Skin barrier.
Skin barrier disordersMay 2020
Prof.Anna Vašků1
Prof.Anna Vašků2
Dąbrowska AK, Spano F,
Derler S, Adlhart C, Spencer
ND, Rossi RM. The
relationship between skin
function, barrier properties,
and body-dependent factors.
Skin Res Technol.
2018;24(2):165‐174.
doi:10.1111/srt.12424
Prof.Anna Vašků3
Body‐dependent factors influencing human
skin. Ethnicity
̶ Skin tone varies among ethnic groups due to different levels of the
four chromophores responsible for skin color: hemoglobin and
oxyhemoglobin (pinkish tones), melanin (brownish shades), and
carotenoids, responsible for yellow‐orange tones.
̶ Ethnicity also influences the natural hydration level of the skin as
well as the decrease in hydration level with age. It has been
reported that Caucasians and African‐Americans have slightly
drier skin, compared to Chinese, due to the lower levels of SC
natural moisturizing factors.
Prof.Anna Vašků4
Ethnicity
̶ Caucasians exhibit higher dryness with age than Chinese, which may be
caused by different eating habits and avoidance of sun exposure among
Chinese. It has been shown that darker skin is more resistant to photo aging
processes. Also, the thickness of the SC was found to be greater for darker
skin. Some studies have also indicated differences in the number of layers
within comparable SC thickness, suggesting that African‐Americans have
more cell layers within the SC than do Caucasians (16 and 9 layers,
respectively), the skin thus being more resistant to chemicals and damage.
Most studies demonstrated higher transepidermal water loss (TEWL) for
African‐Americans than for Caucasians as well as larger gland pore sizes and
a higher level of sebum secretion.
Prof.Anna Vašků5
Age
̶ Overall, the hydration level of the skin decreases significantly with age, mainly because of the decrease
in the amount of natural moisturizers present in the skin.
̶ The influence of the skin‐aging processes on skin hydration can vary between different ethnic groups,
being the most significant for Caucasians.
̶ The elasticity of the skin is also known to decrease, predominantly due to the decreasing collagen
production in the dermis and reduction in the resilience of existing collagen and elastin fibers.
̶ The thickness of skin initially increases with age, showing a maximum value for women at around
30‐40 years of age and for men at around 40‐50 years, and then significantly decreases with age.
̶ The amount of sebum secretion has been reported to be either independent or slightly decreasing with
age. The sweating rate slightly decreases with age.
̶ Skin pH has been found to be higher for older subjects, due to an age‐related decrease in the amount
of acidic natural moisturizing factors present in the skin.
̶ Skin roughness, the dimensions of the primary lines and anisotropy were all found to increase with age.
Prof.Anna Vašků6
Gender
Some researchers found that TEWL is higher for men, explaining this by the
fact that they spend more time outdoors and their skin is more damaged and
therefore more prone to transepidermal water loss.
Sebum secretion is considered to be either independent of gender or slightly
higher in males due to a higher testosterone level.
The sweating rate was found to be 30%‐40% higher in males than in females
(taking the difference in body surface area into consideration). Results show
no clear relationship between gender and SC thickness, but it was also found
that the cellular epidermis is slightly thicker in males than in females.
Measurements have shown no clear and statistically significant difference
between the elastic properties and pH of the skin in females and males for the
same anatomical sites.
Prof.Anna Vašků7
Skin type
̶ Skin type, its pigmentation, hydration, roughness, and many other
parameters are very individual. Significant variations can be
observed between people from the same ethnic groups, living in
the same environment and sharing the same lifestyle, but having
different complexions.
Prof.Anna Vašků8
Anatomical sites
̶ Skin differs not only between different people but also between anatomical sites for the same
person.
̶ The SC thickness varies significantly with the investigated anatomical site. It was found that
the thickest SC layer is to be found in heels, having 86 ± 36 cell layers, whereas the smallest
number of cell layers (6 ± 2) has been observed for genital skin. The thickness of the
epidermis depends on the body site in a similar way. The SC thickness is related to many
other phenomena, such as surface morphology, hydration level, and permeability to various
substances. Since the SC acts as a barrier layer, penetration through the skin is higher on
body sites with thinner SC. The roughness (Ra) of the index finger lies within the range of
19‐33 μm, whereas it is lower (12‐20 μm) for the volar forearm. Also, sebum secretion varies
between different anatomical regions, not only as far as the amount is concerned, but also
the chemical composition.
