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BC4022 KN > Lecture 2 > Flashcards

Lecture 2 Flashcards

1
Q

Drosophila Toll is activated as a result of…

A

a proteolytic cascade initiated by pathogen recognition

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2
Q

Pathogen recognition pathway by Toll in Drosophila

A
  1. PGRP-SA & GNBP1 cooperate in pathogen recognition
  2. Initiation of protease cascade
  3. Cleavage of Spatzle protein
  4. Spatzle binds Toll, causing Toll dimerisation
  5. TIR domains of Toll recruit dMyD88, which activates a signalling pathway similar to NF-κβ
  6. Transcription factor DIF enters nucleus & activates transcription of genes encoding AMPs
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3
Q

TLR3 binds

A

dsRNA viruses, poly I:C

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4
Q

TLR5 binds

A

Flagellin

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5
Q

TLR7 and TLR8 bind

A

ssRNA viruses

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6
Q

TLR9 binds

A

DNA with unmethylated CpG (e.g. HSV)

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7
Q

How does TLR4 bind LPS, in association with MD-2?

A

5 acyl chains of LPS can bind a pocket within MD-2, but one acyl chain is free. This free chain binds to surface of another TLR4, inducing a dimer. An LPS molecule bound to the second TLR4/MD-2 molecule stabilises the dimer.

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8
Q

Dimerised TLRs recruit __ and __ to activate the E3 ubiquitin ligase, __.

A

IRAK1 and IRAK4
TRAF-6

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9
Q

TRAF-6 creates a scaffold for activation of __

A

TAK1

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10
Q

What happens when bacterial ligands bind to NOD proteins in the cytoplasm?

A

RIP2 is recruited, which activates TAK1. TAK1 phosphorylates IKK beta, leading to IKK activation and subsequent NF-κβ activation.

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11
Q

NF-κβ induces expression of genes for…

A

inflammatory cytokines and enzymes involved in nitric oxide production

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12
Q

Main adaptor protein for TLRs

A

MyD88

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13
Q

Adaptor protein for TLR3

A

TRIF

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14
Q

Loss-of-function mutation in NOD2 gene can inhibit activation of __

A

NF-κβ

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15
Q

Loss-of-function mutation in NOD2 is associated with which inflammatory disease?

A

Crohn’s disease

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16
Q

Gain-of-function mutation in NOD2 can lead to…

A

excessive NF-κβ signalling

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17
Q

All NLRs contain a central __ domain. What is the function of this domain?

A

NACHT domain - a motif that permits oligomerization of individual NLRs into supercomplexes

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18
Q

Breifly describe the NLRP3 inflammasome pathway

A

K+ efflux induces dissociation of chaperones that keep NLRP3 inactive.
NLRP3 pathogen recognition causes NLRP3 to form oligomers with ASC, which leads to proteolytic cleavage of pro-caspase 1. Active caspase releases pro-inflammatory cytokines, IL-1β & IL-18. Induction of pyroptosis (inflammatory cell death).

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19
Q

NLRP3 inflammasome consists of…

A

NLRP3 - sensor
ASC - adaptor protein
Caspase 1 - effector

20
Q

Examples of activators of NLPR3

A

Genetics, urate crystals, α-synuclein, cholesterol crystals

21
Q

NLRP3 inflammasome activation can lead to __ cleavage, which results in pore formation in the cell membrane.

A

GSDMD

22
Q

What happens when RIG-I-like receptors detect cytoplasmic viral RNA?

A

Viral RNA alters conformation of RIG-I, inducing binding & aggregation with MAVS (this requires K63-linked polyubiquitin & TRIM25). Aggregated MAVS recruits TRAFs and induces generation of free K63-linked polyubiquitin chains that activate IRFs and NK-κβ pathway.

23
Q

Briefly describe the STING pathway

A

dsDNA from viruses activates cGAS to produce cGAMP, which binds to STING dimer on ER membrane to activate its signalling. STING activates the kinase TBK1 to phosphorylate IRF3, which enters the nucleus to induce expression of type 1 IFN genes.

24
Q

What pro-inflammatory cytokines are released by activated macrophages and DCs to promote T cell differentiation and lymphocyte effector function?

A

IL-12 and IL-23

25
Q

Cytokine receptors of the hematopoietin family are associated with the __ family of tyrosine kinases, which activate __ transcription factors.

A

JAK family
STAT transcription factors

26
Q

Which domains of the cytokine receptor bind JAKs?

A

cytoplasmic

27
Q

CXCL8 recruits…

A

neutrophils, basophils and T cells to infection site

28
Q

IL-12 induces differentiation of CD4+ T cells into __

A

T helper 1 cells

29
Q

What types of interferons are important in the immune response to viruses?

A

1 and 3

30
Q

What type of interferon is important in response to intracellular bacteria?

A

Type 2 (IFN-𝛾 secretion by Th1 cells)

31
Q

CXC chemokines are chemotactic for __

A

neutrophils (e.g. CXCL8)

32
Q

CC chemokines are chemotactic for __

A

monocytes and a small subset of lymphocytes (CCL2)

33
Q

Selectins initiate…

A

leukocyte-endothelial interaction

34
Q

Example of an integrin binding a cell-adhesion molecule

A

LFA-1 (integrin) binds ICAM-1/ICAM-2

35
Q

What happens when vessels collapse in sepsis?

A

Disseminated intravascular coagulation leading to wasting and multiple organ failure (can lead to death)

36
Q

TNFα triggers local containment of infection but induces __ when released

A

shock

37
Q

Example of anti-TNFα mAbs

A

Infliximab, Adalimumab

38
Q

The Fc region of Adalimumab has been shown to…

A

bind Fc receptors in gut macrophages, changing them to an anti-inflammatory M2 phenotype

39
Q

Indications of anti-TNFα mAbs

A

Crohn’s, UC, RA

40
Q

Cytokines that induce the acute phase response

A

IL-1β, IL-6, TNFα

41
Q

Examples of acute phase proteins produced by hepatocytes

A

C-reactive protein, mannose-binding lectin

42
Q

What do acute phase proteins activate?

A

Complement
- CRP binds phosphocholine on bacterial surfaces and acts as an opsonin

43
Q

How does TNFα released by DCs initiate the adaptive immune response?

A

TNFα stimulates migration to lymph nodes and maturation

44
Q

Type 1 IFN signalling pathway

A
  1. Type 1 IFNs activate STAT1 & STAT2, which combine with IRF9 to form ISGF3
  2. Induction of Mx proteins, adenosine oligomers and PKR cause resistance to viral replication
  3. Expression of IFIT proteins suppress viral RNA translation
  4. Increased MHC I expression and Ag presentation in all cells
  5. Activation of DCs, macrophages & NK cells
  6. Chemokines released to recruit lymphocytes
45
Q

NK cells express the TNF family ligand __ on their cell surface, which can bind and activate __ and __ expressed by some target cells.

A

TRAIL
DR4 and DR5

46
Q

DR4 and DR5 signal via __ to activate __, which induces apoptosis in the target cells.

A

FADD to activate caspase 8

BC4022 KN (6 decks)

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