Download Chapter 45 - McGraw

text of stem cells: Tumor properties and
therapeutic implications. Biochim Biophys Acta 1756:25, 2005
65. Schweizer J et al: New consensus
nomenclature for mammalian keratins.
J Cell Biol 174:169, 2006
67. Fuchs E, Weber K: Intermediate filaments: Structure, dynamics, function,
CHAPTER 45
Skin as an Organ
of Protection
The skin’s most important function is to
form an effective barrier between the “inside” and the “outside” of the organism.
Life on dry land requires the presence of a
barrier to regulate water loss and prevent
desiccation, commonly referred to as the
80. Coulombe PA, Wong P: Cytoplasmic
intermediate filaments revealed as
dynamic and multipurpose scaffolds.
Nat Cell Biol 6:699, 2004
117. Candi E, Schmidt R, Melino G: The
cornified envelope: A model of cell
death in the skin. Nat Rev Mol Cell Biol
6:328, 2005
inside-outside barrier. The skin also provides
an outside-inside barrier to protect against
mechanical, chemical, and microbial assaults from the external environment (Fig.
45-1). To perform these functions, the epidermis undergoes keratinization, a process in which epidermal cells progressively mature from basal cells with
proliferative potential to the lifeless, flattened squames of the stratum corneum
(SC) (Fig. 45-2). Both the SC and the
deeper skin layers protect the skin from
ultraviolet (UV) radiation, mechanical
forces, and cold and hot temperatures. To
effectively perform this multiplicity of
functions, the skin contains different
types of barriers. The physical barrier consists mainly of the SC, but the nucleated
SKIN BARRIER
AT A GLANCE
■ The most important function of the skin is
to form a barrier between the organism
and the environment.
■ The skin barrier prevents excessive water
loss (inside-outside barrier) and the entry
of harmful substances from the environment (outside-inside barrier).
■ The physical barrier is predominantly
located in the stratum corneum.
■ The stratum corneum barrier is composed of corneocytes and intercellular lipids, cholesterol, free fatty acids, and
ceramides.
■ Keratins and cornified envelope proteins
are important for the mechanical stability
of the corneocytes.
■ The cornified envelope protein involucrin
binds ceramides covalently, forming a
backbone for the subsequent attachment
of free ceramides.
CHAPTER 45 ■ SKIN AS AN ORGAN OF PROTECTION
Ehrhardt Proksch
Jens-Michael Jensen
and disease. Annu Rev Biochem 63:345,
1994
68. Omary MB, Coulombe PA, McLean
WH: Intermediate filament proteins and
their associated diseases. N Engl J Med
351:2087, 2004
71. Fuchs E: Keratins and the skin. Annu Rev
Cell Dev Biol 1995;11:123, 1995
■ The nucleated epidermis through tight
junctions and desmosomes also contributes to the barrier.
■ Experimental barrier disruption increases
epidermal lipids and changes in epidermal differentiation.
■ The signals for barrier recovery are cytokines and the calcium ion gradient.
■ Several diseases are characterized by a
probably genetically disturbed barrier
function. The disturbed barrier function
contributes to disease pathology, in
particular in contact dermatitis, atopic
dermatitis, forms of ichthyosis, and
psoriasis.
■ Lipid or lipid-like creams and ointments
can repair disturbed barrier function.
FIGURE 45-1 Functions of the epidermal “inside-outside” and “outside-inside” barrier. UV = ultraviolet.
383
FIGURE 45-2 Progressive maturation of the epidermis from the stratum
basale (SB), via the stratum
spinosum (SS) and stratum
granulosum (SG) to the terminal differentiated layer,
the stratum corneum (SC).
Key molecules of the epidermal structure are derived
during the differentiation
process.
SECTION 7 ■ DISORDERS OF EPIDERMAL DIFFERENTIATION AND KERATINIZATION
epidermis, in particular the tight junctions,
provides another important barrier component. The chemical-biochemical (antimicrobial) barrier consists of lipids, acids,
lysozymes, and antimicrobial peptides.
The humoral and cellular immune system
provides a barrier to infectious disease
(see Chap. 10), but immune hyperactivity
may lead to allergy (Table 45-1).
Although the skin is of central importance for preventing water loss in a dry
environment, aquatic animals also require a skin barrier to protect them from
the high salinity of their surrounding
environment. Terrestrial mammals with
dense fur have much thinner skin than
animals without this protective coat,
demonstrating that fur itself is a considerable barrier. The relatively hairless
skin of pigs shows much similarity to
human skin and is therefore a good
model for skin research.
In addition to the SC, the entire skin, as
a whole, serves a protective function. The
innermost region of human skin, the subcutaneous fat layer, offers mechanical
shock protection, insulates the body
against external heat and cold, and is active in general energy metabolism and
storage. The dermis is composed of collagen bundles and elastic fibers and is very
important for the mechanical strength of
the skin. The epidermis, the skin’s outer
layer, consisting primarily of stratified nucleated keratinocytes and the SC, is most
important for skin protection and the focus of this chapter. Sweat glands and
blood vessels regulate body temperature.
Sebaceous glands secrete sebaceous lipids
to protect the hair from the environmental stress. In animals, sebaceous lipids
serve as a water repellent for the fur, aiding in buoyancy and temperature regulation, and also preventing desiccation of
the body and UV damage. The role of sebaceous lipids for SC barrier function and
for dry skin is still a matter of discussion.1
Sebaceous glands also transport glycerol
to the skin surface, which is important
for SC hydration.2 Nerve fibers are
chemosensitive and act as a warning system against external trauma.
