1. Barrier function and immunology of the skin: skin health and skin disease
Julia Schofield

2. Barrier function
Why does it matter?

3. Childhood eczema Eczema is common Mild, moderate or severe
20% under one year olds
Big impact on families
Recent research shows importance of barrier function
Relevant to eczema of all types in all ages

4. Barrier function and atopic eczema

5. A Healthy Skin Barrier NMF H2O NMF H2O NMF H2O Filaggrin Profilaggrin
Swelled corneocytes
Cornified envelope
Intact Corneodesmosomes
Lipid Lamellae
pH 5.5
NMF
H2O
NMF
H2O
NMF
H2O
Degradatory Proteases
Protease Inhibitors
Profilaggrin
Filaggrin
Lipid delivery
Lipid processing
Corneocytes are filled with natural moisturising factor, a collection of natural humectants which maintain skin hydration
The constituents of NMF are derived from profilaggrin, a structural component of the CE expressed during keratinocytes differentiation.
NMF is important for maintaining an acid environment at the outer surface of the SC
In order to balance the introduction of new cells in the basal layer of the epidermis, mature corneocytes are shed from the surface of the SC is a process referred to as desquamation.
Desquamation involves the degradation of the extracellular corneodesmosomes by a cocktail of proteases regulated by protease inhibitors.
The optimum pH for serine protease activity is slightly alkaline in contrast to the normal acidic pH of the skin.
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield. 5

6. Lipid delivery & processing Natural moisturizing factor
A Healthy Skin Barrier
Lipid Lamellae
Ceramide: cholesterol:
fatty acids
Cornified envelope
Lipid delivery & processing
Swelled corneocytes
Filaggrin
NMF
H2O
Natural moisturizing factor
Urocanic acid, Pyrrolidone carboxylic acid, lactic acid, urea
Intact corneodesmosomes
pH 5.5
Degradatory proteases
Protease inhibitors
Corneocytes are filled with natural moisturising factor, a collection of natural humectants which maintain skin hydration
The constituents of NMF are derived from profilaggrin, a structural component of the CE expressed during keratinocytes differentiation.
NMF is important for maintaining an acid environment at the outer surface of the SC
In order to balance the introduction of new cells in the basal layer of the epidermis, mature corneocytes are shed from the surface of the SC is a process referred to as desquamation.
Desquamation involves the degradation of the extracellular corneodesmosomes by a cocktail of proteases regulated by protease inhibitors.
The optimum pH for serine protease activity is slightly alkaline in contrast to the normal acidic pH of the skin.
5/28/2019
Danby SG & Cork MJ, The Academic Unit of Dermatology Research, The University of Sheffield. 6

7. Allergens & Irritants Water pH 5.5 NMF H2O
The normal intact SC acts as an efficient barrier to the penetration of irritants and allergens and to the loss of water. Barrier function is often determined by measuring TEWL
Water
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield. 7

8. Brick => Corneocyte
Mortar => Lipid Lamellae
3/26/09
The Academic Unit of Dermatology Research, University of Sheffield 8

9. Mortar => Lipid Lamellae
Ceramides +
Fatty acids
Cholesterol
3/26/09
The Academic Unit of Dermatology Research, University of Sheffield 9

10. The Normal Skin Barrier
3/26/09
The Academic Unit of Dermatology Research, University of Sheffield
Cork et al 2006 JACI 10

11. Irritants & allergens
The normal intact SC acts as an efficient barrier to the penetration of irritants and allergens and to the loss of water. Barrier function is often determined by measuring TEWL
5/28/2019
Danby SG & Cork MJ, The Academic Unit of Dermatology Research, The University of Sheffield. 11

12. What goes wrong in childhood eczema?

13. Infant skin has a low epidermal barrier reserve (i)
(i)Nikolovski J, Stamatas GN, Kollias N, Wiegand BC. J Invest Dermatol Jul;128(7):
(picture:) Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, Guy RH, Macgowan AL, Tazi-Ahnini R, Ward SJ.
Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol Aug;129(8):

14. When is the skin barrier not optimum?
5/28/2019
Danby SG & Cork MJ, The Academic Unit of Dermatology Research, The University of Sheffield. 14

15. A Defective Skin Barrier in AD
Defective lipid lamellae
Degraded Corneodesmosomes
Abnormal cornified envelope
(Reduced levels of ceramides)
pH 7.0
NMF
H2O
NMF
H2O
NMF
H2O
Degradatory Proteases
Protease Inhibitors
Profilaggrin
Filaggrin
Lipid delivery
Lipid processing
(Reduced levels of ceramides)
The defective epidermal barrier is characterised by:
Abnormal expression of differentiation dependent proteins leading to corneocytes with an abnormal morphology and defective CE.
There is defective LL with reduced levels of ceramides and altered FFA profiles. This affects the structure of the lamellar membranes and there ability to efficiently prohibit water permeation. The interaction between the corneocytes and the LL is also compromised.
There is a reduced expression of profilaggrin leading to decreased filaggrin – structural defect, decreased NMF – reduced SC hydration – development of gaps between corneocytes.
There is an elevated skin surface pH associated with the reduction in NMF – optimum for protease hyperactivity
Increased protease activity leading to increased degradation of the corneodesmosomal junctions – barrier breakdown
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield. 15

16. PAR = Proteinase-activated Receptor-2

17. An allergic response is elicited
Allergens
NMF
H2O
NMF
H2O
NMF
H2O
Th2
Th1 ?
Cork, Danby et al (2009) In Skin Moisturization. Academic Unit of Dermatology Research, The University of Sheffield

