2 Chapter 14 :: Skin Barrier
:: Akiharu Kubo & Masayuki Amagai
AT-A-GLANCE
■ One of the most important functions of the skin
is to form a barrier between the organism and the
external environment.
■ The skin protects our bodies from physical damage
Part 2
caused by desiccation, physical stress, infection,
overheating or heat loss, and ultraviolet (UV)
irradiation.
■
::
The skin is covered by the epidermis, a cornified,
stratified epithelial cellular sheet that is equipped
Structure and Function of Skin
with a barrier formed by the stratum corneum and
tight junctions.
■ The stratum corneum is an air–liquid interface
barrier on the body surface that prevents excessive
water loss (inside–outside barrier) and the entry
of harmful substances from the environment
(outside–inside barrier).
■ The stratum corneum barrier is composed
of corneocytes and intercorneocyte water-
impermeable lipid lamellae. Corneocytes are
wrapped with cornified cell envelope and
corneocyte lipid envelope and contain keratin
filaments associated with filaggrin, which is
degraded to natural moisturizing factors.
■ The tight junctions seal the intercellular space
between neighboring cells at the second layer in
the stratum granulosum and form a liquid–liquid
interface barrier that limits molecular movement
through the paracellular pathway.
■ Langerhans cells are located in the epidermis
under the tight junction barrier in steady state but
extend their dendrites to the outside tight junction
barrier upon activation to capture external antigens
at the tips of the dendrites.
■ Antimicrobial peptides, lipids, the acidic pH
of the stratum corneum, and continuous daily
desquamation (daily detachment of dead skin cells)
control the skin microbiota and protect us from
infection by bacteria, yeasts, fungi, and viruses
■ UV light is reflected from the stratum corneum and
absorbed by urocanic acid and melanin molecules,
which protect genomic DNA from UV irradiation
damage.
■ Sweating, blood flow control, and heat storage in
subcutaneous adipose tissue protect us from cold
and overheating.
Kang_CH014_p0206-0231.indd 206
INTRODUCTION
The skin is the integument of vertebrates (Table 14-1).
One of the key functions of the skin is to form a protec-
tive physical barrier between the body and the external
environment. The limitation of molecular movement
across the skin is largely dependent on the epider-
mis and especially the stratum corneum in mammals.
The epidermis prevents the inward and outward pas-
sage of water, electrolytes, lipids, and proteins, as
well as insults from chemicals, bacteria, fungi, virus,
toxins, and allergens. Defects in the formation of the
epidermal barrier cause various congenital diseases
(Table 14-2).
The skin protects the body from various external
stresses. In protecting from heat and cold stresses, the
skin maintains the internal organs at a certain constant
temperature by regulating blood flow, sweat produc-
tion, thermal storage in the fat layer, and thermogen-
esis in brown fat cells. The skin protects the body from
physical stresses through coordination of the rigid
surface armor of the stratum corneum; keratin cyto-
skeleton; and cell adhesions between keratinocytes, epi-
dermal–dermal junctions, and dermal collagen fibers;
these are discussed in Chaps. 15 and 60. Furthermore,
the epidermis reflects and absorbs ultraviolet (UV)
radiation from the sun to protect the genomic DNA of
cells; this is particularly important in preventing car-
cinogenesis, which is discussed in Chaps. 19 and 20.
Skin appendages, such as sweat and sebaceous glands,
hairs, and nails, also have physical and chemical bar-
rier functions; these are discussed in Chaps. 6, 7, and 8,
respectively.
The skin is also equipped with immunologic barri-
ers to the innate and acquired immune systems. Anti-
microbial proteins are a diverse group of proteins that
form a chemical barrier against microorganisms on the
surface of the epidermis. Toll-like receptors on kera-
tinocytes detect pathogen-associated molecular pat-
terns such as lipoprotein and peptidoglycans that are
broadly shared by bacteria but distinguishable from
host molecules and control the immune responses
against the microorganisms. Dendritic cells within
the skin govern the acquired immunologic and aller-
gic responses to external insults. The mechanisms of
acquired immunity that protect our skin are discussed
in Chaps. 10 and 11.
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 TABLE 14-1
Short Commentary on Jargons
Integument
The tough outer protective layer of an animal or plant that demarcates
the body from the external environment
Occlusive junction
Cell–cell adhesive junction that seals the intercellular space and
controls paracellular molecular movement. Invertebrates and ver-
tebrates have different occlusive junction structures. The occlusive
junction of invertebrates is called a septate junction, and that of
vertebrates is called a tight junction.
Comparative Biology
Comparative biology exploits natural variation and disparities
among species or taxa to understand the patterns of life by inves-
tigating phylogenies, evolution, development, physiology, and
genomics
Kelvin’s Tetrakaidecahedron
Fourteen-sided polyhedron composed of eight hexagons and six
squares, proposed in 1887 by William Thomson (Lord Kelvin) as the
best shape for packing equal-sized cells together to fill the space
using the minimal surface area of each cell142
Transepidermal Water Loss
The loss of water that passes from inside to outside a body through
the epidermis. Measurement of transepidermal water loss is useful
to evaluate the stratum corneum barrier as the elevation rates of
transepidermal water loss are basically in proportion to the level of
barrier damage or formation.
COMPARATIVE BIOLOGY
OF THE EPIDERMAL
BARRIER
The lipid bilayer cell membrane provides a fundamen-
tal barrier in unicellular organisms. The cell membrane
compartmentalizes the cell from the external environ-
ment. Homeostasis of the cell is maintained within the
compartment demarcated by the cell membrane in an
energy-dependent manner. Because the lipid bilayer
membrane is highly fragile, most unicellular organ-
isms have an additional barrier structure outside of
the cell membrane (ie, the cell wall) that functions as a
type of armor (Fig. 14-1).
The body’s barrier to multicellular organisms is
analogous to its barrier to unicellular organisms. The
cell membrane of unicellular organisms corresponds
to the epidermis, which is the epithelial cellular sheet
that delineates the surface of multicellular organisms
(see Fig. 14-1). To form a barrier with a sheet of cells,
prevention of the leakage of water and solutes through
intercellular spaces is crucial. Thus, the intercellular
spaces are sealed by occlusive junctions, such as sep-
tate junctions in arthropods and tight junctions in ver-
tebrates (see Table 14-1). The epidermis is composed of
a single layer of cells in cephalochordates and urochor-
dates, but multilayered (stratified) cells in vertebrates
(see Fig. 14-1). Because the epidermal cells are fragile
when directly exposed to harsh external environmen-
tal factors, such as hypotonic fresh water, hypertonic
Kang_CH014_p0206-0231.indd 207
sea water, or dry air, the surface of the epidermis of
higher organisms is covered by various external bar-
2
riers. Examples of these barriers include the cuticles
of arthropods, tunics of tunicates, mucous of fish and
amphibians, and cornified cell layer (stratum cor-
neum) of adult amphibians, reptiles, birds, and mam-
mals (see Fig. 14-1).1
BASIC STRUCTURE
OF THE EPIDERMIS
The human epidermis is a stratified epithelial cellu-
Chapter 14 :: Skin Barrier
lar sheet, the uppermost part of which is cornified to
form the stratum corneum. The viable (enucleated)
cell layers of the epidermis consist of the stratum
basale (basal cell layer), stratum spinosum (spinous
cell layer), and stratum granulosum (granular cell
layer) (Fig. 14-2). The stratum granulosum consists of
at least three layers of flattened granular cells.2-5 From
outside to inside, the layers are named SG1, SG2, and
SG3, and tight junctions seal the intercellular spaces
in the SG2 layer.3,5 The stratum corneum consists of
dead cornified cells (corneocytes) and functions as an
air–liquid interface barrier. The intercellular spaces of
the stratum corneum are filled with water-imperme-
able lipid lamellae. Under the stratum corneum, cells
are immersed in a water environment. The extracel-
lular water environment of the epidermis is divided
into two parts by the tight junction barrier, which
is a liquid–liquid interface barrier (see Fig. 14-2). To
form the stratum corneum, the SG1 cells terminally
differentiate into corneocytes by filling their intercel-
lular spaces with lipid lamellae. The multilayered
structure of the epidermis is maintained, and the
epidermal cells are continuously turned over. Epider-
mal cells proliferate only in the basal layer, differenti-
ate with detachment from the basement membrane,
move upward, become flattened at the stratum gran-
ulosum, form a tight junction at the SG2 layer, lose
the tight junction at the SG1 layer, terminally differ-
entiate into corneocytes, and detach from the top of
the cornified layer as squamous scales. Continuous
turnover of the epidermis enables foreign substances
attached to the skin to be discarded with the daily
detachment of scales.
STRATUM CORNEUM
The stratum corneum of human skin is the outer-
most barrier of the body’s surface. The stratum
corneum in humans is approximately 10 to 20 µm
thick and contains about 10 to 25 layers of cornified
cells.6 The stratum corneum is directly exposed to
air and protects the inner cells from damage by des-
iccation. It acts as a two-way barrier to prevent not
only inward penetration of external molecules and
microorganisms but also outward leakage of water 207
and solutes.
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Kang_CH014_p0206-0231.indd 208

2
208
Structure and Function of Skin :: Part 2

TABLE 14-2
Diseases and Their Animal Models Showing Aberrant Stratum Corneum
ANIMAL
CLASSIFICATION GENE PROTEIN FUNCTION DISEASE NAME MIM REFERENCES MODEL

