / inflammation / tissue damage
  • pathogen recognition
  • can recognize lysophosphatidylcholine on dead/dying cells/bacteria -> activate complement system

MBL - collectin

  • eliminate pathogens
  • pathogen recognition

Serum amyloid protein - also acute phase protein

  • can interact w/ TLRs, CD36 to activate cells to produce inflammatory cytokines
22

Q: MBL

A) recognize lipid molecules

B) is a PAMP

C) activates alternative pathway

D) is member of collectin family as opsonin

ANSWER: D

23

acute phase response *** important info

  • increases supply of recognition molecules of innate immunity
  1. bacteria bind macrophages -> IL6 made -> liver produce APP (acute phase proteins) = CRPs, MLBs made
  2. now 2 things happen:
    • CRP triggers classical pathway if antibodies are absent (dont need antibody to do it)
      • binds to phosphocholine on bacteria + act as opsonin
    • MLB bind to carbs on bacteria (act as opsonin = activate complement pathway)
      • bind to C4 = make C4a
      • activate complement = lysis of bacteria

BASICALLY - CRP activate classical pathway without antibodies and MBL attach to carbs = act as opsonin = activate lectin pathway

-both stimulate complement

24

inflammation

  • cytokines:
    • TNF-a
    • IL-1
    • IL6
  • effects:
    • liver - help generate acute phase proteins (CRP + MBL)
      • activate complement opsonization
    • bone marrow endothelium - increase neutrophil mobilization = more phagocytes
    • hypothalmus - inc body temp -> decrease viral/bacterial replication
    • fat, muscle - protein + energy mobilization to inc body temp -> decrease viral/bacterial replication
  • cytokines recruit phagocytes + induce systemic responses -> do NOT directly trigger/induce phagocytosis
25

Q: CRP

A) belongs to fam of pentraxins

B) can activate C1/classical pathway

C) recognize phosphorylcholine

D) is an acute phase protein

E) All of above

ANSWER: E

26

Pentraxins - phylogeny

  • from invertebrates thru mammals -> show importance in immune system early on
  • highly conserved
27

Q: How does evolution suggest importance of pentraxins in immune system

A) pentraxins have coevolved w/ humans to protect them

B) pentraxins conserved from invertebrates - present

C) pentraxins, CRP, triggers classical (conserved) path

D) Pentraxins = important part of alternative path

ANSWER: C

28

MBL functions

card image
  • activated MBL complex -> cleaves C4 + C2 = C4b + C2a
    • = forms classical + lectin path C3 convertase
    • (the convertase for these 2 pathways)
    • = amplification of C3 convertase
  1. activated MASP-2 cleaves C4 -> C4a+C2b + some C4b bind to surface
  2. cleave C2 -> C2a + C2b
  3. C2a bind to surface C4b = C3 convertase = C4b2a
  4. C4bc2a bind C3 -> cleave =C3a + C3b -> C3b bind to surface
  • ***This process takes longer than alternative path
  • rest of pathway after C3 = same
29

Q: Lectin path recognizes

  • B) Carb molecules

correct

30

complement (C1) binding to CRP on pathogen surface activate classical pathway

card image

*** C' C1 - CRP - phosphorylcholine on pathogen -> then classical -> cleave C4 -> C4a + C4b

  • bc cleaves the C4 -> way of getting the classical pathway to start bc gets it to make it C3 convertase
31

Q: Lectin path of C' activation

A) unable to activate C5 + generate MAC

B) recognize carbs on surface of bacteria we dont have

C) use C5

D) use antibodies

E) all correct

ANSWER: B

32

lectin path start w/ MBL bind to carb on pathogen + use C4bC2a classical C3 convertase

***classical/lectin pathway use same convertase

  • both use C4 + C2
  • classical start w/ Ag/Ab complex
  • lectin start w/ MBL
33

recruitment of phagocytes from blood

  1. cytokines produced by macrophages -> cause dilation of local/small vessels
  2. leukocytes move to periphery of blood vessel bc of inc adhesion by endothelium
  3. leukocytes extravasate (get out of vessel) at infection site
  4. blood clotting occur in microvessels

neutrophils direction to site

pic: neutrophil moving towards infection site

  • tissue
  • interactions btw adhesion molecules
  • cytokines induce expression selectin on endothelium -> allow phage to bind to leukocytes
  • neutrophils roll along endothelium -> see selectin -> bind
  • 4 stages (CXCL8 chemokine)