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Syllabus cAD Flashcards

1
Q

increased incidence in CAD:

A

beagle, bichon frise, boxer, bulldog, bull mastiff, great Dane, Labrador retriever, pug, shar-pei, Staffordshire terrier and West Highland white terrier (WHWT)]

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2
Q

new def

A

hereditary, gener- ally pruritic and predominantly T-cell-driven inflamma- tory skin disease,

involving an interplay between skin
barrier abnormalities, allergen sensitisation and mi- crobial dysbiosis

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3
Q

5 breeds predisposed world- wide

A

boxer, bulldog, Labrador retriever, pug and WHWT

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4
Q

AD sensu stricto

A
  • positive intradermal test and/or serological confirmation of allergen-specific immunoglobulin (Ig)E
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5
Q

atopic-like dermatitis

A

clinical diagnosis of AD, negative intradermal test and negative serological results

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5
Q

Genes associated with AD

A
  1. fillagrin- LR
  2. PROM 1 (prominin 1) -GR
  3. RAB3C (ras-related protein Rab-3c)-GR
  4. high IgE -chromsome 5 (LR),35 (WHWT)
    +GSD-PKP2 (but it was latter disputed)
  5. chromosome 3 (CFA), F2R (thrombin receptor/member of PAR familiy)- WHWT
  6. WHWT-CFA17 with a candidate gene PTPN22
  7. SNPs in IL-4R and IL-13-
    IL-4R Cys 688 variant reduces the risk of AD in dachshund
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6
Q

PTPN22- for what is it used

A

protein tyrosine phosphatase nonreceptor type 22
-involved in the negative regulation of both the innate and adaptive (via downregulation both B- and T-cell receptor signalling) immune response

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7
Q

how are miRNA inflencing allergies

A

-influence the cells of the innate and adaptive immune system including the keratinocytes, thereby potentially affecting the course of the disease.
-biomarker

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8
Q

studies on miRNA genes

A
  1. incerased PDE4D in PBMC
  2. decrease of PIAS1, RORA and SH2B1
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9
Q

protective factors in human AD

A

-growing up in a rural environment
-contact with farm animals (“farming effect”)
- a diet rich in dietary fibre
-high food diversity
-early contact with siblings or peers

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10
Q

Protective factors for AD in dogs

A

-living with another dog
-been born in the current owner’s household
-living in a detached house (compared to an apartmen
-nonprocessed meat-based diet early in life
-living with another dog
-walking in wood, fields, beaches

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11
Q

Risk facors in dogs

A

-dogs living in extremely clean households
-urban environment
-receiving flea control
-being allowed on furniture

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12
Q

Does the exposure to endotoxins and microbial proteases has a protective effect for AD

A

-no stat significance

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13
Q

synthetic triacylated lipopeptide (TLR1/2 ligand) cell-wall component of Staphylococcus spp. induces what

A

TSLP via Toll-like receptor 2 (TLR2) activation in a canine keratinocyte cell line

-contriubutes to Th2 response ?

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14
Q

do dogs with non food-induced AD have a risk for sensitization to M. pachydermatis

A

-yes
-11/15 dogs

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15
Q

Does the T. canis has a protecive role in AD

A

YES
-infected dogs higher levels of T. canis spec IgG, IgE, D.faine IgE and total IgE and LOWER LESIONAL SCORES and SHORTER DURATION of pruritus

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16
Q

Which protease groups of HDM promote allergic sensitisation

A
  1. cysteine (group 1 mite allergens)
  2. serine ( group3, 6,9 allergens)
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17
Q

What is thought the moa for serine proteases in AD

A

-D.farinae-derived serine can upregulate IL-33 mRNA expression via protease-activated receptor-2 (PAR-2) activation

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18
Q

Group 2 and 7 mite allergens are speculated to play a role in what

A

TLR interactions

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19
Q

Dermatophagoides genus is the most common allergen in dogs (h). what is positivity rate

A

-60-90%
≤63% of clinically healthy dogs can show positive IDT reactions to HDM, while ASIS can be positive in ≤97% of cases.