Cornified envelope LOR Loricrin Major component of cornified envelope Vohwinkel syndrome with ichthyosis 604117 24 Mouse153
formation TGM1 Transglutaminase 1 Protein crosslinking to form cornified envelope ARCI 1 242300 20 Mouse16
Cholesterol biosynthesis NSDHL NAD(P)H steroid dehydrogenase-like protein C4 demethylase CHILD syndrome 308050 34 Mouse154
MSMO1 Methylsterol monooxygenase 1 Methylsterol monooxygenase MCCPD 616834 33 —
Acylceramide biosynthesis ELOVL4 Elongation of very-long-chain fatty acid–like 4 Elongation of very-long-chain fatty acids ISQMR 614457 155 Mouse156
CYP4F22 Cytochrome P450 4F22 γ-Hydroxylation of ultra-long-chain fatty acids ARCI5 604777 157 —
CERS3 Ceramide synthase 3 Catalyzing the linkage between a fatty acyl-CoA and ARCI9 615023 158,159 Mouse160
a sphingoid base to produce ceramide
ABHD5 ABHD5/CGI58 ω-O-esterification of ceramide with linoleic acid Chanarin-Dorfman syndrome 275630 161 —
PNPLA1 Patatin-like phospholipase domain containing 1 ARCI10 615024 62 Dog162
ALOX12B Arachidonate 12-lipoxygenase type12R Oxidation of linoleic acid in ceramide ARCI2 242100 163 Mouse164
ALOXE3 Arachidonate lipoxygenase 3 ARCI3 606545 163 Mouse164
Lipid transport ABCA12 ATP-binding cassette A12 Lipid trafficking on the lamellar granule membrane ARCI4A 242500 26,27 Mouse165
ARCI4B (Harlequin ichthyosis)
Desquamation ST14 Matriptase Extracellular serine protease ARCI11 602400 54 Mouse166
SPINK5 LEKTI Inhibitor of kallikrein proteases Netherton syndrome 256500 55 Mouse167,168
Desmosomes and CDSN Corneodesmosin Constituent of the corneodesmosome Peeling skin syndrome 1 270300 56,57 Mouse169
corneodesmosomes DSG1 Desmoglein1 Cell–cell adhesion molecule of the desmosome SAM syndrome 615508 58 —
Filaggrin metabolism FLG Filaggrin Bundling keratin filaments in the stratum corneum, Ichthyosis vulgaris (predisposed to 146700 72,74 Mouse75,170
source of natural moisturizing factors atopic dermatitis)
CASP14 Caspase 14 Profilaggrin processing ARCI12 617320 71 Mouse67
Tight junctions CLDN1 Claudin-1 Cell–cell adhesion molecule of the tight junction NISCH syndrome 607626 104 Mouse102,103

ABHD5, abhydrolase domain-containing 5; ARCI, autosomal recessive congenital ichthyosis; ATP, adenosine triphosphate; CGI58, comparative gene identification 58; CHILD syndrome, congenital hemidysplasia with ichthyosiform eryth-
roderma and limb defects syndrome; CoA, coenzyme A; ISQMR, ichthyosis, spastic quadriplegia, and mental retardation; LEKTI, lymphoepithelial Kazal-type-related inhibitor; MCCPD, microcephaly, congenital cataract, and psoriasiform
dermatitis; MIM, Mendelian Inheritance in Man; NISCH syndrome, neonatal ichthyosis-sclerosing cholangitis syndrome; SAM syndrome, severe dermatitis, multiple allergies and metabolic wasting syndrome.
30/11/18 12:22 pm
 Basic structure of the surface barrier of unicellular and multicellular organisms
2
Occlusive
junction

Outer
barrier
Connective
Basement tissue
membrane

Lipid bilayer
cell membrane
Monocellular organism Multicellular organism

Chapter 14 :: Skin Barrier

A

Simple epithelia Stratified epithelia

KEY Stratum corneum

Tight junction Mucus
Basement
membrane

Mucus, tunic, etc.

Urochordate Fish Amphibian adult,

cephalochordate amphibian tadpole aves, reptiles,
mammals

Vertebrate

B Chordate

Figure 14-1 Basic structure of the surface barrier of unicellular and multicellular organisms. A, The lipid bilayer cell
membrane is a basic diffusion barrier on the body surface of both monocellular organisms and multicellular organisms.
In multicellular organisms, the intercellular spaces are sealed with occlusive junctions to limit leakage of the barrier
through the paracellular pathway (see Fig. 14-9). In essence, both monocellular organisms and multicellular organisms
are equipped with additional outer barriers (ie, a cell wall for monocellular organisms and mucus, cuticles, tunic matrix,
or stratum corneum for multicellular organisms). B, Development of a stratified epithelium and stratum corneum were
the two major evolutional events in vertebrate skin. Under the outer barrier, tight junctions seal the intercellular spaces
in vertebrates.

may cause the stratum corneum to be mistaken for a

BASIC STRUCTURE OF THE
STRATUM CORNEUM
The stratum corneum consists of stratified corneocytes
and an intercorneocyte lipid-rich matrix (Fig. 14-3).
The barrier function of the stratum corneum depends
on both the protein-rich materials of the corneocytes
and the intercellular lipid-rich matrix. Corneocytes
are terminally differentiated dead keratinocytes that
adhere to one another via proteinaceous cell–cell
adhesion complexes called corneodesmosomes and
the adhesive force of intercellular lipid lamellae
(Fig. 14-4). On routine hematoxylin and eosin stain-
ing of paraffin-embedded skin sections, the stratum
corneum shows a basket-weave structure, which
porous structure that does not have a barrier function;
the basket-weave structure is, in fact, an artifact of
the processing of specimens. During paraffin removal
using xylene, intercorneocyte lipid is extracted, and
the intercellular lipid-dependent adhesion between
corneocytes becomes weakened. Because the cor-
neodesmosomes make the lateral adhesions between
corneocytes more stable than the apicobasal adhe-
sions, the corneocyte layers detach from one another
while maintaining their lateral adhesions, resulting in
the formation of a basket-weave structure in paraffin-
embedded sections7,8 (Fig. 14-5). Proper fixation and
staining procedures reveal the tightly packed, well-
organized structure of the stratum corneum in verti-
cal sections of the skin2,9 (see Fig. 14-5). 209

Kang_CH014_p0206-0231.indd 209 30/11/18 12:22 pm

 2 Basic structure of the epidermis and major epidermal barriers

Physical assaults
(dessication, irritation, UV irradiation, heat and cold shock)

Microbial assaults Chemical assaults

(bacteria, fungus, virus) (irritants, allergens)

Scale desquamation

Stratum
Cell differentiation and continuous cell turnover

corneum
Cornification
Part 2

SG1

Stratum SG2 Tight junction

granulosum
SG3
::
Structure and Function of Skin

Prevention of loss
of water, solutes,
Stratum and nutrients
spinosum

Melanin cap

Stratum
basale

Basement
membrane
Cutaneous
Heat control vasculature

KEY
Tight junction LEKTI KLKs
A
Composition of the
acidic extracellular space
Desquamation

Cell Intercellular lipid lamellae

pH gradient

Stratum turnover (Lipid-based air–liquid

corneum interface barrier)

Cornification and
intercellular lipid
neutral barrier formation Extracellular aqueous
SG1 environment outside
TJ barrier tight junction
Stratum (Liquid–liquid
SG2 interface barrier)
granulosum Extracellular aqueous
environment
SG3 inside tight junction

Lamellar body
B

Figure 14-2 Basic structure of the epidermis and major epidermal barriers. A, Epidermal barriers protect the body against
various outside-in physical, chemical, and microbial assaults in addition to inside-out leakage of water and solutes. Mela-
nin caps protect the genomic DNA of basal cells from ultraviolet (UV) damage. Cells are continuously turned over to renew
the epidermis and its barriers. At least three cell layers (SG1, SG2, and SG3 from outside to inside, respectively) exist in the
stratum granulosum under the stratum corneum, where tight junctions (TJs) seal the intercellular spaces between the SG2
cells. B, Intercellular spaces are filled with lipids in, and with water under, the stratum corneum. The extracellular water
environment is considered to be divided into two by the TJ barrier (extracellular space outside TJ barrier, light blue; extra-
cellular space inside TJ barrier, purple). SG1 cells are ready to cornify at the outside TJ barrier. Contents of lamellar bodies
(lipids, antimicrobial proteins, proteases, and protease inhibitors) are basically exocytosed from the apical surface of the
SG2 cells to the outside TJ barrier. Kallikrein proteases (KLKs) are activated via the lower-pH-induced detachment of lym-
phoepithelial Kazal-type-related inhibitor (LEKTI) in the upper layers of the stratum corneum for desquamation. (Modified
from Proksch E, Jensen J-M. Skin as an organ of protection. In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s
210 Dermatology in General Medicine, 8th ed. New York: McGraw-Hill; 2012.)