Prof.Anna Vašků9
Anatomical sites
̶ Due to many reasons, such as exposure to harsh environmental conditions or the frequency of washing
with detergents, certain body parts, eg, hands, are more prone to having a lower hydration level of the
superficial stratum corneum (SSC). The highest density of sweat glands can be found on the soles of
the feet (620 ± 20 sweat glands per cm2), whereas the lowest density of sweat glands is found on the
upper lips (16 sweat glands per cm2). In general, the SC thickness is directly related to the TEWL and
anatomical sites characterized by the thickest SC display the lowest TEWL values. However, TEWL
levels are also dependent on other factors, such as SC lipid content, blood flow, or skin temperature.
This explains the fact, that the TEWL of the palm (characterized by a thick SC layer but a low level of
barrier lipids) is higher than that of the leg.
̶ The elastic properties of skin depend on the collagen structure in the dermis, the local thickness of the
skin and other parameters that depend on the anatomical site. For example, facial skin was found to be
less elastic than the skin on the arm and on the back. As the properties of human skin are rarely
independent of each other but work as a system, a variation in one property is generally coupled with a
variation in others. For example, the frictional behavior of human skin varies with body site because it
depends on SC roughness, elastic properties, thickness, hydration level, sweating rate as well as on the
presence of hair and sebum.
Prof.Anna Vašků10
Lifestyle and body‐mass index
̶ Lifestyle is considered to be one of the factors influencing the extrinsic aging process, which
is related to visible aging caused by the exposure to external factors.
̶ Proper sun protection prevents accelerated skin aging and the risk of skin cancer and other
skin damage.
̶ A healthy diet, containing significant amount of fruits and vegetables, as well as a calm,
low‐stress lifestyle, leads to a higher concentration of carotenoids and may result in a slower
rate of skin aging. Higher daily vitamin C intake has been connected to a decreased
formation of wrinkles, while a higher linoleic acid dose has been associated with a lower level
of dryness.
̶ Smoking is associated with an altered skin condition (wrinkling, larger pores, rougher skin
surface, and presence of discoloration). It also significantly increases the risk of skin
diseases, as it decreases the self‐healing abilities of the skin.
Prof.Anna Vašků11
Lifestyle and body‐mass index
̶ Skin properties are also dependent on the body‐mass index (BMI).
̶ TEWL is usually higher for obese people.
̶ Obesity is also correlated to elevated sweat gland activity and
higher skin blood flow.
̶ Obesity can also increase the risk of various skin disorders and
impaired wound healing. For example, 74% of examined obese
people have been found to suffer from acanthosis nigricans, also
related to insulin resistance. In another study, 40% of obese
children were diagnosed with striae disease.
Prof.Anna Vašků12
Skin hydration
̶ As skin hydration is a very important parameter responsible for skin homeostasis, all deviations from a
normal hydration level can result in significant changes in human skin properties and functions. Among
the main causes of dry skin, one can list skin aging, the wrong or no skin care or malnutrition.
̶ Skin hydration can also be influenced by environmental factors or by anatomical location (eg, skin on
the palms and legs is drier than on the forehead).
̶ Skin dryness can also be a consequence of various diseases, not only directly related to the skin, such
as atopic dermatitis, but also other health problems, eg, hypothyroidism. A lower hydration level results
in a lower elasticity of the skin, faster skin aging and wrinkle creation, higher surface roughness, and
lower mechanical resistance.
̶ Dry skin is also more susceptible to skin diseases and more prone to redness and itchiness. The
frictional behavior of human skin also depends on hydration. It was reported that moist skin shows
higher friction‐coefficient values than dry or completely wet skin. Drier skin is more prone to mechanical
failure, flakiness, irritation, and other problems. Irritated skin leads to difficulties in achieving and
maintaining an adequate hydration level. This results in drier skin and may lead to more severe skin
conditions, if untreated.