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20
Q

How common are other dust and storage mite allergies

A

Tyrophagus putrescentiae (36%–80%)
Acarus siro (18%–80%)

(≥45%) co-sensitised to house dust and storage mites
-parallel exposure and sensitization, in vitro cross reactivity

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21
Q

Most common plant based allergens

A

Japan-Japanese cedar
+Bermuda rye, fescue
-South Korea-ash, sage, Johnson grass, plantain, oak, white ash, seeps sorrrel, mugwort, Bermuda grass

-pollen reacivity is increased during summer and autumn!

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22
Q

What are miRNAs?

A

short, single-stranded RNA molecules, of about 22 nu- cleotides in length, that play a role in the regulation of gene expression at the post-transcriptional level

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23
Q

Do molds play a role in sensitization of AD dog

A

-Rhizopus and mold mix- 2nd most common after HDM
+ in one study it was + 67% patients

-ASIS-44.8 % for Pullalaria and 39.6% Alternaria
-Aspergillus in 39.6%
-variable results depending on geographical and climatic factors

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24
Q

What is the rate of positivity to Malassezia

A

ASIS- 21.9-60%
IDT-24-73%

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25
Q

What is major allergen

A

if ≥50% of patients allergic to the “parent” allergen source have detectable positive IgE serological results or immediate skin test reactivity

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26
Q

Major allergens in dogs

A
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27
Q

Major allergens in humans

A

D.pteronyssinus (Der p 1 and Der p 2)
D. farinae (Der f 1 and Der f 2)

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28
Q

What are the potential genetic biomarkes of cAD

A

miR- 141, miR-187, miR-200a, miR-203, miR-215 and miR-429

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29
Q

General info about IL-33

A

-member of the IL-1 cytokine family
- binds to IL-1 receptor family member suppression of tumorigenicity 2 (ST2)

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29
Q

Where is IL-33 expressed

A

constitutively expressed as a nuclear protein in epithelial tissues of various organs, such as the lung, stomach and skin

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30
Q

How is IL-33 released

A

It is released extracellularly upon tissue damage and cell death or cell stress, and functions as an endogenous danger signal (alarmin)

-released full-length IL-33 is already active,
+ it can be processed by inflammatory proteases into a shorter ‘hyperactive’ mature form to further enhance allergic inflammation

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31
Q

How is IL-33 up or down regulated in skin/blood

A

-higher transcription levels in ch lesions of AD (when compared to helathy)
-expressed in KC, endothelial cells and dermal infiltrating cells in AD skin (IHC)
(no staining in helathy skin)

+ higher transcription levels in skin lesions with EXCORIATIONS (slef trauma may be associated with up regulation?)

-mRNA was upregulated in skin and PBMC in expterimnetal AD dogs

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32
Q

What is TSLP

A

epithelial cell-derived cytokine

-has a critical role in linking events between the body and environment to Th2 responses and the development of allergic inflammation
-might be involved in induction of flares in AD

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33
Q

How can be TSLP upregulated

A

-trypsin (a protease activated receptor-2 , PAR-2)- receptor for HDM derived proteases
-synthetic triacylated lipopeptide (TLR1/2 ligand)- receptors for membrane proteins of Staphylococcus

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34
Q

What staining pattern is seen with TSLP and cAD

A

-condensed staining pattern in SB

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35
Q

What is CCL17

A

-C-C motif chemokine ligand 17
-thymus and activation regulated chemokine (TARC),

  • potent Th2 chemoattractant via its receptor CCR4 that is selectively expressed on Th2 cells
    -PAR -2 agonist causes production of TARC
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36
Q

IS CCL17 up or down regulated in cAD

A

-upregulated
-significant differnece between helathy and lesional skin (but not with non-lesional)

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37
Q

Does CCL17 correlates with diseae severity- dog, people?

A

-hAD- correlates with disease severity
-serum CCL17/TARC concentration showed moderate correlation with CADESI-04

+ after tretamnet with GC, oclacitinib- significant reduction of CCL17

-biomarker

38
Q

Has CCR4 inhibitor (AZ445) been tesed in dogs?

