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I&I SC1 > Innate machanisms > Flashcards

Innate machanisms Flashcards

Lectures: -Week 1, day 2, lecture 2: Innate immunity - Pattern recognition receptors -Week 1, day 2, lecture 3: Innate immunity - The complement system

1
Q

What are pattern recognition receptors?

A

Receptors that recognize patterns that are often found on pathogens

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2
Q

What is a PAMP?

A

Pathogen-associated molecular pattern, can be recognized by PRR’s

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3
Q

What is a DAMP?

A

Danger-associated molecular pattern; endogenous molecules that signal danger

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4
Q

What are the three main groups of PRR’s?

A
  1. Free receptors in the serum
  2. Membrane-bound signaling receptors
  3. Cytoplasmic signaling receptors
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5
Q

Which are the subgroups of the group of free PRR’s in the serum? (4)

A
  1. Complement proteins
  2. Pentraxins
  3. Collectins
  4. Ficolins
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6
Q

What are the subgroups of the membrane-bound PRR’s? (3)

A
  1. Toll-like receptors (TLR)
  2. C-lectin receptors (CLR)
  3. Scavenger receptors
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7
Q

What are the subgroups of the cytoplasmic PRR’s? (3)

A
  1. NOD-like receptors (NLR)
  2. RIG-I-like receptors (RLR)
  3. Cytosolic DNA sensors
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8
Q

What is the main structural difference between plasma membrane-bound TLR’s and endosomal membrane-bound TLR’s?

A

Plasma membrane-bound TLR’s are usually dimers, whereas endosomal TLR’s are usually monomers

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9
Q

What do plasma membrane-bound TLR’s recognize?

A

Patterns on the outside of pathogens

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10
Q

What do endosomal membrane-bound TLR’s recognize?

A

RNA/DNA in the cytosol

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11
Q

Why is TLR4 an important TLR?

A

Recognizes LPS -> major component of bacteria

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12
Q

In what way can TLR4 on multiple cells be activated by LPS from a single bacterium?

A

LPS-binding protein extracts LPS from the bacterium -> bacterium is not bound to one cell

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13
Q

What is an important adaptor molecule for intracellular TLR’s?

A

TRIF -> leads to the production of type I interferon via IRF3 activation

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14
Q

In what way does the system of TLR’s provide redundancy?

A

Many TLR’s use the same pathway -> a defect in one of the TLR’s does not prohibit the activation of the immune pathway

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15
Q

What do C- type lectin receptors (CLR’s) recognize? Against which class of pathogens are they especially effective?

A

Carbohydrate structures; often found on fungi -> important for defence against fungal infections

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16
Q

Where are CLR’s located?

A

CLR’s are always bound to the plasma membrane

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17
Q

What does the ‘C’ in C-type lectin receptors refer to?

A

Calcium-dependent

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18
Q

What is the main adaptor molecule for CLR signaling? What kind of response does it induce?

A

Syk; induces release of IL-23, resulting in a Th17 antimicrobial response that defends epithelial surfaces

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19
Q

What is a symptom of a CLR-mutation?

A

Frequent candida infections

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20
Q

What are the NOD-like receptors?

A

A family of receptors with similar NOD-like domains

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21
Q

Where are NLR’s located?

A

In the cytoplasm

22
Q

When are NLR’s activated? What does this result in?

A

NLR’s are activated upon dimerization, resulting in the activation of NF-κB

23
Q

When are TLR’s activated?

A

TLR’s are often activated upon dimerization

24
Q

What is an inflammasome?

A

The inflammasome is a complex of molecules in the cytoplasm of the cell, activated by NLR’s
The inflammasome cleaves pro-IL-1β into IL-1β through the caspase-pathway

25
Q

How is dimerization of NLR’s prevented when there is no pathogen present? How is this mechanism reversed upon encounter of pathogens?

A

NLR’s are chaperoned, these chaperons dissociate when the [K+] drops, which occurs upon infections

26
Q

Which disease is (partly) the result of unwanted inflammasome activation?

A

Gout -> inflammasome activated by urate crystals

27
Q

In what way can loss-of-function of NOD2 result in Crohn’s disease?