Prof.Anna Vašků13
Cause and effect chain for the example of the decrease in skin
hydration level. “+” and “‐” symbolize positive and negative
correlation
Dąbrowska AK, Spano F, Derler S, Adlhart C, Spencer ND, Rossi RM. The relationship between skin function,
barrier properties, and body-dependent factors. Skin Res Technol. 2018;24(2):165‐174. doi:10.1111/srt.12424
Prof.Anna Vašků14
Penetration through skin
̶ Our skin is constantly in contact with various substances that are either
present in the environment or deliberately applied to the surface of the skin.
Numerous substances have been applied to the skin surface for medical or
religious reasons since the beginning of humanity, which provides a hint that
the absorption properties of the skin were already known a long time ago.
Depending on the circumstances, the barrier properties of human skin, given
mainly by its horny layer (SC), may be perceived as being either an
advantage or an obstacle. In everyday life, the skin can be exposed to
various substances in the solid, liquid, or gaseous states. Some of them, such
as harmful chemicals, allergens, pathogens etc. can be dangerous and lead
to irritation, rashes, burns, or other health problems following the topical
application or penetration of these substances into deeper layers of the skin.
Prof.Anna Vašků15
Penetration through skin
̶ The epidermis and dermis are the skin layers involved in the penetration
processes, but the SC composition and properties are mainly responsible for
the barrier function of human skin. Skin protects the body from penetrating
substances through various mechanisms, either mechanically blocking
particles from further migration into the skin or neutralizing, attacking, or
degrading them. Substances that penetrate through the SC barrier layer still
have to overcome many other obstacles, such as the antimicrobial barrier and
immunological or enzymatic systems.There are three different pathways that
can be used by substances penetrating the skin mentioned in the literature:
intercellular, transcellular, and transappendageal.
Prof.Anna Vašků16
Three penetration pathways for the skin: intercellular,
transcellular, and transappendageal
Dąbrowska AK,
Spano F, Derler S,
Adlhart C,
Spencer ND, Rossi
RM. The
relationship
between skin
function, barrier
properties, and
body-dependent
factors. Skin Res
Technol.
2018;24(2):165‐1
74.
doi:10.1111/srt.1
2424
Prof.Anna Vašků17
The intercellular pathway
̶ involves the transport of substances between the cells of the SC layer. This
mechanism plays a major role in skin permeability and requires the presence
of component lipids, such as ceramides, that allow free lateral water diffusion
by forming nanometric spaces via short range repulsive forces.
̶ The diffusion rate depends on the properties of penetrating particles, such as
volume, weight, solubility, lipophilicity, or hydrogen‐bonding ability. It is
assumed that particles with a size of 5‐7 nm can be efficiently transported
through the intercellular pathway. Although the SC is a thin layer, reaching a
thickness of some 20 μm for the volar forearm, the intercellular pathway is
much longer and reaches 400 μm, which reduces penetration rate
significantly.
Prof.Anna Vašků18
The transcellular pathway
̶ involves keratinocytes in the transport of substances. Despite the
seemingly short distances involved, this pathway is very selective.
Penetrating particles have to overcome various barriers that are
repeated many times in the skin structure; lipophilic cell
membranes, hydrophilic cellular contents with keratin, and
phospholipidic cell barriers.
Prof.Anna Vašků19
The transappendageal pathway
̶ involves appendages, such as sweat and sebaceous glands and hair follicles and is a typical
route for the penetration of water‐soluble substances.
̶ The size of particles penetrating the skin through aqueous pores can be around 36 nm,
whereas trans‐follicularly penetrating particles may potentially have a diameter of up to
210 μm (this being the maximum size of the follicular openings). However, other researchers
have argued that only particles with sizes up to 40 nm or even as small as 20 nm can
effectively penetrate through follicles into deeper skin layers, whereas bigger particles will
only be transported deep into the hair follicle.
̶ The transappendageal pathway used to be considered as the least significant penetration
passage, as the appendages cover only 0.1% of the skin surface. On the other hand, it is the
only penetration pathway for particles larger than few nm. In addition, appendages may play
a role as reservoirs for topically applied substances and therefore could potentially be an
efficient penetration path.