A

-no significant overall reduction of CADESI-03 scores

BUT, five treated dogs (35%) showed a moderate clinical improvement (40% reduction of CADESI-03 scores) with a reduction of acanthosis and dermal inflammation

39
Q

What is CCL22?

A

C-C motif chemokine ligand 22, also known as macrophage-derived chemokine (MDC),
-another ligand for CCR4;

40
Q

What is the function of CCL22

A

-CCL22/MDC also can recruit Th2 cells to the inflammatory loci of AD skin.

41
Q

Any stuides about CCL22 in dogs

A

-upregulation of CCL22/MDC mRNA expression in both lesional and nonlesional skin

-positive correlation with pVAS and CADESI-04 scores

-might play an essential role in the pathogenesis of Th2-dominated cAD skin lesion

42
Q

Role of IL-4

A

-potent regulator of immunity
-primarily secreted by Th2 cells, mast cells, eosinophils and basophils

-important role in leucocyte survival in Th2 cell-mediated immune responses and in IgE class switching of B cells;

43
Q

How is IL-4 expressed in cAD

A

-variable
-HDM-induced cAD-elevated mRNA & protein expression in skin

4 studies using serum-no difference betwen healthy and AD dogs

-Incerased expression of IL-4RA (alpha subunit) in skin, but IL-4 levels remain uncahnged (incerased susceptibility in the skin? )

-maybe plays a role during acute flares / induction , diffrenet phenotypes of AD
-during 1 year oclacitinib- no change in % of IL-4 producing T regs

44
Q

Importance of IL-5

A

produced primarily by Th2 cells and mast cells

-induces survival, activation and migration of eosinophils;

45
Q

Do we see some imporvement with mepolizumab (anti IL-5) and is it elevated

A
  • upregulated mRNA in skin of diffrenet AD models
    -limited success in humans
46
Q

What are the functions of IL-13

A

-contributes to IgE production
- differentiation of T cells towards the Th2 subtype.

47
Q

Name mAb for IL-13

A

-dupilumab (the monoclonal an- tibody targeting the common receptor of IL-4 and IL-13; IL-4RA)

-lebrikizumab and tralokinumab

48
Q

Is IL- 13 up or down regulated in cAD?

A

increased mRNA or protein levels of IL-13 in either skin or blood (sera or PBMCs)

49
Q

How many mRNA splice variants of IL-31 receptor alpha subunit (IL-31RA) are in dogs and how many protein forms do they encode

A
  • 5 varinats

-encode 2 protein isoforms:
1. the full-length isoform X1
2. truncated isoform X2 (lacks the N-terminal signal peptide and parts of the cytokine-binding domain; therefore, it may not bind to IL-31)

50
Q

Is there a diffrence between transcription of isoform X1 and X2

A

-transcription of IL-31RA X2 was significantly higher than that of IL-31RA X1 in both HDM-induced atopic and healthy dogs

  • the difference in the function remains to be confirmed
51
Q

Has IL-31RA been demonstraed on dorsal root ganglia neurons and in nerve fibers in the skin

A

yes

52
Q

Is there a connection between anti-IL 31 and TEWL

A

-decreased trans epidermal water loss (TEWL) during 12weeks of treatment
-suggesting a direct or indirect contribution of excessive IL-31 to skin barrier dysfunction

53
Q

When used proactively, lokivetmab prevents flares in what %

A

-for more than one year in 28% of client-owned dogs, when it was used as proactive monotherapy

54
Q

Is there any evidence for anti-IL31 vaccine in cAD

A

-IL-31 coupled to virus-like particles
- induced the production of anti-IL-31 antibodies
- resulted in an apparent reduction of itching (HDM)

55
Q

Function of IFN-gamma

A

-produced by Th1 cells, Tc cells and natural killer cells
-promoting Th1 responses by enhanc- ing antigen presentation and inhibiting viral replication
-inhibits Th2 immune responses.

