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Immunology - CORE > Immune Signalling > Flashcards

Immune Signalling Flashcards

1
Q

What is immune signalling?

A

conversion of external stimuli to effective immune responses

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2
Q

What are the medical uses of immune signalling?

A
  • immunomodulatory biologics
  • modulates TCR and BCR signals to control direction and magnitude of lymphocyte responses
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3
Q

Describe Muromonab-CD3

A
  • 1st immunomodulatory biologic
  • directed against CD3 - essential for T cell signal transduction
  • stimulates initial T Cell proliferation followed by depletion
  • depletion within hours in periphery
  • prevents transplant rejection
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4
Q

Describe Abatacept

A
  • directed against CTLA-4 - immune checkpoint molecule
  • fusion protein - Fc portion of IgG1 and extracellular domain of CTLA-4
  • binds to CD80 or CD86
  • 2nd line agent for rheumatoid arthritis treatment
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5
Q

Describe Lokivetmab

A
  • 1st Mab for animal use
  • recombinant anti-IL-31
  • triggers cell mediated immunity against pathogens
  • controls atopic dermatitis - crucial for causing pruritis
  • single dose ablates symptoms for 4-8 weeks
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6
Q

Describe Signalling Families/Pathways

A
  • involves cell surface receptors
  • not all immune specific pathways
  • ‘information highways’ between cell surface and nucleus to link environmental signals to genomic responses
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7
Q

Give 4 signalling families/pathways

A
  • JAK/STAT pathway - cytokines
  • NGkB - inflammation
  • MAPK/ERK - inflammation, cell proliferation/death
  • TLR - innate immune activation, inflammation
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8
Q

Describe the JAK/STAT pathway

A

Primary signalling cascade in response to cytokines:
- JAKS associated with cell surface that lack kinase activity
- receptors oligomerise on ligand binding
- JAK phosphorylates tyrosine residues on itself and receptor cell
- STAT proteins with SH2 domains bind to residues
- JAK phosphorylates STAT residues
- STAT proteins form dimers and translocate to nucleus to initiate transcription of genes
- also initiates transcription of SOCS
- JAK/STAT signalling can integrate into other pathways

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9
Q

Describe STAT proteins initiating transcription of genes

A
  • STAT proteins are transcription factors with DNA-binding domains
  • currently 4 JAK and 7 STAT proteins
  • different combinations bind to specific receptors
  • e.g., IFNү signalling uses JAK1/JAK2 and STAT1 proteins to initiate IFN-inducible gene expression
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10
Q

Describe STAT proteins initiating SOCS transcription

A
  • suppressor of cytokine signalling - negative regulator
  • acts via ubiquination of JAK proteins
  • targets for degradation in proteosome
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11
Q

Describe JAK/STAT signalling integrating into other pathways

A

via signalling proteins which contain SH2 domains:
- P13K/AKT/mTOR: P13K has domain
- MAPK/ERK: Grb2 has domain and initiates MAPK/ERK signalling

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12
Q

Describe the NF-KB pathway

A

protein complex controlling gene transcription: central to inflammation
- signalling involved in TLR, TNF, IL-1, TCR & BCR pathways
- in steady state - repressed by IKB (inhibitor KB) proteins
- upon ligation of upstream receptors - signal cascades
- phosphorylated IKB ubiquitinated and degraded by proteosome
- complex translocated to nucleus to initiate gene transcription including IKB - feedback loop

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13
Q

Describe what occurs upon ligation of upstream receptors in NF-KB pathway

A
  • signal cascades
  • results in activation of IKB Kinase
  • phosphorylates serine residues on IKB
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14
Q

What are the 2 pathways that NF-KB is split into?

A
  • classical
  • alternate
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15
Q

Describe the classical NF-KB pathway

A
  • initiated by TNF, IL-1 and TLR stimulation
  • IKK regulated by NEMO - NF-KB essential modulator
  • phosphorylation of IKK results in ubiquitination of NEMO and degradation by proteosome
  • involves p65/50 subunits of NF-KB complex
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16
Q

Describe the alternate NF-KB pathway

A
  • initiated by CD40L, BAFF, stimulation
  • activation of NIKS (NF-KB inducing kinase) phosphorylates IKK
  • IKK phosphorylates p100 precursor to be degraded to p52
  • dimerises with RelB
17
Q

Describe MAPK pathways

A
  • highly conserved pathway in prokaryotes and mammalian cells
  • 3-tier kinase pathways initiated by an activator and terminating in transcription factor
  • ‘phospho-relays’ where protein kinases phosphorylate serine and tyrosine residues to potentiate intracellular signalling cascades from cell surface to nucleus
18
Q

Describe ERK pathways

A
  • Highly conserved pathway in prokaryotes and mammalian cells
  • controls cell proliferation and differentiation
19
Q

What are MAPK/ERK pathways activated by?