Prof.Anna Vašků20
Body‐dependent factors influencing skin permeability. “+” and “‐” symbolize
positive and negative correlation between single factors and skin permeability
Dąbrowska AK, Spano F, Derler S, Adlhart C, Spencer ND, Rossi RM. The relationship between skin function, barrier properties,
and body-dependent factors. Skin Res Technol. 2018;24(2):165‐174. doi:10.1111/srt.12424
Prof.Anna Vašků21
Barrier function of the skin
̶ The barrier function of the skin is largely dependent on the stratum corneum (SC), the
outermost layer of the epidermis. The SC is formed through a course of tightly regulated
processes of keratinocyte differentiation called keratinization. Keratinization is achieved by
keratinocytes passing through four cell layers of the epidermis: the stratum basale, the
stratum spinosum, the stratum granulosum (SG), and the SC.
̶ In the SG, keratinocytes start to produce two membrane-circumscribed granules: keratohyalin
granules and lamellar bodies. Keratohyalin granules contain intracellular components of the
SC (such as filaggrin [FLG], loricrin, and keratin filaments), whereas lamellar bodies contain
extracellular components (such as lipids, corneodesmosin, and kallikreins).
̶ In the SC, keratinocytes are flattened and denucleated (which are then called as
corneocytes) and simultaneously, corneocyte cell membranes are replaced by a specific
barrier structure called a cornified envelope (CE). At the transition from the SG to the SC,
lamellar bodies are secreted into the intercellular space of corneocytes and fill it up with
lipids. These structures are often described as bricks (corneocytes) and mortar (intercellular
lipids).
Prof.Anna Vašků22
Schema of the FLG metabolic
process. In the stratum
granulosum, profilaggrins are
stored in keratohyalin granules
and then cleaved into FLG
monomers. FLG monomers
bind to keratin filaments in
corneocytes. At the upper layer
of the SC, FLG monomers are
released from keratins and
cleaved into free amino acids,
followed by conversion into
pyrolidin carboxilic acid (PCA)
and urocanic acid (UCA).
UCA significantly reduced
costimulatory molecule
expression on dendritic cells
and increased their ability to
induce a regulatory T cells. In
contrast, PCA is a major
constituent of natural
moisturizing factors (NMFs),
which are responsible for
retaining water in the SC.
Egawa G, Kabashima K.
Barrier dysfunction in the
skin allergy. Allergol Int.
2018;67(1):3‐11.
doi:10.1016/j.alit.2017.1
0.002
Prof.Anna Vašků23
The cornified envelope (CE) is a
specific barrier structure formed
beneath the cell membrane of
corneocytes.
The CE consists of highly crosslinked
insoluble proteins and the extracellular
lipids anchoring on it. This structure
acts as a vital physical barrier to the
SC. The structures of the cornified
envelope and corneodesmosome.
Involucrin forms the scaffold and is
reinforced by loricrin and SRRs.
Envoplakin-periplakin heterodimers
conjugate keratin filaments.
Egawa G, Kabashima K. Barrier dysfunction in the skin allergy.
Allergol Int. 2018;67(1):3‐11. doi:10.1016/j.alit.2017.10.002
Prof.Anna Vašků24
Niehues H,
Bouwstra JA, El
Ghalbzouri A,
Brandner JM,
Zeeuwen PLJM,
van den Bogaard
EH. 3D skin
models for 3R
research: The
potential of 3D
reconstructed skin
models to study
skin barrier
function. Exp
Dermatol.
2018;27(5):501‐51
1.
doi:10.1111/exd.1
3531
Skin Barrier
Skin barrier
̶ The structural integrity of the stratum corneum is
maintained by the presence of corneodesmosomes.
Corneodesmosomes lock the together and provide tensile
strength for the stratum corneum to resist shearing forces.
̶ Elias visualized the stratum corneum as being similar to a
brick wall, with the analogous to bricks and the lamellae
acting as cement. Extending this model, the
corneodesmosomes can be thought of as analogous to
iron rods that pass down though holes in the bricks to give
the wall its tensile strength.
Prof.Anna Vašků26
Schematic drawing denoting the different barriers in the epidermis and their interaction with the TJ barrier. Lilac
spheres: desmosomes, grey spheres: corneodesmosomes. SB: stratum basale, SC: stratum corneum, SG: stratum
granulosum, SS: stratum spinosum. Continous arrows denote interactions already experimentally shown. Dotted arrows
denote hypothetical interactions.
