ICADA Cytokines, Chemokines Flashcards
Which test modality allows sequencing of the full transcriptome at the single-cell level
Next-generation sequencing (NGS)
What is the effect of protease processing on IL-33
IL-33 is always expressed and active, but when processed by proteases, it can become a shorter “hyperactive” form –> enhances allergic inflammation
IL-33 expression levels in acute and chronic cAD
High in cAD dogs, not present in healthy dogs
Associated with pruritus, excoriations
Keratinocyte (innate) receptor for HDM-derived proteases
PAR-2
Keratinocyte (innate) receptor for Staphylococcus membrane proteins
TLR 1/2
Which cytokine made by keratinocytes was found to be upregulated in acute cAD flares from HDM or Staphylococcal infections in 1 study, but mRNA was downregulated in another
TSLP
Potent chemoattractant for Th2 cells
TARC/CCL17
Receptor for TARC
CCR4
Which cells express CCR4
Th2 cells (TARC ligand is a chemoattractant for Th2)
Which cytokine is associated with cAD severity
TARC
What cytokine should be considered a biomarker for cAD?
TARC
Which medications have shown a reduction in TARC
*Prednisolone
*Apoquel
How are CCR4 inhibitors (TARC receptor) for cAD therapy?
Moderate reduction in CADESI, but not statistically significant.
May be d/t different cAD endotypes
Ligands for CCR4
TARC, MDC
T or F: Macrophage-derived chemokine (MDC) can recruit Th2 to inflammatory loci in cAD skin
True
T or F: high MDC level was associated with higher pVAS and CADESI scores in cAD dogs
True
Which cells secrete IL-4
*Th2
*Mast cells
*Eosinophils
*Basophils
Major functions of IL-4 (2)
*Th2 leukocyte survival
*IgE class switching of B cells
Are IL-4 levels different in cAD vs healthy skin
Conflicting studies
BUT
*IL-4 is increased in acute phase of cAD, but maybe not chronic cAD
*IL-4 R is increased in cAD skin
Cells that produce IL-5
*Th2
*Mast cells
Function of IL-5
*Survival, activation, migration of eosinophils
Is IL-5 increased or decreased in cAD skin
Increased
Receptor for IL-13
IL-4RA
Functions of IL-13
*IgE production
*Th2 differentiation
Is IL-13 increased or decreased in cAD
Increased
Mutations in which gene was associated with increased cAD in miniature dachshunds
IL-4Ra (IL-13, IL-4 bind)
When receptor was defective, less allergic inflammation, less cAD!!
Cells that make IL-31
Th2, T cells
Do cAD dogs have higher IL-31RA X1 (binds IL-31) or IL-31RA X2 (can’t bind)
ILRA X2 isoform
Where can you find IL-31RA?
*Dorsal root ganglion
*Nerve fibers in cAD epidermis
*Also keratinocytes
How does IL-31 cause itch?
Direct action on sensory neurons
T or F: IL-31 does not affect the skin barrier
F: Cytopoint decrease TEWL!
Are IL-31 levels increased or decreased with cAD?
Increased
Is there a correlation of cytokine mRNA and protein expression between skin and blood
No
When does IL-31 expression peak after allergy flare
24-48 hr later
What percent of dogs have prevention of itch/skin lesions for >1 year when using Cytopoitn proactively
28%
Does the anti-IL-31 vaccine work to reduce itching to HDM allergens
Yes.
Which cells make IFNg?
*Th1
*Tc
*NK cells
Functions of IFNg
*Inhibits Th2
*Promotes Th1
*Increased APC ability
*Inhibit viral replication
Level of IFNg in chronic cAD dogs
CONFLICTING. INCREASED in some studies, unaffected in many studies, reduced in others
A Th1 cytokine BUT we think IFNg is increased in chronic lesions
Name 3 IFNg INDUCING factors
*IL-12
*IL-15
*IL-18
Which subunit of IL-12 is a more specific inducer of Th1 (IL-12p35 or IL-12p40)
IL-12p40
What is unique about IL-18 in the ABSENCE of IL-12
Stimulates both Th1 and Th2 responses
What are the 3 cell surface molecules that define a Treg
*CD4
*CD25
*Foxp3
Are IL-10 and TGF-b increased or decreased in cAD?
Conflicting studies!
*Likely a functional insufficiency of Treg cells in cAD
Is IL-10 and TGFb increased or decreased after 1 year of ASIT?