A
  • hormones
  • growth factors
  • differentiation factors
  • oncogenic substances
20
Q

Describe MAPK/ERK pathways

A
  • receptor linked tyrosine kinases activates GTPases
  • Gr2b binds - recruits SOS - converts RasGDP to RasGTP
  • activates Raf (MAPKKK)
  • phosphorylates MEK1 or MEK2 (MAPKK)
  • phosphorylates ERK1 (MAPK)
  • ERK can phosphorylate transcription factors to form AP-1 but also activates p90-RSK
21
Q

What is a TLR pathway?

A
  • toll-like receptors - pattern recognition receptors mostly found on innate immune cells
  • up to 13 TLRs depending on species:
  • murine 1-13
  • human 1-10
  • bovine 1-10
22
Q

Describe TLR pathway

A
  • recognises wide range of molecular patterns
  • mostly cell surface but TLR3, 7, 8 and 9 within intracellular vesicles
  • dimerise on ligand binding to initiate signalling
  • all signal through Toll/IL-01 receptor domains (TIR) on the intracellular portion to complex with and TIR containing adaptor proteins
23
Q

Describe TLR-4 pathway

A
  • TLR4 recognises lipopolysaccharide (LPS) from gram-negative bacteria in conjunction with CD14, MD2 and LPB
  • TLR4 dimerises on binding with LPS
  • MyD88 activates IRAK4 and IRAK1
24
Q

Describe TLR4 dimerising after binding to LPS

A
  • conformational change and recruitment of TIRAP and MyD88
  • both TIR containing proteins
25
Q

Describe MyD88 activating IRAK4 and IRAK1

A
  • phosphorylates TRAF6
  • complexes with TAK1 and TAB2/3
  • initiates MAPK pathways - ERK, p38, JNK and NF-KB
26
Q

What does the TLR-4 pathway lead to?

A
  • cell differentiation
  • cell maturation
  • cytokine secretion
  • receptor expression
  • inflammation
27
Q

Describe how Muromonab-CD3 works

A
  • intracellular portions contain immunoreceptor tyrosine-based activation motifs (ITAM)
  • phosphorylation of ITAM on CD3Ϛ chain allows binding of ZAP70
  • initiates signalling cascade within T cells
  • muromonab-CD3 binds to CD3 - early activation of T cells, mass cytokine release and T cell death by activation induced apoptosis pathway
28
Q

Describe how Abatacept works

A
  • downregulates immune response when bound to CD80 or CD86 - signal 2 in T cell activation
  • expressed on Tregs and upregulated on conventional T cells upon activation
  • inhibition mechanism controversial
29
Q

How is the inhibition mechanism of abatacept controversial?

A

Evidence for:
- recruitment of a phosphate to disrupt TCR signalling
- depleting CD80 and CD86 from APC
- skewing immune system synapse formation in CD-Treg interaction resulting in ‘lethargic DC’ - reducing T cell priming

30
Q

Describe how Lokivetmab works

A
  • binds to IL-31 receptor A (IL-31RA) complex expressed on monocytes, epithelial cells and dorsal root ganglia
  • dorsal root ganglia contributes to itching sensation (pruritis)
  • IL-31RA signalling contributes to JAK/STAT, P13K/AKT, MAPK/ERK
31
Q

What are the main ways of studying immune signalling?

A
  • cellular output
  • microscopy and stain cells
  • western blotting
  • reporter assays - confirms use of a signalling pathway
32
Q

Describe cellular output for studying immune signalling

A

confirms interaction took place but not pathway unless inhibitors are used:
- cytokine secretion
- cell surface receptor changes
- transcription in response to stimulation

33
Q

Describe microscopy and stain cells for studying immune signalling

A
  • extract protein lysates
  • stain for phosphorylated signalling molecules to confirm signal transfer

Immunology - CORE (18 decks)

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