56
Q

Are Th1 cytokines incerased or decerased in cAD

A

-inconsistent
-1 study incerased mRNA in PBMC
-reduced in serum, plasma and PBMC

-after oclacitinib: reduced on day 240,300

57
Q

WHich cytokines are considered as IFN-gamma inducing factors

A

-Interleukin-12, IL-15 and IL-18

-part of the Th1 cy- tokine group.88

58
Q

Are T regs elevated or decerased in cAD

A

-controversial results
-probable functional insufficeny of T regs

-AIT - presumed action inceraseing i
IL-10, and TGF-beta but study from 2021 could not find any difference after 1 year of ASIT

59
Q

Function of IL-17

A

-IL-17A-F

  • potent inducers of local tissue inflammation through the upregulation of proinflammatory and neutrophil-mobilising cytokines- IL-6, GM-CSF, TNF-alpha, IL-1 beta..
60
Q

IL-17A showed upregulation of what cytokines in canine

A

-IL19, GM-CSF, S100 A8, IL-8,
+ plays a role in Th2 associated inflammation

-no upregulation of CCL17, CCL22, IFN-gama

61
Q

Is IL-17 up or down regulated

A

-up in PBMC
-down in skin (mRNA)

62
Q

IL-22 ?

A

-activator of keratinocyte proliferation
- induce the expression of epidermal host defence peptides (HDPs), such as S100A7, S100A8, S100A9, β-defensins and cathelicidin, and neutrophil chemoattractants, such as CXCL1, CXCL5 and CXCL

63
Q

IL-7 roles

A

-haematopoietic growth factor
-secreted by stromal cells in the bone marrow and thymus, although it is also produced by keratinocytes

-development and homeostasis of immune cells, including CD4+ memory T cell

64
Q

DOwn or upregulated IL-7

A

-up in cAD

65
Q

IL-34 ?

A

-expressed by keratinocytes and by neurons in the brain

66
Q

Il-34 in cAD

A

-higher serum IL-34 concentrations compared to healthy dogs with a significant positive correlation with CADESI-04 and pVAS scores

+ remained increased after GC and olcacitinib

67
Q

IL-36

A

-expressed mainly on the barrier sites of the body- bronchial, intestinal and dermal epithelium
-secreted in an inactive form and activated by different proteases
-associated with host defence against pathogenic microbes- Staphyloccoucus + for amplification of inflammation
-upregulated

68
Q

MIF - macrophage migration inhibitor factor

A

-expressed on both immune and nonimmune cells
-involved in T-cell activation and delayed-type hypersensitivity by recruiting and activating macrophages at inflammatory loci

69
Q

MIF -up or down regulated

A

-upregulated in cAD in serum but no correlation between CADESI-04 or pVAS

70
Q

Which factors are associated with neurogenic inflammation and how do they promote ch AD

A

-NGF, Substance P, periostin
-promoting vasodilation and leucocyte-mediated inflammation

71
Q

NGF?

A
  • keratinocytes and promotes the growth
    fibroblasts, epithelial and endothelial cells
71
Q

-NGF- elevated or down

A

-up 6 h after allergen challenge
-decrease after 48 h

-NGF+ KC increased in lesional skin after 72h of epicutaneous exposure

-involved in flares ?

72
Q

Substance P - up or downregulated

A

-up by RNA-seq analysis in lesional skin , but mRNA did not change in ac canine model of HDM-induced skin lesions

73
Q

Substance P -role

A

secreted from free nerve endings in the skin, keratinocytes and various inflammatory cells
- may induce cutaneous inflammation

74
Q

Periostin- role

A

-extracellular matrix protein secreted by produced by keratinocytes and promotes the growth fibroblasts, epithelial and endothelial cell

-promotes differentiation and migration of fibroblasts and proliferation of keratinocytes
-a critical role in the remodelling and repair of damaged tissues
-directly activates itch sensory neurons - robust itch

75
Q

Periostin- down or up regulated

A

-up

76
Q

Which cermides are most commonly altered in cAD

A

-ceramide 1/CER[EOS],
-ceramide 9/CER[EOP]
-ceramide CER[NP]