Prof.Anna Vašků27
Schematic structures of major bicellular tight junction proteins. The tight junction (TJ) is part of
cell-cell junction complex. Major bicellular TJ proteins include three transmembrane protein
families: occludin, claudins, and junctional adhesion molecules (JAMs) and a few families of
peripheral intracellular membrane proteins such as zonula occludens (ZOs), which connect the
transmembrane TJ molecules to the actin filament cytoskeleton.
Shi J, Barakat M, Chen D,
Chen L. Bicellular Tight
Junctions and Wound
Healing. Int J Mol Sci.
2018;19(12):3862.
Published 2018 Dec 4.
doi:10.3390/ijms1912386
2
Prof.Anna Vašků28
Localization of TJs and TJ proteins in the epidermis and
molecular composition of TJs. Cldn: claudin; JAM: junctional
adhesion molecule, MUPP1: Multi-PDZ domain protein 1, Ocln:
occludin. Bar:20 μm.
Prof.Anna Vašků29
The structure of the epidermis. The red line represents tight junctions in the stratum
granulosum. B, Magnified view of the cell in the stratum granulosum. C, The “bricks and
mortars” structure of the stratum corneum.
Egawa G, Kabashima K. Barrier dysfunction in the skin allergy. Allergol Int. 2018;67(1):3‐11.
doi:10.1016/j.alit.2017.10.002
Prof.Anna Vašků30
Impaired epidermal barrier
̶ The skin covers the entire body and protects us from various kinds of external stimuli. An
impaired epidermal barrier allows the enhanced penetration of external antigens and readily
induces skin inflammation. This facilitates the interaction of external antigens with local
immune cells and may lead to systemic immune responses. This is called the “outside-toinside”
hypothesis, and it explains the association between skin barrier dysfunction and an
increased risk of developing allergic diseases, including atopic dermatitis (AD), asthma, food
allergies, and allergic rhinitis. In addition, it is evident that persistent skin inflammation, in
turn, causes further attenuation of the skin barrier, suggesting the existence of an
exacerbation loop between the skin barrier and skin immunity (the “outside-to-inside-andback-to-outside”
hypothesis). These observations suggest that maintaining the skin barrier
function is important not only for effective management of allergic diseases but also for
preventing their development.
Prof.Anna Vašků31
Immunological modulation of skin barriers
̶ Accumulating evidence suggests that immune cells influence skin integrity through the
production of cytokines. Although complex interaction of immune cells creates AD skin
lesions, the immunopathogenesis of AD is characterized by Th2-skewed responses.
̶ IL-4 and IL-13, the two major Th2 cytokines, downregulate the production of 1) FLG and
keratins, 2) the CE components (loricrin and involucrin), 3) cell adhesion molecules
(desmogleins, ZO-1), and 4) ceramide lipids.
̶ IL-31, another Th2 cytokine dominantly produced by Th2 cells, also downregulates FLG
expression. Furthermore, a recent study has shown that IL-33, an alarmin that is abundantly
stored in keratinocytes, has the potency to downregulate FLG expression as well.
̶ The original purpose of these immunological modulations against skin integrity may be to
facilitate the desquamation and replacement of damaged corneocytes; however, to achieve
this, dysregulation of the skin barrier is essential. A series of these modulations may cause
problems, particularly in AD patients. The exacerbation loop between congenital barrier
deficiency and immunogenic barrier deficiency leads to the formation of chronic, persistent
skin inflammation in AD.
Prof.Anna Vašků32
Alteration of tight junction proteins in skin diseases. The different colors denote the
different diseases and the corresponding TJ protein alterations. AD: atopic dermaitits;
Cldn: claudin; IV: ichthyosis vulgaris; NISCH: neonatal ichthyosis sclerosing
cholangitis; Ocln: occludin, ZO-1: zonula occludens 1.
Bäsler K, Bergmann S, Heisig M, Naegel A, Zorn-Kruppa M, Brandner JM. The role of tight junctions in skin
barrier function and dermal absorption. J Control Release. 2016;242:105‐118.
doi:10.1016/j.jconrel.2016.08.007
The brick wall analogy of the stratum corneum of the epidermal barrier. In healthy
skin the corneodesmosomes (iron rods) are intact throughout the stratum corneum. At
the surface, the corneodesmosomes start to break down as part of the normal
desquamation process, analogous to iron rods rusting (A). In an individual genetically
predisposed to AD, premature breakdown of the corneodesmosomes leads to enhanced
desquamation, analogous to having rusty iron rods all the way down through the brick
wall (B). If the iron rods are already weakened, an environmental agent, such as soap,
can corrode them much more easily. The brick wall starts falling apart (C) and allows
the penetration of allergens (D).
