CAD Flashcards
(32 cards)
What breed of dog has filaggrin mutations been implicated?
Labrador retrievers in the UK, NOT WHWTs. Filaggrin is also implicated in humans with AD
What are some single-nucleotide polymorphisms associated with AD in Goldens?
Prominent 1 (PROM1)
Ras-related protein Rab-3c (RAB3C)
What are some microRNAs that are potential genetic biomarkers in cAD?
- 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)
What genes are potential genetic biomarkers in cAD?
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
What are the actions of phosphodiesterase 4D (PDE4D) which is increased in cAD?
- degrades cAMP
- regulates pro- and anti-inflammatory activities of many immune cells
- involved in epthelial functions including skin barrier
What are the most common allergens of cAD worldwide?
HDM: Der f 2, Der f1 5, Der f 18, and Zen 1
know this
good
What mutations are seen in JAK-STAT signaling associated with atopic dermatitis-like eczema and Staphylococcal colonization?
- 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
What mutations are seen in the stratum corneum barrier associated with atopic dermatitis-like eczema and Staphylococcal colonization?
- loss-of-function mutations in FLG = ichthyosis vulgarism
- loss-of-function mutations in SPINK5 = netherton syndrome
What mutations are seen in the junctional barrier associated with atopic dermatitis-like eczema and Staphylococcal colonization?
- 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
What mutations are seen in keratinocyte differentiation associated with atopic dermatitis-like eczema and Staphylococcal colonization?
- loss-of-function mutations in ADAM17
- loss-of-function mutations in EDFR
What is Job’s syndrome?
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
What mutation causes hyper-IgE syndrome (Job’s syndrome)?
dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) cause the autosomal dominant condition
Why is filaggrin important?
- 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)
What is netherton syndrome?
a red and scaly skin (ichthyosiform erythroderma), atopic manifestations, and S. aureus colonization
What causes netherton syndrome?
Loss-of-function mutations in serine protease inhibitor Kazal type 5 (SPINK5) encoding the lymph-epithelial Kasal-type-related inhibitor (LEKTI)
What does LEKTI (lympho-epithelial Kazal-type-related inhibitor) do and what does a mutation causing loss of function do?
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.
What is the result of mutations in desmoglein 1 and desmoplakin?
severe eczematous dermatitis, multiple allergies and Staph skin infections.
What is the result of a lack of corneodesmosin?
Corneodesmosin is an adhesion protein in corneodesmosomes and lack of it causes epidermal barrier defects, atopic manifestations, and S. aureus infections
What is EGFR and what regulates it?
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
_______ is required for ILC2 development.
Retinoic acid-related orphan receptor alpha
Name the transcription factors activating cytokines, producing cytokines, and functions for natural killer cells and ILC1
T-bet
IL-15, IL-12, IL-18
IFNg, granzyme, perforin
Type 1 immunity, intracellular microbial infections, and cancers
Name the transcription factors activating cytokines, producing cytokines, and functions for ILC2
GATA-3
IL-33, IL-25
IL-4, IL-5, IL-9, IL-13
Type 2 immunity, parasite infections and allergy, metabolic homeostasis
Name the transcription factors activating cytokines, producing cytokines, and functions for lymphoid tissue inducer cells and ILC3
RORgt
IL-1B, IL-23
IL-17, IL-22, TNF
Type 3 immunity, lymphoid tissue development, extracellular microbial infections