18. Allergens & Irritants Water pH 7.0 NMF H2O NMF H2O NMF H2O
The barrier defect in patients with AD leads to an increased risk of irritant and allergen penetration and increased loss of water.
The skin is characterised by increased TEWL
Water
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield. 18

19. Irritants & allergens TEWL
The normal intact SC acts as an efficient barrier to the penetration of irritants and allergens and to the loss of water. Barrier function is often determined by measuring TEWL
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield. 19

20. What do we mean by irritants?

21. Identifying irritants: ask about skin care regime
Bath or shower
How often, per day, per week
Products used for washing/showering, added to bath
Products used for laundry

22. Common irritants

23. Common cause of irritancy!
TOO MUCH WASHING!!!!

24. Itching: some simple tips
STOP ALL IRRITANTS:
Shower gels
Soaps
Biological washing powders
Fabric conditioners
Leave on moisturiser
NOT AQUEOUS CREAM

25. The effect of topical products/treatments on pH and protease activity

26. A Healthy Skin Barrier NMF H2O NMF H2O NMF H2O Filaggrin Profilaggrin
Swelled corneocytes
Cornified envelope
Intact Corneodesmosomes
Lipid Lamellae
pH 5.5
NMF
H2O
NMF
H2O
NMF
H2O
Degradatory Proteases
Protease Inhibitors
Profilaggrin
Filaggrin
Lipid delivery
Lipid processing
Corneocytes are filled with natural moisturising factor, a collection of natural humectants which maintain skin hydration
The constituents of NMF are derived from profilaggrin, a structural component of the CE expressed during keratinocytes differentiation.
NMF is important for maintaining an acid environment at the outer surface of the SC
In order to balance the introduction of new cells in the basal layer of the epidermis, mature corneocytes are shed from the surface of the SC is a process referred to as desquamation.
Desquamation involves the degradation of the extracellular corneodesmosomes by a cocktail of proteases regulated by protease inhibitors.
The optimum pH for serine protease activity is slightly alkaline in contrast to the normal acidic pH of the skin.
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield. 26

27. A Defective Skin Barrier in AD
Defective lipid lamellae
Degraded Corneodesmosomes
Abnormal cornified envelope
(Reduced levels of ceramides)
pH 7.0
NMF
H2O
NMF
H2O
NMF
H2O
Degradatory Proteases
Protease Inhibitors
Profilaggrin
Filaggrin
Lipid delivery
Lipid processing
(Reduced levels of ceramides)
The defective epidermal barrier is characterised by:
Abnormal expression of differentiation dependent proteins leading to corneocytes with an abnormal morphology and defective CE.
There is defective LL with reduced levels of ceramides and altered FFA profiles. This affects the structure of the lamellar membranes and there ability to efficiently prohibit water permeation. The interaction between the corneocytes and the LL is also compromised.
There is a reduced expression of profilaggrin leading to decreased filaggrin – structural defect, decreased NMF – reduced SC hydration – development of gaps between corneocytes.
There is an elevated skin surface pH associated with the reduction in NMF – optimum for protease hyperactivity
Increased protease activity leading to increased degradation of the corneodesmosomal junctions – barrier breakdown
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield. 27

28. Protease activity in the skin barrier
(in the stratum corneum - no red stain)
Nucleated layers (nuclear material stained red)
Dermis
The Academic Unit of Dermatology Research, University of Sheffield

29. The effect of pH on skin barrier protease activity: clinical relevance
Acute AD pH 7.3
Current AD pH 5.7
Normal skin pH 5.0
The Academic Unit of Dermatology Research, University of Sheffield

30. The Effect of Washing with Liquid Soap on Skin Surface pH
*p = <0.05; ***p = <0.001; n = 3
5/28/2019
Danby SG & Cork MJ, The Academic Unit of Dermatology Research, The University of Sheffield. 30

31. The Effect of Washing with Liquid Soap on Skin Surface pH
Acute AD
Current AD
(non-lesional site)
Clinical relevance*
*p = <0.05; ***p = <0.001; n = 3
5/28/2019
Danby SG & Cork MJ, The Academic Unit of Dermatology Research, The University of Sheffield. 31

32. Aqueous cream – first appeared in the BNF in 1958
Its formulation containing SLS remains largely unchanged today

33. Aqueous Cream Leave-On compared with No Treatment for 4 weeks
Skin Barrier Integrity: End Point
5/28/2019
The Academic Unit of Dermatology Research, The University of Sheffield 33

34. Atopic eczema and domestic water hardness.
McNally NJ, Williams HC, Phillips DR, Smallman-Raynor M, Lewis S, Venn A, Britton J.
Lancet Aug 15;352(9127):
“Living in a hard water area is significantly associated with an increased lifetime prevalence of AD”
Confirmed by 2 replicate studies (in Japan and Spain)
5/28/2019
Danby SG & Cork MJ, The Academic Unit of Dermatology Research, The University of Sheffield. 34

35. A Randomised Controlled Trial of Ion-Exchange Water Softeners for the Treatment of Eczema in Children
Kim S. Thomas, Tara Dean, Caroline O'Leary, Tracey H. Sach, Karin Koller, Anthony Frost, Hywel C. Williams, and the SWET Trial Team PLoS Med February; 8(2): e

36. To summarise

37. Atopic eczema: pathophysiology
BRICK WALL THEORY

38. Irritants penetrate and trigger inflammatory response
The Brick Wall theory
Leads to dry skin
Irritants penetrate and trigger inflammatory response

39. Brick wall theory: correct barrier function
Correcting barrier function reduces dry skin and penetration of irritants and inflammation

40. EMOLLIENTS EMOLLIENTS EMOLLIENTS!