No change
Does the amount of IL-10 and TGFb correlate with ASIT treatment success
No
So we don’t even KNOW if ASIT works via affecting Tregs anymore!
Which Th type is a potent producer of local tissue inflammation via upregulation of proinflammatory and neutrophil-mobilizing cytokines
Th17
Cytokines made by Th17 cells
*IL-6
*granulocyte-macrophage colony=stimulating factor (GM-CSF)
*TNF-a
*IL-1b
*CXCL1
*MCP1
*MCP3
*MIP-3a
*MMPs
Which Th is involved in psoriasis
Th17
Which cells are activated by GM-CSF
Langerhan cells
Which cells are chemoattracted by S100A8 and IL-8
Neutrophils
Impact of IL-17 on S100A8 and IL-8
Increase, more neutrophil chemotaxis
Does IL-17 signaling increased Th1 or Th2 more
Increased Th2 from IL-17 signaling more
(but also increases IFNg, which is Th1)
Is IL-17 increased or decreased in cAD skin
No change
Which cytokine is an activator of keratinocyte proliferation
IL-22
Which cytokine can increase epidermal host defense peptides and neutrophil chemoattractants
IL-22
Name 5 host defense peptides
*B-defensin
*Cathelicidin
*S100A8
*S100A9
*S100A7
Is IL-22 increased or decreased in cAD skin?
Conflicting studies in dogs
In human AD, it is increased significantly in chronic lesions, but also present in acute lesions
Cells that make IL-7
*Stromal cells of bone marrow, thymus
*Keratinocytes
Function of IL-7
*Development of memory Th cells (crucial for cAD and asthma)
Levels of IL-7 in cAD skin
Possibly increased! (one study)
Cells that make IL-34
- Keratinocytes
- Neurons in brain
Function of IL-34
Development of myeloid cells (LC in skin, microglia in brain)
Level of IL-34 in human AD skin; in dogs
Humans: Decreased
IL-34 inhibits propagation of inflammatory cascade
Dogs: Increased, but unchanged even with successful tx.
Likely IL-34 unimportant for cAD
Cells that make IL-36
*Barrier sites: bronchial, intestinal, dermal epithelium
Is IL-36 immediately active when expressed?
No, needs N-terminus cleaved
Function of IL-36
*Host defense against Staphylococcus
*Amplifies inflammatory response in skin
Level of IL-36 in cAD skin
INCREASED
To help fight off Staphylococcus
Cells that produces macrophage migration inhibitor factor (MIF)
Immune and nonimmune cells
Function of MIF (macrophage inhibition factor)
*T cell activation
*Recruits/activates macrophages at inflammatory loci –> delayed-type hypersensitivity
Level of MIF in cAD serum
HIGHER
BUT no association with CADESI or pVAS
Vasodilation and leukocyte-mediated inflammation mediated by neruopeptides is called ________
Neurogenic inflammation;
Potentiates chronic cAD
Cells that produce nerve growth factor (NGF)
Keratinocytes
Function of nerve growth factor
Promote growth of nerve endings in skin –> neuronal sensitization
Level of NGF in cAD vs healthy skin
HIGH NGF in cAD skin
Which neuropeptide is associated with induction of cAD flares
Nerve growth factor
NOT changed in non-lesional skin though!
Does mAB against NGF decrease cAD flares or pruritus?
No
Cells that produce substance P
*Free nerve endings in skin
*Keratinocytes
*inflammatory cells
Function of substance P
*Mediator of pruritus
*Can induce cutaneous inflammation
Level of substance P in cAD skin
Increased
But not changed in nonlesional skin; not increased in acute experimental flare model
Which medication substance p blocker is effective for pruritus and skin lesions in cats
Ceremia (SP receptor antagonist; blocks neurokinin 1 receptor)
Receptor for substance P
1) Neurokinin 1 R
*Cerenia = NK1R antagonist
2) Mrgpr
ONLY Mrgpr IS RESPONSIBLE FOR PRURITUS
So it is possible an Mrgpr blocker would work better than cerenia
Which cell produces periostin
Fibroblasts
Epithelial cells
Endothelial cells
Which type of protein is periostin
Extracellular matrix protein
Function of periostin
*Differentiation and migration of fibroblasts
*Proliferation of keratinocytes
Wound healing, remodeling, repair
*NEW: activates itch sensory neurons!!
When cAD skin is cultured with IL-13, what happens to periostin levels
Increased –> mnore itch!
Periostin may increased Th2 cytokines
Is periostin increased or decreased in cAD skin
INCREASED (more itch!)