Kang_CH014_p0206-0231.indd 210 30/11/18 12:23 pm

 Basic structure of the stratum corneum
Corneocyte Intercellular lipid Paracellular route
lamellae of permeation
Lipid-enriched Ceramide coat of Protein-based
extracellular matrix cornified envelope cornified cell
with lipid lamellae (corneocyte lipid envelope
envelope)
Figure 14-3 Basic structure of the stratum corneum.
The stratum corneum comprises protein-based bricks
(corneocytes) and lipid-based mortar (intercellular
lipid lamellae). The surface of the corneocytes is coated
with a thin layer of ceramide (lipid envelope). Details of
how this structure is produced are shown in Fig. 14-6.
(Modified from Proksch E, Jensen J-M. Skin as an organ
of protection. In: Goldsmith LA, Katz SI, Gilchrest BA,
et al, eds. Fitzpatrick’s Dermatology in General Medicine,
8th ed. New York: McGraw-Hill; 2012.)
FORMATION OF A
CORNIFIED CELL ENVELOPE
AND CORNEOCYTE LIPID
ENVELOPE
Granular layer cells terminally differentiate into cor-
neocytes to form the stratum corneum. During cor-
nification, a cornified cell envelope consisting of a
10-nm-thick layer of highly cross-linked insoluble pro-
teins is formed beneath the plasma membrane,10 and
the lipid bilayer of plasma membrane is replaced by a
5-nm-thick layer of acylceramides, which is called cor-
neocyte lipid envelope11-13 (Fig. 14-6).
The formation of a cornified cell envelope and cor-
neocyte lipid envelope is described as follows14,15 (see
Fig. 14-6). Envoplakin, periplakin, and involucrin
expressed in granular layer cells associate with the
inner surface of the plasma membrane in a calcium-
dependent manner and are cross-linked to one another
by transglutaminase 1.16 Transglutaminase 1 also
cross-links to other membrane-associated proteins
and desmosomal proteins, fixing the cell junctions and
associated cytoskeletons to the proteinaceous scaffold.
The involucrin-envoplakin-periplakin–based scaf-
fold eventually forms a monomolecular layer along
Kang_CH014_p0206-0231.indd 211
the entire inner surface of the plasma membrane.10,17-19
Defects in transglutaminase 1 are known to cause con-
2
genital ichthyosis (see Table 14-2).20
Before the scaffold covers the inner surface of the
plasma membrane, lamellar bodies are produced
from the Golgi complex and become fused to the
plasma membrane. The limiting membrane of the
lamellar bodies is rich in acylceramides composed
of omega-hydroxylated ultra-long-chain fatty acids.
The fusion of the limiting membrane with the plasma
membrane gradually increases the amount of acyl-
ceramides within the lipid bilayer of the plasma
membrane. The acylceramides become covalently
bound to the outer surface of the scaffold of the cor-
Chapter 14 :: Skin Barrier
nified envelope by the membrane-anchored form of
transglutaminase 1.21,22 The acylceramides eventually
replace the plasma membrane, which is called the
corneocyte lipid envelope11,12 (see Fig. 14-6).
The involucrin-envoplakin-periplakin–based scaf-
fold is further reinforced in the later stage of corni-
fication. On the inner surface of the scaffold, loricrin
molecules are translocated from the cytosol and cova-
lently cross-linked onto the scaffold to build the corni-
fied cell envelope. Loricrin, an insoluble protein that
may contribute to the water resistance of the cornified
cell envelope, eventually becomes the major compo-
nent of the cornified cell envelope. Varying amounts
of small proline-rich proteins with minor amounts of
other proteins (eg, repetin, trichohyalin, cystatin A,
elafin, and late envelope proteins) are also cross-linked
to the inner surface of the cornified envelope.23 Defects
in loricrin are known to cause congenital ichthyosis
(see Table 14-2).24
FORMATION OF
THE LAMELLAE OF
INTERCORNEOCYTE LIPIDS
Keratinocytes of the stratum granulosum develop a
specific system of lamellar bodies that allow secre-
tion of intercorneocyte lipid lamellae.25 Lamellar bod-
ies are produced from the Golgi complex and stored
within the cytoplasm in SG3 cells as intracellular
vesicles. Lamellar bodies are enriched in polar lipids,
glycosphingolipids, free sterols, and phospholipids.
ABCA12 functions in cellular lipid trafficking on the
limiting membrane of lamellar bodies, in which severe
defects cause Harlequin ichthyosis (see Table 14-2).26,27
The lamellar bodies may also contain proteins, such
as hydrolytic enzymes to modify lipids, corneodes-
mosins to modify corneodesmosomes, antimicrobial
peptides, and proteases and protease inhibitors to
control desquamation. The contents of the lamel-
lar bodies are delivered into the extracellular milieu
through exocytosis occurring via the apical cell mem-
brane, most probably in the SG2 cells and SG1 cells, to
fill the extracellular space surrounding the SG1 cells28 211
(see Fig. 14-2).
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 2 E

De
Part 2

A B
::
Structure and Function of Skin

LB

CD

200 nm 200 nm
C D

Lipid lamellae

200 nm
E

Figure 14-4 Major structures related to cornification, as seen under electron microscopy. A, Desmosomes (De) adhering
to spinous layer cells. B, A lamellar body (LB) exocytosing its contents into the extracellular space at the apical surface of
the SG1 cell. C, Contents of the lamellar body (LB) showing stripes of lipids. D, Corneodesmosomes (CD), cell–cell adhesion
complexes between corneocytes. E, Intercellular lipid lamellae between corneocytes. (Images C and E, used with permis-
sion from Dr. Akemi Ishida-Yamamoto. Images A and D, used with permission from Dr. Toshihiro Nagai. Image B modified
from Proksch E, Jensen J-M. Skin as an organ of protection. In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s
Dermatology in General Medicine, 8th ed. New York: McGraw-Hill;2012.)

The lipids exocytosed from the lamellar bodies are

subsequently organized into a characteristic lamel-
lar structure that lies parallel to the cornified cell
envelope during cornification of the SG1 cells (see
Fig. 14-4). The covalently bound acylceramides of
the corneocyte lipid envelope act as a scaffold allow-
ing regular lamellar formation of the intercellular
lipids (see Figs. 14-4 and 14-6).22 After extrusion of
the lamellar bodies into the extracellular spaces, the
polar lipids are enzymatically converted into non-
polar products. Glycosphingolipids are hydrolyzed
to generate ceramides, and phospholipids are con-
verted into free fatty acids. These lipids form the
intercellular lamellar component of the stratified
lipid bilayer, a very dense structure packed into the
interstices of corneocytes, thus forming a water-
212
impermeable barrier.
LIPID COMPOSITION OF
THE STRATUM CORNEUM
Intercellular lipids are indispensable in the formation
of the permeability barrier of the stratum corneum.
The major classes of lipids in the stratum corneum are
cholesterol, free fatty acids, and ceramides.29
Cholesterol forms part of the plasma membrane
in viable cell layers in the epidermis and part of the
intercellular lipid lamellae in the stratum corneum.
Whereas basal-layer keratinocytes are capable of
resorbing cholesterol from the circulation, epider-
mal keratinocytes actively biosynthesize choles-
terol and free fatty acids (Fig. 14-7). The majority
of the cholesterol in the epidermis is synthesized

Kang_CH014_p0206-0231.indd 212 30/11/18 12:23 pm


A deficiency, respectively33-35 (see Table 14-2).
B body are called essential fatty acids. Essential fatty
C of cholesterol or phospholipids), they are a major
Figure 14-5 Morphology of the epidermis in cross-sec-
tions. A, Hematoxylin and eosin staining of paraffin-
embedded section of human skin showing the basket
weave–like pattern of the stratum corneum. B, Frozen
section of hamster ear skin stained with methylene blue,
expanded in an alkaline solution with a pH of 12 and show-
ing a regular alignment of corneocytes. A remarkably
ordered structure of flattened stratum granulosum cells
and anucleate corneocytes can be seen. The corneocytes
show a regular zigzag interdigitation pattern between
cell columns. C, Frozen section of human abdominal skin
stained with methylene blue and expanded in an alka-
line solution showing partially regular alignment of cor-
neocytes. (Image B from Mackenzie IC. Ordered structure
of the epidermis. J Invest Dermatol. 1975;65:45-51, with
permission; Image C from Mackenzie IC, Zimmerman K,
Peterson L. The pattern of cellular organization of human
epidermis. J Invest Dermatol. 1981;76:459-461, with
permission. Copyright © The Society for Investigative
Dermatology.)
in situ from acetyl coenzyme A (acetyl CoA).30 The
rate-limiting step in cholesterol biosynthesis is cata-
lyzed by hydroxymethylglutaryl CoA (HMG CoA)
reductase (see Fig. 14-7). Epidermal cholesterol bio-
synthesis is upregulated during barrier repair.31 The
cholesterol biosynthesis pathway in the epidermis
is also important for the production of vitamin D.32
Kang_CH014_p0206-0231.indd 213
The metabolic intermediate of cholesterol biosyn-
thesis, 7-dehydrocholesterol, is converted to previ-
2
tamin D in a photolytic reaction by UVB radiation;
this is followed by thermal isomerization to form
vitamin D3. Deficiency in the enzymes of NSDHL and
MSMO1 corresponding to cholesterol biosynthesis
causes inflammatory ichthyotic skin lesions through
the accumulation of toxic intermediates in CHILD
(congenital hemidysplasia with ichthyosiform eryth-
roderma and limb defects) syndrome and MSMO1
The skin contains free fatty acids, as well as fatty
acids bound in triglycerides, phospholipids, glycosyl-
ceramides, and ceramides. Although biosynthesis of
Chapter 14 :: Skin Barrier
cholesterol originates from HMG-CoA, free fatty acid
synthesis originates from malonyl-CoA produced from
acetyl-CoA via acetyl-CoA carboxylase (see Fig. 14-7).
Saturated and monounsaturated fatty acids are syn-
thesized in the epidermis. However, not all fatty acids
can be synthesized by the epidermis or the human
body. Fatty acids unable to be produced by the human
acid deficiency (EFAD), caused by unusual diets or
malabsorption in humans or experimentally induced
in rodents, leads to rough, scaly, and erythematous
skin with severe permeability barrier defects of the
epidermis.36,37
Ceramides consist of long-chain amino alcohols,
called sphingoid bases, linked to a fatty acid via an
amide bond (see Fig. 14-7). Ceramides are synthe-
sized by serine palmitoyltransferase and hydroly-
sis of both glucosylceramide and sphingomyelin
in the epidermis. Whereas ceramides are a minor
lipid component in the mammalian body (<10%
lipid component in the stratum corneum, account-
ing for 30% to 40% of lipids by weight.29 Such a
high ceramide content is only observed in the stra-
tum corneum and not in the stratum granulosum,
stratum spinosum, or stratum basale. This distribu-
tion indicates that ceramide biosynthesis is spatio-
temporally controlled and highly activated in the
uppermost keratinocytes under terminal differen-
tiation to corneocytes.
Among the epidermal ceramides with marked
molecular heterogeneity, acylceramide is essential not
only for the formation of the corneocyte lipid enve-
lope, as described earlier, but also for the proper orga-
nization of intercorneocyte lipid lamellae and thereby
the barrier function of the stratum corneum.38-42 Acyl-
ceramide is synthesized via esterification of omega-
hydroxyceramide with linoleic acid. Acylceramide
is an unusual ceramide, the N-acyl chain of which is
composed of omega-hydroxylated ultra-long-chain
fatty acids (see Fig. 14-7). It has been suggested that
the ultra-long-chain fatty acid of acylceramide spans
a bilayer of lipid lamellae to link the two membranes
together in the lipid lamellae and thus serves as a
molecular rivet to form stratified lipid lamellae.43
Deficiencies of the biosynthesis pathway of acylce-
ramide cause several types of congenital ichthyosis44 213
(see Table 14-2).
30/11/18 12:23 pm
 2 Formation of the cornified cell envelope, corneocyte lipid envelope, and intercorneocyte
lipid lamellae

