CAD

Question 1

What breed of dog has filaggrin mutations been implicated?

Answer 1

Labrador retrievers in the UK, NOT WHWTs. Filaggrin is also implicated in humans with AD

Question 2

What are some single-nucleotide polymorphisms associated with AD in Goldens?

Answer 2

Prominent 1 (PROM1)
Ras-related protein Rab-3c (RAB3C)

Question 3

What are some microRNAs that are potential genetic biomarkers in cAD?

Answer 3

• miR-141, miR-200a, miR-429 (decreased in both lesional and nonlesional compared to healthy and may be involved in skin barrier defects)
• miR-187 (decreased in lesional skin, may be associated with decreased TGFb expression)
• miR-203 (increased in plasma of AD dogs)
• miR-215 (decreased in lesional skin of atopic dogs, increased in healthy and non-lesional: anti-inflammatory, possibly through suppression of IL-17 receptor activation)

Question 4

What genes are potential genetic biomarkers in cAD?

Answer 4

INCREASED
PED4D: phosphodiesterase 4D

DECREASED
PIAS1: Protein inhibitor of activated STAT 1
RORA: RAR-related orphan receptor A (downregulation may decrease serum IL-10)
SH2B1: SH2B adaptor protein 1

Question 5

What are the actions of phosphodiesterase 4D (PDE4D) which is increased in cAD?

Answer 5

• degrades cAMP
• regulates pro- and anti-inflammatory activities of many immune cells
• involved in epthelial functions including skin barrier

Question 6

What are the most common allergens of cAD worldwide?

Answer 6

HDM: Der f 2, Der f1 5, Der f 18, and Zen 1

Question 7

know this

Answer 7

good

Question 8

What mutations are seen in JAK-STAT signaling associated with atopic dermatitis-like eczema and Staphylococcal colonization?

Answer 8

• Dominant negative mutations in STAT3 = Autosomal dominant hyper immunoglobulin (IgE) syndrome
• gain-of-function mutations in STAT3
• Loss-of-function mutations in STAT5B
• Gain-of-function in JAK1

Question 9

What mutations are seen in the stratum corneum barrier associated with atopic dermatitis-like eczema and Staphylococcal colonization?

Answer 9

• loss-of-function mutations in FLG = ichthyosis vulgarism
• loss-of-function mutations in SPINK5 = netherton syndrome

Question 10

What mutations are seen in the junctional barrier associated with atopic dermatitis-like eczema and Staphylococcal colonization?

Answer 10

• loss-of-function mutations in DSG1 = severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome
• dominant heterozygous mutations in DSP
• loss-of-function mutations in CDSN = peeling skin syndrome

Question 11

What mutations are seen in keratinocyte differentiation associated with atopic dermatitis-like eczema and Staphylococcal colonization?

Answer 11

• loss-of-function mutations in ADAM17
• loss-of-function mutations in EDFR

Question 12

What is Job’s syndrome?

Answer 12

also called hyper-IgE syndrome (STAT-HIES), a monogenic disorder characterized by elevated serum IgE levels, AD-like eczema, recurrent staphyococcal infections and mucocutaneous candidiasis; AD-like eczema is attenuated by Staphylococcus clearance measures, reinforcing the role of S. aureus in driving atopic inflammation

Question 13

What mutation causes hyper-IgE syndrome (Job’s syndrome)?

Answer 13

dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) cause the autosomal dominant condition

Question 14

Why is filaggrin important?

Answer 14

• Filaggrin breakdown products act as natural moisturizing factors (NMFs) and are important for stratum corneum hydration and the maintenance of skin surface pH
• Acidic conditions modulated by NMFs disfavor S. aureus growth
  (the skin of patients with AD tends to be alkaline which favors S. aureus colonization and the pH shifts can be facilitated in part by FLG-deficiency, increased stratum corneum pH activates proteases which cleave IL-1 family cytokines in keratinocytes)

Question 15

What is netherton syndrome?

Answer 15

a red and scaly skin (ichthyosiform erythroderma), atopic manifestations, and S. aureus colonization

Question 16

What causes netherton syndrome?