The corneocytes of the skin barrier are locked together by
corneodesmosomes comprising several adhesion proteins.
Desquamation of corneocytes can only occur once the
corneodesmosome has been broken down by skin-specific proteases,
such as the SCCE. The proteases are kept under control by specific
protease inhibitors, such as the skin-derived antileukoprotease
(SKALP). SLPI, serine leukoprotease inhibitor; LEKTI,
lymphoepithelial Kazal-type 5 serine protease inhibitor.
Corneodesmosomes are not only broken down by endogenous
serine proteases, such as SCCE (SCCE – stratum corneum
chymotryptic enzyme) and SCTE (stratum corneum tryptic
enzyme). Once a flare of AD has been triggered, cells within the
inflammatory infiltrate produce secondary proteases, which can
also break down the skin barrier (eg, MCC). The stratum corneum
is also exposed to many exogenous proteases from the
environment, such as Staphylococcus aureus and house dust mites.
SLPI, serine leukoprotease inhibitor.
In the stratum corneum from healthy , there is a balance between the structural
integrity of the corneodesmosomes and the level of proteases and protease
inhibitors (A). In individuals genetically predisposed to , increased protease
activity leads to premature breakdown of the corneodesmosomes and thinning of
the stratum corneum (B and C). Soap use increases the pH from 5.5 to the optimal
value for activity (≥7.5), further increasing the breakdown of the
corneodesmosomes and desquamation (C). , leukoprotease inhibitor
Prof.Anna Vašků37
Barrier dysfunction is leading pathogenesis of skin allergy
It is now evident that epicutaneous antigens are strong sensitizer of allergic disorders.
In human, sequential acquisition of allergic diseases (atopic march) are frequently observed in both
AD and some genodermatoses, such as Netherton syndrome (mutation in SPINK5), peeling skin
syndrome 1 (Corneodesmosin) and SAM syndrome (Desmoglein1), which strongly suggests that
skin barrier deficiency contributes to the development of atopic march.
Eosinophilic esophagitis is another chronic immune disorder that is associated with hypersensitivity
to food, and has recently been linked to the mutations in Calpain 14 (CAPN14), a protease
specifically expressed in the esophagus.
The barrier deficiency in mucosal epithelium also contribute to the induction of allergic disorders.
Recent clinical trials have shown that epicutaneous antigen exposure induces sensitization while
oral antigen consumption induces immune tolerance.
Egawa G, Kabashima K. Barrier dysfunction in the skin allergy. Allergol Int. 2018;67(1):3‐11.
doi:10.1016/j.alit.2017.10.002
Different combinations of genetic and
environmental factors
contribute to the development of multifactorial diseases, such as AD. Focusing
on the skin barrier, severe barrier breakdown could be caused by a
combination of functional variants in adhesion protein, protease, and
protease inhibitor genes (A) or by a single major environmental insult.
Alternatively, major functional changes in the skin barrier–related genes
could produce a defective skin barrier. Exposure of this defective barrier to
an environmental insult, such as soap and detergents, breaks it down further,
allowing penetration of irritants and allergens (B). A third possibility is the
combination of several changes in skin barrier genes, resulting in small
functional changes (C). Other combinations of both genetic and
environmental factors can also lead to the development of AD (C). A
combination of repeated environmental insults might, alone, also produce
sufficient barrier breakdown to lead to the development of eczematous
lesions (C).
The skin can be considered to be on a spectrum from perfect skin to
eczematous skin. Changes in skin barrier–related genes alter the
epidermal barrier function, making the skin more susceptible to the
development of AD. When a genetic predisposition to barrier
breakdown is combined with exposure to environmental agents, such
as soap, the chance of eczema development is increased substantially.