Differentiation from stratum granulosum cells to corneocytes

3 4 5
Conversion from peripheral Lipid lamellar Conversion from desmosome
cell membrane to corneocyte formation to corneodesmosome
lipid envelope
Desmosome Corneodesmosome
Intercellular space
surrounding SG1 cell
Lipid bilayer
cell membrane Intercorneocyte
lipid lamellae
Corneocyte
lipid envelope
Part 2

(~5 nm thickness)
Acylceramide TG1
Cornified cell
Loricrin envelope
::

Involucrin
and Small (~10 nm thickness)
2 Envoplakin
prorine-rich
Structure and Function of Skin

Secretion of the Periplakvin

proteins
lamellar body
contents
Lipids, proteases, Lattice structure
Keratin protease inhibitors, of keratin filaments
filaments Lamellar and antimicrobial linked with filaggrin
body molecules
6
Formation of cornified
1 envelope by cross-linking
Formation of scaffold proteins via
lamellar body transglutaminzese 1
from Golgi Limiting
membrane
rich in acylceramide

Loricrin
granule

Figure 14-6 Formation of the cornified cell envelope, corneocyte lipid envelope, and intercorneocyte lipid lamellae. The
time-dependent change of cornification (from SG2 cells via SG1 cells to corneocytes) is shown from left to right. A cor-
nified cell envelope is formed beneath the lipid bilayer cell membrane via crosslinking of envoplakin, periplakin, and
involucrin by transglutaminase 1 (TG1), which is further reinforced by loricrin in the later stage of cornification. Lamellar
bodies exocytose their contents to the extracellular space outside tight junctions. The limiting membrane of the lamellar
bodies contains a large number of acylceramides that replace the lipid bilayer cell membrane to form a corneocyte lipid
envelope. As a result, the cornified cell envelope is coated by the corneocyte lipid envelope. The lipids exocytosed from
lamellar bodies form the intercorneocyte lipid lamellae on the corneocyte lipid envelope to fill the intercellular space and
form the water-resistant barrier of the stratum corneum. Corneodesmosin exocytosed from lamellar bodies is integrated
into the desmosome, which is converted to the corneodesmosome. The lamellar bodies also exocytose proteases and
protease inhibitors to control desquamation and antimicrobial proteins (see Fig. 14-12).

of the stratum corneum, and the outermost corneocytes

CORNEODESMOSOMES
Desmosomes are the major cell–cell adhesion structure in
the granular, spinous, and basal cell layers. Corneodes-
mosin is secreted by lamellar bodies into the extracellu-
lar spaces surrounding the SG1 cells (see Figs. 14-2 and
14-6) and then integrated into the desmosomes, result-
ing in the formation of corneodesmosomes (ie, specific
cell adhesion structures between corneocytes)45 (see
Fig. 14-4). Adhesion between corneocytes is dependent
214 on both corneodesmosomes and intercellular lipid lamel-
lae. Corneodesmosomes are degraded in the outer layers
are detached, one by one, from the top layer of the stra-
tum corneum; this process is called desquamation.46
The major proteases involved in the degradation of
corneodesmosomes are serine proteases belonging to
the kallikrein group. Kallikreins 5, 7, and 14 are known
to exist in the stratum corneum. These kallikreins are
also secreted by lamellar bodies into the extracellu-
lar spaces surrounding the SG1 cells (see Fig. 14-2).
Kallikreins are produced as inactive precursors and
activated via proteolytic conversion by kallikreins
themselves (autoactivation) or by matriptase, a trans-
membrane serine protease.47,48 The protease activity

Kang_CH014_p0206-0231.indd 214 30/11/18 12:23 pm

 Synthetic pathways and key enzymes for cholesterol, free fatty acids, ceramides, and acylceramides
2
Acetyl-CoA
HMG-CoA synthase

HMG-CoA Cholesterol synthesis

HMG-CoA reductase
Mevalonic acid

Squalene Deficiencies in
enzymes
Acetyl-CoA Lanosterol Dihydrolanosterol
carboxylase NSDHL / NSDHL / CHILD syndrome
MSMO1 MSMO1 MCCPD

Chapter 14 :: Skin Barrier

Zymosterol Zymostenol

Dehydrodesmosterol 7-Dehydrocholesterol

7-Dehydrocholesterol
reductase Ultraviolet B

Desmosterol Cholesterol Previtamin D

Ceramide synthesis
Fatty acid
synthase ISQMR
Malonyl-CoA Fatty acids ULC-fatty acids
ARCI5

Phospholipase A2
Phospholipids

Serine + Palmitoyl-CoA

Ceramide synthase
Sphinganine Ceramides ARCI9
Chanarin-Dorfman
Food intake Linoleic acid syndrome
(Essential ARCI10
fatty acids) Acylceramides ARCI2
ARCI3

Figure 14-7 Synthetic pathways, key enzymes and deficiencies in the enzymes for cholesterol, free fatty acids, cerami-
des, and acylceramides. CoA, coenzyme A; HMG-CoA, hydroxymethylglutaryl CoA; CHILD syndrome, congenital hemi-
dysplasia with ichthyosiform erythroderma and limb defects syndrome; MCCPD, microcephaly, congenital cataract, and
psoriasiform dermatitis; ISQMR, ichthyosis, spastic quadriplegia, and mental retardation; ARCI, autosomal recessive con-
genital ichthyosis; NSDHL, NAD(P) dependent steroid dehydrogenase-like; MSMO1, methylsterol monooxygenase 1; ULC,
ultra-long-chain.

of the activated kallikreins is thought to be inhibited
by the direct binding of lymphoepithelial Kazal-type-
related inhibitor (LEKTI), which is also secreted into
the intercellular spaces via lamellar bodies.49 The
production of kallikreins as inactive precursors, and
the inhibition of their protease activity by LEKTI, are
considered to prohibit the degradation of corneodes-
mosomes in the lower layer of the stratum corneum
and thus prevent premature desquamation.50 LEKTI
binding to kallikreins has been shown to be pH depen-
dent. The lower pH of the intercellular spaces in the
outer layers of the stratum corneum is thought to facil-
itate the dissociation of kallikreins from LEKTI and the
kallikrein-dependent degradation of corneodesmo-
somes (see Fig. 14-2).51-53 The outermost corneocytes
eventually detach from the skin.
Congenital defects of matriptase induce congenital
ichthyosis showing hyperkeratosis and impaired deg-
radation of corneodesmosomes, probably caused by
insufficient activation of kallikrein proteases.54 In con-
trast, congenital defects of LEKTI induce Netherton
syndrome, in which entire layers of the stratum cor-
neum are prone to being peeled off, probably caused
by the enhanced degradation of corneodesmosomes
by kallikreins.55 Such detachment of whole layers of
the stratum corneum is also observed in the congeni-
tal defects of corneodesmosin or desmoglein 156-58 (see
Table 14-2). Patients prone to total detachment of the
stratum corneum are predisposed to various allergic
conditions, probably via increased allergen penetra-
tion through the defective skin barrier and facilitation 215
of percutaneous sensitization.5,59

Kang_CH014_p0206-0231.indd 215 30/11/18 12:23 pm

 2 KERATIN CYTOSKELETON
AND FILAGGRIN
Filaggrin is the major protein of the stratum cor-
neum. Various mutations in the filaggrin gene predis-
pose patients to atopic eczema, allergic rhinitis, food
allergies, and asthma complicated with eczema.60-63
In humans, filaggrin is expressed only in cornified
stratified epithelia; therefore, it is expressed in skin
but not in the esophagus or airways.64 Profilaggrin
is expressed in the stratum granulosum and forms
intracellular aggregates known as keratohyalin gran-
ules. Under cornification, profilaggrin is processed by
various proteases into mature filaggrin monomers63
(Fig. 14-8). Filaggrin monomers bundle keratin

Multi-domain structure of the stratum corneum and multi-step maturation/degradation of filaggrin

H2O Hg 2+, Cr 2+, K+ Allergens UV

Part 2

Fluorescein
::

Water-soluble small molecules

Structure and Function of Skin

Corneocytes of permeate into the upper layers of

the upper SC the stratum corneum where protein
structure is proteolytically degraded.