Answer 16

Loss-of-function mutations in serine protease inhibitor Kazal type 5 (SPINK5) encoding the lymph-epithelial Kasal-type-related inhibitor (LEKTI)

Question 17

What does LEKTI (lympho-epithelial Kazal-type-related inhibitor) do and what does a mutation causing loss of function do?

Answer 17

LEKTI inhibits kallikrein family proteases which control desquamation of the epidermis
The lack of LEKTI function allows enhanced proteolytic activity in the epidermis leading to abnormal formation of the stratum corneum and S. aureus colonization
Activation of kallikrein results in the up regulation of proteinase-activated receptor 2 and induces nuclear factor k B-mediated over expression of TSLP, which promotes Type 2 immune responses that contribute to atopic inflammation.

Question 18

What is the result of mutations in desmoglein 1 and desmoplakin?

Answer 18

severe eczematous dermatitis, multiple allergies and Staph skin infections.

Question 19

What is the result of a lack of corneodesmosin?

Answer 19

Corneodesmosin is an adhesion protein in corneodesmosomes and lack of it causes epidermal barrier defects, atopic manifestations, and S. aureus infections

Question 20

What is EGFR and what regulates it?

Answer 20

Epidermal growth factor receptor signaling is regulated by the upstream disintegrin and metalloprotease domain 17 (ADAM17) via the release of the membrane-bound form of EGFR ligands; keratinocyte specific depletion of ADAM17 in mice resulted in chronic atopic-like dermatitis with barrier impairment with dysbiosis; deletion of EGFR in the epidermis of mice led to S. aureus overgrowth and atopic-like dermatitis resembling the skin phenotype of ADAM17-deficient mice and loss-of-function mutations in EGFR share clinical features with ADAM17 deficiency in humans and cutaneous adverse effects including dry, erythematous skin, and bacterial skin infections including S. aureus are often observed in patients treated with EGFR inhibitors during cancer therapy

Question 21

_______ is required for ILC2 development.

Answer 21

Retinoic acid-related orphan receptor alpha

Question 22

Name the transcription factors activating cytokines, producing cytokines, and functions for natural killer cells and ILC1

Answer 22

T-bet
IL-15, IL-12, IL-18
IFNg, granzyme, perforin
Type 1 immunity, intracellular microbial infections, and cancers

Question 23

Name the transcription factors activating cytokines, producing cytokines, and functions for ILC2

Answer 23

GATA-3
IL-33, IL-25
IL-4, IL-5, IL-9, IL-13
Type 2 immunity, parasite infections and allergy, metabolic homeostasis

Question 24

Name the transcription factors activating cytokines, producing cytokines, and functions for lymphoid tissue inducer cells and ILC3

Answer 24

RORgt
IL-1B, IL-23
IL-17, IL-22, TNF
Type 3 immunity, lymphoid tissue development, extracellular microbial infections

Question 25

What are the ceramides most frequently found to be altered in AD compared to healthy controls?

Answer 25

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

Question 26

What is the ratio of ceramides in affected skin that has a nonlinear negative correlation with the clinical severity of AD?

Answer 26

decreased ratio of CER[NS] C44/C34; the spatial organization and carbon atom composition of ceramide may be as important as the amount of ceramides present in the SC of atopic skin

Question 27

What is the organization of lipids in the stratum corneum of AD dogs and how does that compare to healthy skin?

Answer 27

SC of atopic dogs characterized by a hexagonal lipid packing instead of the classic orthorhombic packing characterizing the lamellar organization of lipids in healthy skin

Question 28

Which of the following structural proteins had heterogenous immunoreactivity and reduced intensity after a single HDM epicutaneous challenge?
E-cadherin
desmocollin-1
desmoglein-1
corneodesmosin
claudin-1

Answer 28

corneodesmosin and claudin-1

Question 29

What tight junction proteins have been shown to be significantly decreased in skin of atopic dogs?

Answer 29

claudin-1 and occludin

Question 30

What structural protein has decreased expression and distribution in atopic skin?

Answer 30

corneodesmosin

Question 31

What is the S100 fused-type protein involved in the production of natural moisturizing factors (NMFs) and is an integral component of the cornified envelope?

Answer 31

Filaggrin 2

Question 32

What are some host defense peptides that have been shown to have increased gene expression in the skin of atopic dogs?

Answer 32

B-defensins (like B-defensin 103) and cathelicidin