Hypothalamic-hypophyseos axis
and skin
Psoriasis: General aspects
̶ Psoriasis is a chronic, inflammatory, immune-mediated skin disease
affecting ~2% of the European population1
̶ The disease usually occurs in individuals with genetic susceptibility in
conjunction with environmental stimuli, and may involve an immune
response to autoantigens2
̶ Evidence supports a central role for dendritic cells and T cells in
establishing and maintaining the "vicious cycle" of psoriatic plaque
development2,3
1. Gudjonsson JE, Elder JT. Clin Dermatol. 2007;25(6):535-46. 2. Griffiths
CE, Barker JN. Lancet. 2007;370:263-71. 3. Nickoloff BJ, Nestle FO. J Clin
Invest. 2004; 113:1664-75. S1/4
Prof.Anna Vašků43
Pathophysiology of psoriasis
Rendon A, Schäkel K. Psoriasis Pathogenesis and Treatment. Int J Mol Sci.
2019;20(6):1475. Published 2019 Mar 23. doi:10.3390/ijms20061475
Prof.Anna Vašků44
Atopic dermatitis
̶ Atopic dermatitis is a systemic disorder characterized by abnormal barrier
function across multiple organ sites. Causes of epidermal barrier breakdown
are complex and driven by a combination of structural, genetic, environmental
and immunological factors. In addition, alteration in microflora diversity can
influence disease severity, duration, and response to treatment. Clinically,
atopic dermatitis can progress from skin disease to food allergy, allergic
rhinitis, and later asthma, a phenomenon commonly known as the atopic
march. The mechanism by which atopic dermatitis progresses towards
gastrointestinal or airway disease remains to be elucidated.
Prof.Anna Vašků45
Effects of cytokines on epidermis in AD. Disrupted
epidermal barrier and environmental triggers stimulate
keratinocytes to release IL-1β, IL-25, IL-33, MDC, TARC,
and TSLP, which activate dendritic cells and Langerhans
cells. Activated dendritic cells stimulate Th2 cells to produce
IL-4, IL-5, IL-13, IL-31, and IL-33, which leads to barrier
dysfunction, decreased AMP production, impaired
keratinocyte differentiation, and itch symptoms.
Chronic AD is characterized by recruitment of Th1, Th22,
and Th17 subsets, which results in epidermal thickening
and abnormal keratinocyte proliferation.
AD = atopic dermatitis; AMP = antimicrobial peptide; DC =
dendric cell; IFN = interferon; IL = interleukin; KC =
keratinocyte; LC = Langerhans cell; MDC = macrophagederived
chemokine; S100A = S100 calcium-binding protein
A; Th = T-helper type; TARC = thymus and activationregulated
chemokine; TSLP = thymic stromal
lymphopoietin.
Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: Clinical implications. Allergy
Asthma Proc. 2019;40(2):84‐92. doi:10.2500/aap.2019.40.4202
Prof.Anna Vašků46
Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: Clinical implications. Allergy Asthma Proc.
2019;40(2):84‐92. doi:10.2500/aap.2019.40.4202
Prof.Anna Vašků47
Prof.Anna Vašků48
Skin barrier disruption
̶ Stratum corneum (SC) barrier damage often occurs as a result of a decrease in surface
microbial diversity, FLG expression, antimicrobial peptide production and SC lipid synthesis
[measured by increased skin pH and transepidermal water loss (TEWL)].
̶ After SC breakdown, protease‐inactive allergens and bacterial molecules are taken up by
resident Langerhans cells (LCs), which migrate to draining lymph nodes to trigger an
adaptive immune response. Engagement of the T‐cell receptor (TCR) with major
histocompatibility complex (MHC) containing antigen and concomitant engagement of
costimulatory complex (CD80:CD28) activate the naive T cell. Additional factors secreted by
LCs include interleukin (IL)‐4, IL‐5 and IL‐13, which induce T helper (Th)2 differentiation.
Alternatively, protease‐active antigens can directly cause SC breakdown and activate
protease‐activated receptors (PARs) and Toll‐like receptors (TLRs) on keratinocytes (black
arrows), triggering production of proinflammatory cytokines including tumour necrosis factor
(TNF)‐α, IL‐1 and thymic stromal lymphopoietin (TSLP), which can mediate permeability
defects at other sites, such as the intestinal and respiratory tracts. TJ, tight junction; AJ,
Prof.Anna Vašků49
Prof.Anna Vašků50
Itch and interleukin (IL)‐31 signalling
pathway
̶ The itch–scratch cycle is a common phenomenon whereby scratching behaviour induced by
itch sensory transmission causes breakdown of the skin barrier. Antigen presenting cells
such as dendritic cells (DCs) and macrophages are then sensitized to exogenous antigen.