Caspase 14 plus
additional peptidases Amino In the middle layers of the stratum
Bieomycin
Corneocytes of hydrolase
acids
corneum, filaggrin degraded into
the middle SC +UCA
+PCA natural moisturizing factors.

Intermediate species NMF

PAD1 and
PAD3 TGMs
In the lower layers of the stratum
Corneocytes of corneum, filaggrin monomers
the lower SC Formation of bundle keratin filaments.
keratin-based Nucleus
matrix
Nuclei and intracellular
organella are degraded.
Profilaggrin
Ca2+
Dephosphorylation Profilaggrin proteolytically
Proteolysis Multiple protease degraded into mature
filaggrin monomers.
Cornification

Mature filaggrin A and B domain of profilaggrin

Nucleus monomers move into the nucleus.

Keratohyalin
granules
Profilaggrin forms keratohyalin
granules.

Stratum Keratin IFs

KEY
granulosum
Profilaggrin
A domain Filaggrin
Nucleus B domain Free
amino
C-terminal domain acid

Figure 14-8 Multidomain structure of the stratum corneum and multistep maturation and degradation of filaggrin. The
stratum corneum is thought to consist of at least three types of corneocytes undergoing different differentiation steps
(corneocytes of the lower, middle, and upper stratum corneum). NMF, natural moisturizing factor; PAD, peptidylarginine
deiminase; PCA, 2-pyrrolidone-5-carboxylic acid; IF, intermediate filament; SC, stratum corneum; TGM, transglutaminase;
216 UCA, urocanic acid. (Modified from McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease.
J Allergy Clin Immunol. 2013;131(2):280-291.)

Kang_CH014_p0206-0231.indd 216 30/11/18 12:23 pm

 intermediate filaments and may form a lattice struc-
ture in the lower layer of the stratum corneum.65,66
The lattice structure can be observed under electron
microscopy. In the later stage of cornification, keratin
filaments bundled with filaggrin become cross-linked
to the cornified cell envelope. The dead cornified cells
lose most of their intracellular organelles and consist
mostly of bundled intermediate filaments covalently
attached to, and enclosed within, the cell envelope.
FILAGGRIN DEGRADATION
AND NATURAL
MOISTURIZING FACTORS
Filaggrin monomers bundle keratin filaments in the
innermost layers of the stratum corneum. Because
new corneocytes are continuously supplied at the
bottom and old corneocytes are desquamated from
the surface of the stratum corneum, each corneocyte
gradually moves to the upper layers. During this
upward movement of the corneocyte, intracellular
filaggrin molecules are degraded into free amino
acids and their derivatives by proteases, including
caspase 14 and bleomycin hydrolase. Representative
examples of the derivatives are trans-urocanic acid
catalyzed from histidine by histidase and pyrrol-
idone carboxylic acid catalyzed from glutamine.63,67-69
The natural moisturizing factors of the stratum cor-
neum are composed primarily of these amino acids
and their derivatives, together with lactic acid,
urea, citrate, and sugars.61,70 Deficiency of caspase
14 causes a defect in the proper degradation of
filaggrin and the resultant phenotype of ichthyosis71
(see Table 14-2).
Haploinsufficiency of filaggrin, because of various
heterozygous mutations in the gene encoding filag-
grin, causes ichthyosis vulgaris, a dry skin condition,72
and predisposes patients to atopic dermatitis and
various allergic diseases accompanied by eczema
(eg, food allergy and asthma)73,74 (see Table 14-2).
The decrease in filaggrin induces a decrease in natu-
ral moisturizing factors, a disturbance of the lattice
structure of the keratin filaments in the innermost lay-
ers of the stratum corneum, and a probable increase
in the incidence of barrier breakage of the stratum
corneum.75 Such a weakness in the stratum corneum
barrier may increase the chance of external allergens
penetrating into the skin and the risk of percutaneous
sensitization against various allergens. Most patients
with severe stratum barrier defects, such as those with
Netherton syndrome, have multiple allergies. In con-
trast, most patients who have mutations in the filag-
grin gene basically develop ichthyosis vulgaris, and
only some of these patients develop allergic diseases.
This suggests that the barrier deficiency induced by
filaggrin mutations is moderate and that the develop-
ment of allergic diseases in these patients is modu-
lated by various additional factors, such as genetic
differences in immune reactions,76 differences in the
Kang_CH014_p0206-0231.indd 217
skin microbiota,77-79 and environmental factors such as
low air humidity80 and air pollution.81
2
MULTIDOMAIN STRUCTURE
OF THE STRATUM
CORNEUM
Conventional cell biological analyses of the stratum
corneum have been hampered by the insolubility of
covalently cross-linked proteins. To overcome this dif-
ficulty, the stratum corneum has been analyzed by vari-
Chapter 14 :: Skin Barrier
ous special methods, such as cryoelectron microscopy,
immunoelectron microscopy, Raman spectromicros-
copy analysis, and time-of-flight secondary ion mass
spectroscopy.82-85 Based on the results of these analyses,
the stratum corneum is considered to be divisible into
several different parts with different characteristics,
most likely into three parts (the upper, middle, and
lower layers). For example, water-soluble small mol-
ecules soak in and out at the upper part of the stratum
corneum, where the protein-based structure of the cor-
neocytes is proteolytically degraded, and the corneo-
cytes are thought to function as a sponge.83,85 Further
permeation of water-soluble small molecules into the
middle part of the stratum corneum is rather limited,
indicating that permeation barriers exist within the
middle part of this structure.83 The middle part of the
stratum corneum also has a large potential to absorb
and hold water, likely corresponding to the enrichment
of natural moisturizing factors, which are mostly pro-
duced by the degradation of mature filaggrin.63,82 The
corneocytes of the lower part of the stratum corneum
show an intracellular lattice structure of keratin fila-
ments, integrated by mature filaggrin monomers, which
is believed to contribute to the physical strength of the
stratum corneum84 (Fig. 14-9). The stratum corneum
is a pile of “dead” corneocytes that lack any energy-
dependent activities, such as adenosine triphosphate–
dependent active transport, translation of proteins, and
mRNA transcription. It is still largely unknown how
the stratum corneum maintains homeostasis using the
distinct features in its upper, middle, and lower layers.
PERCUTANEOUS
ABSORPTION THROUGH
THE STRATUM CORNEUM
Knowledge of how external molecules penetrate the epi-
dermis is important not only for a better understanding
of the pathogenesis of various skin diseases but also for
the development of drug delivery for topical treatments.
The paracellular route is a major pathway by which
external molecules can penetrate the stratum corneum
(see Fig. 14-3). Other routes of penetration into the skin
are by the sebaceous glands or hair follicles, but the exact 217
mechanisms of these pathways remain to be elucidated.86
30/11/18 12:23 pm
 2 Tight junction barrier and cell polarity in simple and stratified epithelial cellular sheets

Outside TJ Simple epithelium Outside TJ Cornified epidermis

corneum
Stratum
Apical
membrane TJ SG1

Stratum granulosum
SG2

SG3
Part 2

Basolateral
membrane
Paracellular Transcellular
Inside TJ pathway pathway Inside TJ
::
Structure and Function of Skin

Cell membrane Claudins

TJ strands

N
C

Occludin

100 nm
C

Intercellular space

Figure 14-9 Tight junction (TJ) barrier in simple and stratified epithelial cellular sheets. The extracellular environment
and plasma membrane are divided into two parts at the TJ barrier in simple epithelia. Solutes move between the two
compartments via paracellular and transcellular pathways. In the epidermis, increasing evidence suggests that both the
extracellular environment and plasma membrane are also divided into two parts at the TJ barrier formed between the
SG2 cells, the extracellular environment outside and inside the TJ barrier, and the apical and basolateral cell membrane. In
the electron micrograph (left panel), a TJ appears as a “kissing point” (arrows) where two plasma cell membranes face each
other. The schematic shows the structure of TJ strands on the cell membrane and major transmembrane proteins of TJs. C,
C-terminus; N, N-terminus. (Image used with permission from Dr. Hiroyuki Sasaki.)

Occlusive patches used in patch testing affect the intercor-
neocyte lipid lamellae and increase the permeation of sol-
utes and solvents through the stratum corneum.87 After
passing through the stratum corneum, small molecules
such as haptens can easily permeate the dermis, probably
through the transcellular pathway (see Fig. 14-9). In con-
218 trast, large peptide antigens, such as the antigens of house
dust mites or egg albumin, not only find it difficult to pass
through the stratum corneum barrier but are also prohib-
ited from further permeation into the skin by the tight
junction barrier. Recent studies revealed that a defective
stratum corneum barrier in early childhood is associated
with the development of various allergic diseases, such
as atopic dermatitis, allergic asthma, and food allergies,
probably via enhanced antigen penetration through the
stratum corneum and percutaneous sensitization.74,88-91

Kang_CH014_p0206-0231.indd 218 30/11/18 12:23 pm

 TIGHT JUNCTIONS
Multicellular organisms use epithelial cellular sheets to
separate their body from the external environment or
their organs from one another. Epithelia serve as selec-
tive permeability barriers to fluids that differ in chemi-
cal composition (Fig. 14-10). The occluding junctions
are specialized intercellular adhesion complexes that
are crucial for limiting molecular movement through
the paracellular pathway (see Fig. 14-10) because they
seal the intercellular spaces of the epithelial cellular
sheets.92 Tight junctions facilitate this barrier in verte-
brates. In the gut of humans, for example, gut epithelia
equipped with tight junction barriers separate body
consist of tight junction strands, which are mainly com-
posed of four-transmembrane proteins of claudins on
2
the plasma membrane that probably function as a zip
lock to seal the adjacent plasma membrane, thereby
forming a barrier against molecular movement through
the paracellular pathway (see Fig. 14-9).94,95 Other major
components of tight junctions are the transmembrane
proteins of occludin, junctional adhesion molecule A
(JAM-A), tricellulin, and angulins, and the intracellu-
lar scaffold proteins of ZO-1, 2, and 3.96,97 Tight junc-
tions do not simply form an impermeable barrier but
also serve as ion- and size-selective barriers that vary in
tightness depending on the cell type and the composi-
tion of their structural adhesive molecules.97-99

Chapter 14 :: Skin Barrier

fluids from the fluid of the gut lumen.