77
Q

HOw are corneocytes changed in AD

A

-SC of atopic dogs is characterised by a hexagonal lipid packing
-instead of the classic orthorhombic packing characteriing the lamellar organisation of lipids in healthy skin

+ decrase in relative abundance of free fatty acids

-decreased ratio of CER[NS] C44/C34 was seen in atopic skin

78
Q

cutaneous dysbiosis definition

A

an imbalance in the composition of microbial population associated with reduction in microbial diversity and in the number of beneficial bacteria

79
Q

Which Malassezia predominates in helathy dogs

A

M. globosa

80
Q

What bacteria were found in AD ears compared to helathy

A

Staphylococcus spp. (Firmicutes) Ralstonia spp. (Proteobacteria) organisms

+ higher abundance of E. coli in healthy

81
Q

Is there a differnce in bacteria diversity in helthy dogs in different areas

A

-no difference in bacterial diversity among the different body sites of healthy dogs
-most abundant bacterial phyla, in descending order, included Actinobacteria, Proteobacteria, Firmicutes and Bacteroidetes

82
Q

What phya was found in dogs with AD regarding bacetrial diversity

A

-no difference in bacterial diversity among body sites
- most abundant organisms belonging to the phyla Proteobacteria and Actinobacteria,
followed by Firmicutes and Bacteroides

83
Q

What was the conclusion in GSD with and without AD about bacterial diversity

A

atopic German shepherd dogs have a different bacterial community composition and a lower diversity when compared to healthy dogs of the same breed.

84
Q

What are the bactera and fungi present in healthy dogs

A

-Cutibacterium acnes, S.pseudinter- medius, Porphyromonas cangingivalis, Capnodiales,

-unclassified fungal species and Alternaria

85
Q

In clinically affeted dogs with AD , what bacteria were found

A

-S.pseudintermedius and S.schleiferi.
-Bacteroides pyogenes and Peptoniphilus grossensis

86
Q

From clinically affeted ears , what bactera and fungi were isolated

A

M.pachydermatis, S.pseudintermedius, S.schleiferi and a few anaerobic bacteria such as Finegoldia magna, Peptostreptococcus canis and P. cangingivalis.

87
Q

Bacteria and fungi found in helthy ears

A

C. acnes, S. pseudintermedius, Streptococcus sp. and the top three most dominant fungi included M. pachydermatis, Capnodiales and Pleosporales

88
Q

What effect did malasseb had on microbial diversity when bathed 2 x weekly for 3 weeks

A
  • no difference in bacterial micorbiome
    -decerase in diversity of Epicoccum and Blumeria in heathy and atopic skin!
89
Q

What was the effect of phototherapy on microbiome in healthy and atopic dogs

A

-phototherapy was associated with a significantly increased relative abundance of Actinobacteria and Cyanobacteria in atopic dogs

-phototherapy resulted in an overall decrease in S.pseudintermedius in atopic dogs.

90
Q

Did the skin was fluid from AD dogs had lower or increasd inhibitory activiti againts Spathylocci and why

A

-lower inhibitory activity
-it suggest poorer antimicrobial activity

91
Q

What did the immuno-scanningelectron microscopy showed in atopic skin and healthy regarding AMP

A

Atopic skin - higher levels of HDP/AMPs retained inside the keratinocytes and a lower level secreted in the supernatant compared to healthy skin

-canine β-defensin 103 was retained on the outermost layer of the SC and the number of bacteria-adhered peptides was higher in atopic when compared to healthy skin

92
Q

What is the conclusion regading AMP in AD

A

-atopic skin shows higher HDP/AMP gene expression nonassociated with an increase in protein expression

-dysregulation in the :
secretion (tendency to be retained in the keratinocytes),
dispersion (tendency to remain attached on the skin surface),
antimicrobial efficacy (lower antibacterial inhibitory effect)

of atopic compared to healthy HDPs.

93
Q

What was concluded in AMP in ears between healthy and atopic dogs

A
  • decreased amount of cBD3-like and cCath in noninfected ears of atopic dogs when compared with healthy ears

MS (20 decks)

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