Subsequent processing in draining lymph nodes engages a naive T cell (Th0) with the DC.
The DC also secretes IL‐4, IL‐5 and IL‐13, which promotes induction of T helper (Th)2
differentiation and circulation to the target organs. IL‐31 is secreted by activated Th2 in
addition to mast cells, eosinophils and basophils. IL‐31 plays a pivotal role in cell‐mediated
immunity in the skin, lung and intestine, and the perception of itch through binding to IL‐31
receptors on nerve‐fibre endings. Immunomodulating cytokines such as transforming growth
factor (TGF)‐β can downregulate IL‐31 levels, whereas bacteria toxins such as
staphylococcal α‐toxin can increase IL‐31 levels. The systemic allergic inflammatory
response ultimately recruits additional pruritic initiators to the site of injury, which further
propagates the itch–scratch cycle. TCR, T‐cell receptor; MHC, major histocompatibility
complex.
Prof.Anna Vašků51
Prof.Anna Vašků52
Gut barrier disruption
̶ Various factors can modulate gastrointestinal permeability and contribute to increased ‘gut
leakiness’. Patients with atopic dermatitis have elevated luminal lactulose, decreased luminal
IgA, and decreased luminal commensal bacteria and short‐chain fatty acids (SCFAs). Normal
gastrointestinal function and homeostasis are regulated by junctional complexes formed by
tight junctions (TJs) and adherens junctions (AJs), mucosal production by goblet cells and the
immune system within the intestinal laminal propria. Systemic inflammatory signals including
interleukin (IL)‐25, IL‐33 and thymic stromal lymphopoietin (TSLP) can promote monocyte
migration, diapedesis and activation into macrophage (arrow). Breaks in the barrier formed by
the junctional complex allow luminal antigens access through the epithelial barrier where they
are phagocytosed by macrophages and subsequently presented to T cells in draining lymph
nodes (arrow head) to trigger visceral T helper 2‐dominant hypersensitivity. Patients with
atopic dermatitis also demonstrate elevated IgE levels in the serum and lamina propria and
increased mast cell number and function, which can contribute to food allergen sensitivity.
Prof.Anna Vašků53
TEWL devices.
(a) Open-chamber TEWL device. A hollow
cylinder is placed in contact with the skin,
and water vapor diffuses through the open
chamber. Spatially separated temperature
and relative humidity sensors detect the
humidity gradient.
(b) Unventilated-chamber TEWL device. The
upper end of the chamber is closed, resulting
in water vapor collecting in the chamber. The
temperature and relative humidity sensors
detect the rate of increase of relative
humidity.
(c) Condenser-chamber TEWL device. The
upper end of the chamber is closed by a
condenser that removes water vapor from
the chamber, enabling continuous TEWL
measurements to be recorded. Water vapor
density is measured by sensors in the
chamber and condenser. TEWL,
transepidermal water loss.
Alexander H, Brown S, Danby S, Flohr C. Research Techniques Made Simple: Transepidermal
Water Loss Measurement as a Research Tool. J Invest Dermatol. 2018;138(11):2295‐2300.e1.
doi:10.1016/j.jid.2018.09.001
Prof.Anna Vašků54
TEWL
Skin care practices also affect TEWL. Detergents such as sodium
lauryl sulfate can damage the skin barrier and lead to increased
TEWL, whereas emollients transiently occlude the skin and reduce
TEWL.
Skin surface temperature and sweating additionally alter TEWL .
Älso seasonal variation in TEWL was shown
TEWL is affected by circadian rhythm and sun exposure.
Prof.Anna Vašků55
TEWL
̶ TEWL has been shown to vary significantly at different anatomical
sites within an individual. TEWL is high at the palms, soles,
axillae, and forehead and low at the calf and forearm. The
increased TEWL at sites such as the palms and soles is linked to
the low sebaceous lipid content at these sites. Regional
differences in TEWL may also be due to differences in sweat
gland activity, occlusion, skin temperature, thickness, and
microvasculature as well as corneocyte size, maturity, and
shedding.
Dermotest
Thank you for your attention
Prof.Anna Vašků57