STRUCTURE OF TIGHT
JUNCTIONS
In simple epithelia, the tight junctions are located at
the apical-most part of the apical junctional complex93
(see Fig. 14-9). The apical junctional complex consists of
tight junctions, beltlike adherens junctions, and desmo-
somes. The cell membrane is divided into two parts at
the tight junctions—the apical cell membrane and baso-
lateral cell membrane—both of which has a different
composition of membranous proteins. Tight junctions
FUNCTION OF TIGHT
JUNCTIONS
Observations of normal human trunk skin and mouse
ear, abdominal, and back skin revealed that only the
single-layer cells of the SG2 layer are equipped with
tight junctions and show apical and basolateral cell
membrane polarity in the epidermis (see Figs. 14-2 and
14-9).100,101 The extracellular spaces of the epidermis are
divided into two parts by the tight junction barrier.5
The SG2 and SG1 cells secret various molecules (ie, lip-
ids and proteases) via lamellar body secretions from

Spatial location of the stratum corneum, tight junctions, and Langerhans cells

Ag
TJ barrier

Stratum
Ag uptake
corneum

SG1 Outside of
TJ barrier
Stratum SG2
granulosum
SG3

Stratum
spinosum Inside of
TJ barrier

Steady- Actiated
state LC LC

Stratum
basale
Basement
membrane

Figure 14-10 Spatial location of the stratum corneum, tight junctions (TJs), and Langerhans cells. SG2 cells form TJs (closed
circle in dark green). SG1 cells are located outside the TJ barrier (light blue). In contrast, SG3 cells, spinous layer cells, and Lang-
erhans cells are located inside the TJ barrier (purple). Dendrites of Langerhans cells in a steady state (left yellow cell) are located
beneath the TJ but penetrate through the TJ barrier in their activated state (right yellow cell) to access to the outside TJ barrier. 219
Antigen (Ag) uptake occurs from the tip of the dendrites (indicated by Ag uptake) at the outside TJ barrier.

Kang_CH014_p0206-0231.indd 219 30/11/18 12:23 pm

 2 their apical cell membrane into the extracellular spaces
surrounding the SG1 cells, which are outside the tight
junction barrier and are probably segregated from
the environment inside the tight junction barrier (see
Fig. 14-2).
A lack of claudin-1, a major claudin of the epidermis,
causes leakage of the epidermal tight junction barrier
and deficient formation of the stratum corneum bar-
rier in mice, resulting in early neonatal death (prob-
ably caused by water loss from the body surface).102
Decreased claudin-1 expression in mice induces an
ichthyosis phenotype and skin inflammation.103 A lack
of claudin-1 in humans results in a very rare congenital
disease called neonatal ichthyosis sclerosing cholangi-
Part 2
tis syndrome104 (see Table 14-2). These observations
indicate that a functional tight junction barrier is cru-
cial for proper formation of the stratum corneum bar-
rier and maintenance of epidermal homeostasis.
::
Structure and Function of Skin
INTERACTION BETWEEN
TIGHT JUNCTION BARRIERS
AND INTRAEPIDERMAL
IMMUNE-MEDIATED CELLS
Langerhans cells are antigen-presenting cells that are
found in the epidermis and have multiple dendrites.
They stay below the tight junction and project their
dendrites upward in their steady state in both human
and mice epidermis.101,105 After activation, Langerhans
cells extend their dendrites beyond the tight junction
barrier and capture external antigens that penetrate
through the stratum corneum (see Fig. 14-10). During
this process, new tight junctions are formed between
Langerhans cell dendrites and keratinocytes of the SG2
layer, enabling the uptake of external antigens without
disturbing the barrier function of the tight junctions.
The Langerhans cells migrate out from the epidermis,
present the captured antigens to T cells in draining
lymph nodes, and are considered to induce humoral
immunity to the captured antigens.101,106
γ-δ T cells are a minor subpopulation of T cells that
express T-cell receptor γ and δ. In the human epider-
mis, γ-δ T cells are rare; however, a large proportion
of T cells are γ-δ T cells in mice epidermis.107-110 The
dendrites of γ-δ T cells have been shown to dock with
the basal side of the tight junction-bearing cells in mice
epidermis, forming immunologic synapses that polar-
ize and anchor T cell projections at keratinocytes.111
SHAPE OF KERATINOCYTES
FOR SKIN BARRIER
HOMEOSTASIS
220 Corneocytes form according to a regular stacking
structure, with regular zigzag interdigitation patterns
Kang_CH014_p0206-0231.indd 220
between adjacent cell columns (see Fig. 14-5B). This
regularly interdigitated stacking structure is most
apparent in the skin of rodent ears but is also observed
in the skin of other body regions in rodents, as well as
in human skin.112 Classic scanning electron microscopic
studies of the skin surface corneocytes of the murine
ear and a recent immunofluorescent microscopic
study of the tight junction-bearing granular layer cells
of the murine ear revealed that the basic shape of the
cell is a flattened variation of Kelvin’s tetrakaideca-
hedron (see Table 14-1) in the stratum corneum and
stratum granulosum4,113,114 (Fig. 14-11). The regular
interdigitation pattern of the corneocytes is believed
result from the regular interdigitated stacking of the
flattened tetrakaidecahedron cells (see Figs. 14-5B
and 14-11C). Computational simulation and in vivo
imaging studies suggested that this regular structure
is formed at the granular layer by transformation of
the three-dimensional shape of cells supplied from
the spinous layer, although the precise molecular
mechanisms underlying the cell shape change are
still unknown.4,115-117 Only a single layer of cells (SG2
layer cells) form tight junctions at the apical edges of
lateral cell–cell contacts. Therefore, tight junctions are
formed at the edges of tetrakaidecahedron cells (see
Fig. 14-11). When a tight junction-forming cell (an old
cell) is replaced by a new cell located just beneath the
old cell, the new cell first forms a new tight junction
polygon beneath the old cell. Thus, each tight junc-
tion polygon becomes temporally double-edged dur-
ing cell replacement (see Fig. 14-11). After that, the
tight junction polygon of the old cells disappears,
and eventually, the old cell is extruded to the outside
of the tight junction barrier (the outside of the SG2
cell layer that forms the tight junction barrier). The
temporal formation of the double-edged tight junc-
tion polygon at each cell turnover site maintains the
homeostasis of the tight junction barrier.4 The regular
interdigitated stacking of the flattened tetrakaideca-
hedron cells enables not only the temporal formation
of the double-edged tight junction polygon but also
to maintain the spatial relationship between cells and
desmosomal cell–cell adhesions during cell turnover
that may be responsible the physical strength of the
epidermis.4 The molecular mechanisms that restrict
tight junction-forming activity to the SG2 cell layer
in the epidermis, the spatiotemporal regulation of
cell turnover while maintaining tight junction bar-
rier homeostasis, and the manner in which the tet-
rakaidecahedron cell shape is produced are currently
unknown.
ANTIMICROBIAL BARRIER
ANTIMICROBIAL PROPERTY
OF THE SKIN SURFACE
The skin constantly encounters microbial patho-
gens. Control of the skin microbiota is important to
prevent bacterial and fungal infections. Continuous
30/11/18 12:23 pm
 Three-dimensional cell shape and a model for cell replacement in the epidermis
2
Tight junction–bearing cells Corneocytes at the surface
in the stratum granulosum of the stratum corneum
Schema of the epidermis based 2
on the tetrakaidekahedron cell shape 3

