Skin Barrier Defect in Pathogenesis of cAD (NAVDF Santoro) Flashcards
4 major branches of the skin barrier
1) Physical (disorganized lamellar layers, reduction of CER 1, CER 9, CER; Lipids organized as hexagonal; decreased claudin/occludin of tight junctions, corneodesmosin)
2) Chemical (Decreased antimicrobial peptides; natural hydration factors, lysozyme, phosphlipase A)
3) Immunological (Treg downregulated, Th2 increased. Hyperactive DC with extra IgE R. Keratinocyte alarmins, chemokines)
4) Microbiological (Dysbiosis; more Staphylococcus. Switch from M restricta to pachydermatis. Bacteria adhere to corneocytes more than normal)
Length of a normal skin turnover cycle
21 days
What layer are lamellar bodies formed
Stratum spinosum
What layer are keratohyalin bodies formed
Stratum spinosum
Where is the cornified envelope formed
Transition between stratum granulosum and stratum corneum
During formation cornified envelope, what is dumped from lamellar bodies into the intercellular space (via fusion with cell membrane)
-Ceramides
-Free fatty acids
-Cholesterol
–> becomes the lipid envelope
What “leaves the body” during desquamation
-Corneocytes
-Allergens
-Microbes
What is the main physical blocker against penetration of external agents in the deeper epidermis?
Tight junctions in SG2
What are the filaggrin degredation products
Urocanic acid
Carboxylic pyrrolidone
What are the roles of urocanic acid and carboxylic pyrrolidone
*Maintain skin pH (ideally, slightly acidic)
*Limit TEWL
How are there “holes” in the skin barrier
*Decreased corneodesmosin –> corneocytes are not holding on
*Decreased tight junctions (downreg occludin, claudin)
*Disorganization of lipid lamellae –> goodbye orthorhombic conformation, hello hexagonal conformation
What is the result of decreased natural hydration factors
*Increase in skin pH (neutral to basic)
*Activation of serum proteases –> further degradation of corneodesmosomes –> less cell cohesion
Which ceramides are reduced in cAD?
*1, 3, 5, 9
*Ceramide 1 / CER [EOS]
*Ceramide 9 / CER [EOP]
*Ceramide [NP]
How are lipid lamellae normally arranged?
Orthorhomic conformation
How are lipid lamellae arranged in cAD skin?
Hexagonal conformation
Name 2 antimicrobial peptides
Defensins
Cathelicidin
S100A proteins
(decreased in cAD)
Why might defensins and cathelicidins be less effective in cAD skin?
They are bound tightly to corneocytes rather than being released and attacking microbes
They are retained inside cell, not on surface, so nonfunctional
How do DCs worsen pathogenesis of cAD?
*Activated DC can extend dendrites to higher levels in epidermis, reaching farther for allergens
*DCs have increased FcR for IgE
How are T cell populations skewed in cAD?
*Decreased TReg
*Increased Th2
*More non-specific inflammatory cytokines
What is the resident yeast population on canine skin?
Malassezia restrica
What is the predominant yeast species on cAD skin?
Malassezia pachydermatis
How does dysbiosis affect skin pH and TEWL?
*Increased skin pH (more neutral, basic)
*Increased TEWL
How do urocanic acid and carboxylic pyrrolidone (NMFs) affect skin pH and protease activity?
Decrease pH (more acidic)
Acidic pH INHIBITS protease activation
Difference between how Staphylococcus intermedis and aureus interact with keratinocytes
*Intermedius sits on TOP of cells. Bacterial ALSO on TOP of cells
*Aureus sits at junctions BETWEEN cells
*Intermedius desquamates, along with allergens
T or F: it is normal to have Staphylococcus epidermidis in the dermis of the skin
TRUE.
It can stimulate keratinocytes to make more B-defensins
(Also some Pseudomonas in the adipose)
Outside-Inside-Outside theory
Primary defects in cutaneous barrier in AD → penetration of more allergens, stimulates immune system → exacerbation of skin barrier defect
***
T or F: there is a decrease in ceramides in NONlesional cAD skin?
True
Which fungal organisms are most abundant on cAD dogs?
Alternaria
Cladosporidium
Poor antimicrobial diversity correlates to ______ score
CADESI
