Skin Barrier Defect in Pathogenesis of cAD (NAVDF Santoro)

Question 1

4 major branches of the skin barrier

Answer 1

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)

Question 2

Length of a normal skin turnover cycle

Answer 2

21 days

Question 3

What layer are lamellar bodies formed

Answer 3

Stratum spinosum

Question 4

What layer are keratohyalin bodies formed

Answer 4

Stratum spinosum

Question 5

Where is the cornified envelope formed

Answer 5

Transition between stratum granulosum and stratum corneum

Question 6

During formation cornified envelope, what is dumped from lamellar bodies into the intercellular space (via fusion with cell membrane)

Answer 6

-Ceramides
-Free fatty acids
-Cholesterol

–> becomes the lipid envelope

Question 7

What “leaves the body” during desquamation

Answer 7

-Corneocytes
-Allergens
-Microbes

Question 8

What is the main physical blocker against penetration of external agents in the deeper epidermis?

Answer 8

Tight junctions in SG2

Question 9

What are the filaggrin degredation products

Answer 9

Urocanic acid
Carboxylic pyrrolidone

Question 10

What are the roles of urocanic acid and carboxylic pyrrolidone

Answer 10

*Maintain skin pH (ideally, slightly acidic)
*Limit TEWL

Question 11

How are there “holes” in the skin barrier

Answer 11

*Decreased corneodesmosin –> corneocytes are not holding on
*Decreased tight junctions (downreg occludin, claudin)
*Disorganization of lipid lamellae –> goodbye orthorhombic conformation, hello hexagonal conformation

Question 12

What is the result of decreased natural hydration factors

Answer 12

*Increase in skin pH (neutral to basic)
*Activation of serum proteases –> further degradation of corneodesmosomes –> less cell cohesion

Question 13

Which ceramides are reduced in cAD?

Answer 13

*1, 3, 5, 9

*Ceramide 1 / CER [EOS]
*Ceramide 9 / CER [EOP]
*Ceramide [NP]

Question 14

How are lipid lamellae normally arranged?

Answer 14

Orthorhomic conformation

Question 15

How are lipid lamellae arranged in cAD skin?

Answer 15

Hexagonal conformation

Question 16

Name 2 antimicrobial peptides

Answer 16

Defensins
Cathelicidin
S100A proteins

(decreased in cAD)

Question 17

Why might defensins and cathelicidins be less effective in cAD skin?

Answer 17

They are bound tightly to corneocytes rather than being released and attacking microbes

They are retained inside cell, not on surface, so nonfunctional

Question 18

How do DCs worsen pathogenesis of cAD?

Answer 18

*Activated DC can extend dendrites to higher levels in epidermis, reaching farther for allergens
*DCs have increased FcR for IgE

Question 19

How are T cell populations skewed in cAD?

Answer 19

*Decreased TReg
*Increased Th2
*More non-specific inflammatory cytokines

Question 20

What is the resident yeast population on canine skin?

Answer 20

Malassezia restrica

Question 21

What is the predominant yeast species on cAD skin?

Answer 21

Malassezia pachydermatis

Question 22

How does dysbiosis affect skin pH and TEWL?

Answer 22

*Increased skin pH (more neutral, basic)
*Increased TEWL

Question 23

How do urocanic acid and carboxylic pyrrolidone (NMFs) affect skin pH and protease activity?

Answer 23

Decrease pH (more acidic)

Acidic pH INHIBITS protease activation

Question 24

Difference between how Staphylococcus intermedis and aureus interact with keratinocytes

Answer 24

*Intermedius sits on TOP of cells. Bacterial ALSO on TOP of cells

*Aureus sits at junctions BETWEEN cells

*Intermedius desquamates, along with allergens

Question 25

T or F: it is normal to have Staphylococcus epidermidis in the dermis of the skin

Answer 25

TRUE.

It can stimulate keratinocytes to make more B-defensins

(Also some Pseudomonas in the adipose)

Question 26

Outside-Inside-Outside theory

Answer 26

Primary defects in cutaneous barrier in AD → penetration of more allergens, stimulates immune system → exacerbation of skin barrier defect
***

Question 27

T or F: there is a decrease in ceramides in NONlesional cAD skin?

Answer 27

True

Question 28

Which fungal organisms are most abundant on cAD dogs?

Answer 28

Alternaria
Cladosporidium

Question 29

Poor antimicrobial diversity correlates to ______ score

Answer 29

CADESI