Stratum corneum
7
1

Stratum granulosum
6
SG1
SG1 S 5
SG1
TJ SG2 TJ
SG2 TJ TJ S
SG2
SG3
SG3 S
SG3

Chapter 14 :: Skin Barrier

A

Kelvin’s tetrakaidecahedron Flattened Kelvin’s

tetrakaidecahedron

Double-edged TJ polygon in the epidermis

Stack of flattened Kelvin’s tetrakaidecahedron KEY

Tight
junction

SG2 SG2 SG2

SG2

B C

2
2 2 2 SG 2
SG SG SG SG

2 2 2 2 2
SG SG SG SG SG
2 SG

Time-dependent TJ replacement and cell extrusion to the outside TJ barrier

D

Figure 14-11 Three-dimensional cell shape of corneocytes and tight junction (TJ)–forming cells. A, Three-dimensional
polyhedral shape of TJ-forming cells in immunofluorescent microscopic view (left panel) and the equivalent shape of cor-
neocytes at the surface of the stratum corneum in scanning electron microscopic view (right panel) suggest that the basic
shape of stratum granulosum cells and corneocytes is a flattened variation of Kelvin’s tetrakaidecahedron. B, Kelvin’s tet-
rakaidecahedron flattened variation of Kelvin’s tetrakaidecahedron, and regular interdigitated stacks of flattened Kelvin’s
tetrakaidecahedron cells. SG2 cells are displayed at the top of cell columns. Three different Z-axis positions of the SG2 cells
are displayed in yellow, pink, and blue on the apical surface of the cells. Tight junctions (green edges) located at the apical
edges of the cell-cell contact between SG2 cells. C, En face view of the TJs (green edges stained by anti-ZO-1 antibody)
in mouse ear skin. Essentially, tight junction polygons are single edged. The double-edged polygon (asterisk) is the site
where a new TJ polygon is formed to relocate a cell from inside to outside of the TJ barrier. D, Conceptual model for the
formation of the double-edged TJ polygon (asterisk) during cell turnover from inside to outside of the TJ barrier. A new
TJ polygon is formed beneath the center yellow-colored cell (asterisk, left panel), resulting in the formation of a double-
edged polygon (middle panel). Then, the outer old polygon is degraded (right panel). The center yellow-colored cell in the
left panel (asterisk) is relocated from inside the TJ barrier (left panel) to outside of the TJ barrier (right panel) after the tem-
poral formation of the double-edged polygon (middle panel). (The scanning electron microscopic picture on the right side
of Image A, is reproduced with permission of Springer Nature from Allen TD, Potten CS. Significance of cell shape in tissue
architecture. Nature. 1976;264:545-547.) The immunofluorescent pictures of parts A and C and schemas in B and D are from 221
Yokouchi M, Atsugi T, Logtestijn M, et al. Epidermal cell turnover across tight junctions based on Kelvin’s tetrakaidecahedron
cell shape. Elife. 2016;5:e19593.

Kang_CH014_p0206-0231.indd 221 30/11/18 12:23 pm

 2 turnover of epidermal cells by desquamation pro-
hibits colonization of microorganisms on the skin.
The physical properties of the skin surface itself
prevents bacterial growth, that is, a low carbohy-
drate and water content and a weakly acidic pH (a
pH of 5.6 to 6.4).118-120 The weak acidic pH is due to
various substances, such as free fatty acids secreted
from sebaceous glands or derived from phospho-
lipid hydrolysis in the stratum corneum, lactic acid
secreted from derived from the eccrine glands, uro-
canic acid mostly derived from the degradation
products of filaggrin, and metabolites produced by
microorganisms.121 The epidermis is also equipped
with an active antimicrobial defense system com-
Part 2
ANTIMICROBIAL PROTEINS
ON THE SKIN SURFACE
Antimicrobial proteins are evolutionarily ancient
innate immune effectors produced by almost all plants
and animals.122,123 Antimicrobial proteins show a broad
antibacterial activity against both gram-positive and
-negative bacteria; some even show antifungal or
antiviral activity. The antimicrobial activity of most
proteins occurs as a result of their unique structural
characteristics, which enable disruption of the micro-
bial membrane while leaving host cell membranes
intact. These proteins also act as “alarmins” to alert

prising antimicrobial proteins (Table 14-3).

host cells to react to injuries and microbial invasions.124
Many proteins act as antimicrobial proteins/
alarmins in the skin, including short proteins, such as
::

β-defensins, cathelicidins, dermcidin, psoriasin, neu-

TABLE 14-3
Structure and Function of Skin

ropeptides, and chemokines, and larger proteins, such

Antimicrobial Proteins on the Skin Surface as lysozymes, elastase, complement, and the S100 pro-
teins. The variety of these antimicrobial proteins may
ANTIMICROBIAL reflect the complexity and long history of the microbial
PEPTIDES EXPRESSION FUNCTION
challenges at the skin surface.
Human Epidermis Antimicrobial activity against The epithelial cells lining the surface of the intestine,
β-defensin 1 gram-negative bacteria respiratory tract, reproductive tract, and skin are the
Role in keratinocyte major source of antimicrobial proteins. Each epithe-
differentiation
lium has many characteristic antimicrobial proteins
Human Epidermis Inducible by microbial compo- that are necessary for each microenvironment. Catheli-
β-defensin 2 nents (Pseudomonas aerugi- cidins and β-defensins are the two major antimicrobial
nosa, Staphylococcus aureus, proteins of the skin and show a broad spectrum of anti-
Candida albicans)
microbial activity in vivo.125
Inducible by TNF-α IL-1
Antimicrobial activity
against Escherichia coli and
P. aeruginosa
Weakly bacteriostatic against
gram-positive bacteria
CELLS THAT PRODUCE
Human Epidermis Induced by TNF-α and bacteria ANTIMICROBIAL PROTEINS
β-defensin 3 Bactericidal activity against
Gram positive bacteria Keratinocytes produce various antimicrobial proteins
(S. aureus and vancomycin-
to defend the skin (Fig. 14-12). In particular, kerati-
resistant Enterococcus faecium)
nocytes in the hair follicle constitutively produce cat-
Cathelicidin Keratinocytes Vitamin D is a major inducer helicidins and β-defensins at a higher level than the
(LL-37) Mast cells Antibacterial, antifungal, and
keratinocytes of the interfollicular epidermis, prob-
Neutrophils antiviral activities
ably because the microenvironment of hair follicles
Eccrine gland Attracts mast cells and
ductal cells neutrophils
facilitates bacterial colonization much more readily
than that of the interfollicular epidermis. Secretory
Psoriasin Keratinocytes Bacterial membrane
cells of the skin, such as those in the eccrine, apocrine,
(S100A7) permeability
and sebaceous glands, secrete their own antimicrobial
Bactericidal against E. coli
Chemoattractant for CD4 cells
proteins and lipids and contribute to the antimicrobial
and neutrophils activity of the skin surface. In the dermis, mast cells
produce large amount of cathelicidins and store them
RNase 7 Stratum Broad spectrum antimicrobial
corneum activity (S. aureus,
within intracellular granules. After skin injuries, mast
Propionibacterium acnes, cells secrete cathelicidins to resist bacterial and viral
P. aeruginosa, E. coli, infections.126 Additionally, commensal bacteria pro-
C. albicans) duce their own antimicrobial proteins. For example,
Induced by IL-1β, IFN-γ, γ
γ, Staphylococcus epidermidis, the dominant commensal
bacterial challenge bacterium of the skin microbiota, produces several
IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α. antimicrobial proteins.127,128 These various antimicro-
From Modlin RL, Miller LS, Bangert C, et al. Innate and adaptive immunity bial proteins derived from host cells and microorgan-
222 in the skin. In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s isms can modulate or regulate the composition of the
Dermatology in General Medicine, 8th ed. New York: McGraw-Hill; 2012. skin microbiota.

Kang_CH014_p0206-0231.indd 222 30/11/18 12:23 pm

 Antimicrobial proteins produced by host cells and commensal bacteria
2
Host-derived AMP Commensal-derived
BD1, BD2, Lysozyme AMP (eg, PSMγ
Staphylococcus BD3 and BD4 SLPI
epidermidis or PSMδ)
Cathelicidin Elafin
RNase7 αMSH
Stratum
Psoriasin Catestatin
corneum
Lactoferrin Calprotectin

Viable cell
layers of the
epidermis

Chapter 14 :: Skin Barrier

Cathelicidin

Mast cell
Dermis
Sebocytes

Eccrine
gland

BD1 and BD2 Cathelicidin

Histone H4 Dermcidin
Psoriasin BD1 and BD2
Cathelicidin
Eccrine epithelial cells

Figure 14-12 Antimicrobial proteins produced by host cells and commensal bacteria. AMP, antimicrobial proteins; BD,
beta defencins; PSM, phenol soluble modulin; MSH, melanocyte-stimulating hormone; SLPI, secretory leukocyte protease
inhibitor. (Adapted with permission from Springer Nature from Gallo RL, Hooper LV. Epithelial antimicrobial defence of the
skin and intestine. Nat Rev Immunol. 2012;12:503.)

cell. For example, LL-37, the human member of the

FUNCTIONS OF
ANTIMICROBIAL PROTEINS
Antimicrobial proteins have various mechanisms
of action122,129,130; many target the cell wall or cell
membrane structure of microorganisms. For exam-
ple, defensins and cathelicidins are usually cationic
and interact with the bacterial membrane surface
through electrostatic interactions. Some defensins
form pores in the bacterial membrane to disrupt
membrane integrity and promote bacterial lysis.
Cathelicidins bind to bacterial membranes and
promote membrane insertion and disruption. The
mechanisms of action of several antimicrobial pro-
teins remain unclear.
Increasing evidence indicates that some antimicro-
bial proteins modulate immune signaling through
chemokine receptors and Toll-like receptors. Antimi-
crobial proteins not only stimulate chemokine and
cytokine secretion from a variety of cell types but
also use chemotactic activity to recruit leukocytes by
direct or indirect mechanisms to modify the inflam-
matory response.122,131-133 The chemotactic activities of
different types of antimicrobial proteins are distinct
from one another, and each recruits different types of
cathelicidin family of antimicrobial peptides, recruits
neutrophils, T cells, monocytes, and mast cells. LL-37
also induces keratinocytes through the mitochondrial
antiviral signaling pathway to promote the production
and secretion of interferon-β, which activates antiviral
responses.134 Toll-like receptors are transmembrane
receptors for pattern recognition and are activated
by the conserved structural pattern of microbial mol-
ecules, such as lipopolysaccharides, flagella, endotox-
ins, RNA, and DNA.135 Toll-like receptor signaling is
not restricted to such microbial molecules but can also
be initiated by some antimicrobial proteins, allowing
the immune cell responses to be modified.136
EPIDERMAL BARRIER
OF NEWBORN SKIN
Full-term newborn babies have a well-developed and
functional skin barrier at birth.137 Although infant skin
has a thinner stratum corneum with low levels of natu-
ral moisturizing factors and greater transepidermal
water loss compared with adult skin, transepidermal
water loss in healthy full-term newborns at birth is 223
equal to or lower than that of adult skin (Table 14-4).138-140