A

Loss-of-function of NOD2 results in abberant NF-κB activation in the gut

28
Q

What are RLR’s?

A

RIG-I-like receptors

29
Q

What do RLR’s recognize? How is this achieved?

A

Viral RNA, by recognizing triphosphate motifs on RNA that are protected by the cap on self-RNA

30
Q

What happpens upon activation of RLR’s?

A

RLR’s bind to MAVS (mitochondrial antiviral signaling proteins), activating antiviral transcription factors

31
Q

What do cytosolic DNA-sensors recognize? What does this result in?

A

Cytosolic DNA; activation results in release of IL-1 or IFN-I

32
Q

What are they key effector functions of the complement system? (4)

A
  1. Elimination of immune complexes
  2. Opsonization
  3. Lytic destruction of micro-organisms
  4. Recruitment of inflammatory cells
33
Q

Which tree complement pathways are there?

A
  1. Lectin pathway
  2. Classical pathway
  3. Alternative pathway
34
Q

What is the common protein for all complement pathways (and ultimately leads to formation of the membrane-attack complex)?

A

C3

35
Q

What is the classical complement pathway activated by?

A

Antigen-antibody complexes

36
Q

What is the lectin complement pathway activated by?

A

Mannose binding lectin binding to pathogen surfaces

37
Q

What is the alternative complement pathway activated by?

A

Pathogen surfaces

38
Q

Which C3-convertase is used by the lectin pathway?

A

C4bC2a

39
Q

Which C3-convertase is used by the classical pathway?

A

C4bC2a

40
Q

In which way is the alternative complement pathway activated?

A

A tick-over mechanism constantly generates alternative C3-convertase C3BbBb
C3BbBb gets inactivated by host cell surfaces, but gets stabilized by pathogen surfaces by factor-P

41
Q

What is the major amplification step of the complement sytem?

A

C3 amplification -> leads to cleavage of C5, leading to the formation of the membrane attack complex

42
Q

What are the effects of the small cleavage products of the complement system? (3) What are these proteins called?

A

C3a, C4a & C5a are anaphylatoxins and result in
1. Initiation of inflammation by recruiting phagocytic cells to the site of infection
2. Increased vascular permeability -> extravasation of complement proteins, antibodies and immune cells
3. Stimulate phagocytosis (C5a)

43
Q

Which complement protein is the main opsonin? Which cofactor is required for effective phagocytosis of pathogens marked by this protein?

A

C3b, requires the presence of C5a (soluble) in the area

44
Q

Which complement proteins form the membrane attack complex?

A

C5-C9

45
Q

Which mechanisms can cause excessive complement activation? (4)

A
  1. Uncontrolled/systemic infection
  2. Tissue damage
  3. Gain of function mutation
  4. Activating auto-antibodies
46
Q

Which mechanisms can cause deficiency of the complement sytem? (3)

A
  1. Consumption (due to auto-immune disease)
  2. Loss of function mutation
  3. Neutralizing auto-antibodies
47
Q

What can complement deficiencies lead to? (2)

A
  1. Higher susceptibility to infectious disease (mainly bacterial infections)
  2. Auto-immune diseases (SLE, hemolytic uremic syndrome, paroxysmal noctural haemoglobulinuremia)
48
Q

How can a C1q deficiency lead to SLE?

A

Impaired clearance of immune complexes and apoptotic cells results in deposition, causing inflammation

49
Q

What is the old way of complement testing? How does this work?

A

Hemolytic essays; addition of patient serum to sheep (classical pathway) or rabbit (alternative pathway) RBC’s and measuring the lysis through the amount of Hb released

50
Q

What are the disadvantages of hemolytic complement testing? (3)

A
  1. Semi-quantitive
  2. Dependent on stable RBC
  3. Laborious
51
Q

What is the current technique that is employed for complement testing? How does this work?

A

Immunoassay = ELISA; addition of patient serum to wells that contain the factors required for activation of the different pathways; this will lead to MAC formation, after wich the presence of this MAC-complex can be shown through secondary antibodies directed against the MAC

52
Q

What can factor-specific immuno-assays of complement proteins be used for?

A

Analysis of individual complement factors to determine which factor might be disfunctional/disrupted

I&I SC1 (20 decks)

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