Kang_CH014_p0206-0231.indd 223 30/11/18 12:23 pm

 2 TABLE 14-4
Similarities and Differences among Newborn, Infant, and Adult Skin
FULL-TERM
COMPOSITIONAL DIFFERENCES PRETERM NEWBORN SKIN NEWBORN SKIN INFANT SKIN ADULT SKIN REFERENCE

Epidermal surface Lacking the stratum corneum Coated by the Thin stratum Thick stratum 137,140,171
(<24 wk of gestation) vernix caseosa corneum corneum
Lacking the vernix caseosa
(<28 wk of gestation)
Natural moisturizing factors None or only in a few layers High in the vernix Low in the stratum High in the stra- 139,172
of the stratum corneum caseosa corneum tum corneum
(<26 wk of gestation)
Surface pH — High Low Low 173-175
Part 2

Sebum — — Low (7-12 mo old) High 176

Stratum corneum water content — — High Low 139
Dermal collagen fiber density — — Low High 140
::

Functional Differences
Structure and Function of Skin

Rate of water absorption — — High Low 139

Transepidermal water loss Very high to high (depending Low High Low 139
on gestation period)

The stratum corneum is developed in utero under

exposure to amniotic fluid, while extensive water expo-
sure disrupts the stratum corneum barrier in adult skin.
One putative mechanism for stratum corneum barrier
development in utero is the formation of the fetal bio-
film vernix caseosa, which coats the entire skin during
the third (last) trimester.141 The vernix caseosa is a com-
plex mixture of water, proteins, and lipids; fetal corneo-
cytes swollen with water are distributed throughout an
amorphous mixture of lipids. The vernix protects the
epidermis from amniotic fluid and facilitates formation
of the stratum corneum beneath it. Vernix retention
after birth, compared with vernix removal immedi-
ately after birth, has been reported to result in greater
skin hydration and a lower skin surface pH at 24 hours
after birth.141 Moreover, vernix contains antimicrobial
agents, including lysozyme and lactoferrin and exhib-
its antifungal and antibacterial activities.142-144 This evi-
dence implies value in retaining the vernix rather than
removing it immediately after birth, as recommended
by the World Health Organization.145
Unlike a full-term infant, a premature infant has a
weak epidermal barrier and mechanically fragile der-
mis at birth. Babies born before 28 weeks of gestation
lack the covering of the vernix. Newborns with very
low birth weight have a greater risk of skin damage as
a result of their insufficient skin barrier. Babies deliv-
ered at 25 weeks of gestation have only a few layers of
the stratum corneum at birth and show transepidermal
water loss of about 70 g/m2/hr.146 The transepider-
mal water loss at birth in preterm newborns gradually
decreases to about 7 g/m2/hr until 35 weeks’ gestation,
around which time the epidermal barrier becomes well
developed in utero. The epidermal barrier continues to
develop after birth, but the transepidermal water loss
224 of extremely preterm infants is significantly higher than
that of full-term infants even at 1 month after delivery.146
BARRIER AGAINST
PHYSICAL STRESSES
PHYSICAL STRUCTURE
PROTECTING AGAINST
MECHANICAL STRESSES
The skin, which protects our body from various
mechanical physical stimuli, consists of stripes of rigid
and soft tissues, that is, the rigid stratum corneum, soft
layers of keratinocytes, rigid collagenous tissue of the
dermis, and soft cushion of the hypodermis (which is
rich in adipocytes). Deficits in the physical strength,
and defects in the border, of each stripe cause various
diseases that lead to physical weakness, such as epider-
molytic ichthyosis; simple, junctional, and dystrophic
epidermolysis bullosa; and Ehlers-Danlos syndromes
(see Chaps. 15, 47, 60, and 72).
BARRIERS AGAINST
ULTRAVIOLET STRESSES
Reflection at the air–skin interface, absorption by
trans-urocanic acid, and diffraction via keratin fila-
ments aligned parallel to the skin surface limit the
penetration of UV radiation into the stratum corneum.
In the viable cell layer of the epidermis, melanin is the
major factor that absorbs UV irradiation and protects
genomic DNA from UV-induced damage. Although
the upper layer cells of the epidermis may undergo
greater DNA damage by UV irradiation than basal

Kang_CH014_p0206-0231.indd 224 30/11/18 12:23 pm

 layer cells because of their location in the epidermis,
the cells are tightly controlled in a nonproliferative
state and are continuously eliminated from the epider-
mis via cell turnover, which prohibits tumorigenesis.
In the proliferative basal layer cells, the damage to
genomic DNA induced by UV irradiation is immedi-
ately repaired by DNA repair enzymes (see Chap. 130).
readily evaporate under fur, it is reasonable that hairy
mammals do not use sweat to cool their body. In con-
2
trast, the furless skin of humans has a high density
of eccrine sweat glands and enables effective cooling
via water evaporation from the body surface. Interest-
ingly, the density of eccrine glands and hair follicles
are conversely determined by one transcription factor,
En1, in the mouse footpad.148

SWEATING TO PROTECT
AGAINST HEAT STRESSES VASCULATURE AND BLOOD
FLOW CONTROL AGAINST
The skin is a protective organ against heat and cold
HEAT STRESSES

Chapter 14 :: Skin Barrier

stress and plays an important role in controlling body
temperature. In humans, cooling is mainly achieved
by the evaporation of water secreted from eccrine
sweat glands. Thermoplegia tends to occur in patients
with congenital and acquired anhidrosis or hypohi-
drosis. Human skin has the highest reported density
of eccrine sweat glands among all mammals.147 Most
mammals have few sweat glands but have dense hairs
covering their body. Because secreted sweat does not
Cooling and maintaining heat are, in part, dependent on
the control of blood flow at the skin surface and counter-
current heat exchange between arteries and veins.149,150
When the body temperature rises, skin surface blood
vessels are dilated, and the skin appears red. The blood
is cooled down via sweat evaporation and radiation-
induced cooling on the skin surface (Fig. 14-13). In cold

Blood flow control in the skin for cooling and heat maintenance

Overheated Cooling

Superficial vein
Deep vein
Sweat evaporation

Radiation cooling

Artery

Cold environment Minimizing the

heat loss
Superficial vein
Deep vein

Artery Countercurrent heat exchange

Precooling of arterial blood by

countercurrent heat exchange

Figure 14-13 Blood flow control in the skin for cooling and heat maintenance. In a hot environment (upper panel), the
superficial veins become dilated, and the blood in the superficial veins is mainly cooled via evaporation of eccrine sweat
from the skin surface. In a cold environment (lower panel), the superficial veins contract, preventing heat loss from the
blood. Countercurrent heat exchange between afferent arteries and dilated efferent deep veins precools the blood in the 225
arteries before it reaches the superficial blood vessels, which also prevents heat loss from the skin surface.

Kang_CH014_p0206-0231.indd 225 30/11/18 12:23 pm

 2 air, the skin turns pale because blood vessels contract to
decrease blood flow and minimize heat loss via radia-
tion cooling. Therefore, the skin regulates blood flow
at the skin surface to maintain homeostasis of the body
temperature.
In the skin, arteries and veins run in close juxtapo-
sition. Vascular countercurrent heat exchange between
arteries and veins has been proposed as the mechanism
by which the core body temperature is maintained
under conditions of extreme cold or heat in homeother-
mic animals. For example, countercurrent heat exchange
between afferent arteries and efferent veins in the legs
of ducks prevents heat loss from the footpads, allow-
ing ducks to paddle in icy water. In mouse skin, arteries
Part 2
and veins are aligned in close juxtaposition. Loss of the
arteriovenous alignment in genetically engineered mice
results in greater heat loss at the skin surface because
warmer arterial blood reaches the skin surface without
::
precooling via countercurrent heat exchange against the
Structure and Function of Skin
venous blood returned from the skin surface. The core
body temperature decreases because of cooler venous
blood returning to the body core.151 These observations,
together with measurements of the blood temperature
in the arteries and veins of humans,150 indicate that
humans also use vascular countercurrent heat exchange
to maintain the core body temperature under extreme
conditions (see Fig. 14-13).
CONCLUSIONS
Skin, which is directly exposed to the external envi-
ronment, shows species-specific adaptations, result-
ing in an amazing diversity among vertebrates and
mammals and even among the human race and parts
of the human body. It is important that dermatologists
understand how human skin adapts to the external
environment and how these adaptations are affected
by disease. Skin is a complex superorgan consisting
of the ectoderm, mesoderm, and skin microbiota. An
integrated understanding of human skin, its microbi-
ota, and the external environment that skin is exposed
to is necessary for further investigation of normal skin
function and of the molecular pathogenesis of vari-
ous skin diseases; this will ultimately improve human
health.
ACKNOWLEDGMENTS
The authors acknowledge the contributions of
Ehrhardt Proksch and Jens-Michael Jensen, authors
of Chap. 47, “Skin as an Organ of Protection,” in
the 8th edition of Fitzpatrick’s Dermatology in General
Medicine.
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