STRUCTURE OF THE STRATUM
CORNEUM: PHYSICAL
PERMEABILITY BARRIER
The SC is the specific location of the
physical barrier.3,4 The typical basketweave appearance of the SC in routine
formalin-embedded sections does not
give the impression that it could function
TABLE 45-1
Different Skin Barriers
Physical barrier
384
Chemical/biochemical (antimicrobial)
barrier (innate immunity)
Immune barrier humoral and cellular
immune system
Stratum corneum, nucleated epidermis (desmosomes,
tight junctions)
Lipids, organic acids, lysozymes, antimicrobial peptides
Lymphocytes, neutrophils, monocytes, Langerhans cells
as an effective barrier. With the advent of
electron microscopy and ruthenium
tetroxide fixation, the structure of the SC
barrier can now be visualized (Fig. 45-3).
The barrier regulating water permeation
is not absolute. The normal movement
of water from the SC into the atmosphere is known as trans-epidermal water
loss (TEWL). The SC also serves as the
principal barrier against the percutaneous
penetration of chemical substances and
microbial assaults and is capable of withstanding mechanical forces.5
The 10 to 20 µm thick SC forms a continuous sheet of protein-enriched cells,
embedded in an intercellular matrix, enriched in nonpolar lipids, and organized as
lamellar lipid layers. The viable epidermis
is a stratified squamous epithelium, consisting of basal, spinous, and granular cell
layers. Each layer is defined by its position, shape, morphology, and the differentiation status of its keratinocytes. On leaving the basal layer, keratinocytes begin to
differentiate and undergo a number of
changes in both structure and composition during the apical migration into the
stratum spinosum and stratum granulosum. Keratinocytes synthesize and express numerous structural proteins and
lipids during their maturation. The final
steps in keratinocyte differentiation are
associated with profound changes in their
structure, resulting in their transformation
into flat and anucleated squamous cells of
the SC, acting mainly with keratin filaments and surrounded by a cell envelope
composed of cross-linked proteins (cornified envelope proteins) as well as a covalently bound lipid envelope (see Fig.
45-2). Extracellular nonpolar lipids surround the corneocytes to form a hydro-
terol, free fatty acids, and ceramides
(Fig. 45-6).8-10
CHOLESTEROL Cholesterol is probably
the most abundant lipid in the entire
body and part of the plasma membrane,
and part of the intercellular lipid lamellae
in the SC. Although basal cells are capable of resorbing cholesterol from circulation, most cholesterol in the epidermis is
synthesized in situ from acetate.11 The
epidermal keratinocyte, the main cell
type in the epidermis, is highly active in
the synthesis of several lipids, including
cholesterol and free fatty acids. The ratelimiting step in cholesterol biosynthesis
is catalyzed by hydroxymethylglutaryl
CoA reductase (Fig. 45-7). Epidermal
cholesterol synthesis is regulated by
these enzymes and increased during permeability barrier repair.12
phobic matrix. The cornified envelope
proteins as well as the covalently bound
lipid envelope are thought to be important for the chemical resistance of the corneocytes (Fig. 45-4). Desmosomes, which
interconnect adjacent keratinocytes, are
important for SC cohesion and are shed
during the desquamation process in the
SC. In the upper spinous and granular layers, characteristic lamellar vesicles appear,
which are called epidermal lamellar bodies
(Figs. 45-3 and 45-5). These are enriched
in polar lipids, glycosphingolipids, free
sterols, phospholipids, and catabolic enzymes, which deliver the lipids required
for the SC’s extracellular layers. The
lamellar bodies may also contain proteins
such as human β-defensin 2.6 In response
to certain signals, probably an increase in
calcium concentration during the transition from the granular layers to the SC,
the lamellar bodies move to the apex of
the upper-most granular cells, fuse with
the plasma membrane, and secrete their
content into the intercellular spaces
through exocytosis. The lipids derived
from the lamellar bodies are subsequently
modified and rearranged into intercellular
lamellae positioned approximately parallel to the cell surface. The covalently
bound lipid envelope acts as a scaffold for
this process. After the extrusion of the
lamellar bodies into the stratum granulosum-SC interface, the polar lipids are en-
zymatically converted into nonpolar
products. Hydrolysis of glycosphingolipids generates ceramides while phospholipids are converted into free fatty acids.
These changes in lipid composition and
cell structure result in the formation of a
very dense structure packed into the interstices of the SC (Table 45-2).7
Lipid Composition and Role of
Lipids in the Stratum Corneum
Confocal laser scanning microscopy and
X-ray microanalysis studies have shown
that the major route of penetration results in the tortuous halfway between
the corneocytes, confirming that intercellular lipids play an irreplaceable role
in regulating skin barrier function.7 The
major lipid classes in the SC are choles-
FIGURE 45-4 The lipid-depleted corneocyte is surrounded by an inner protein envelope and an outer lipid
envelope. Special ceramides are covalently bound to cornified envelope proteins, particularly to involucrin.
CHAPTER 45 ■ SKIN AS AN ORGAN OF PROTECTION
FIGURE 45-3 Electron microscopy revealed that in the stratum granulosum (SG)/stratum corneum (SC)
interface the lamellar bodies (LB) content is extruded to the interface (A), thus forming continuous lipid bilayers (LBL) (B then C). Desmosomes are becoming corneosomes in the process of cornification (D).
FREE FATTY ACIDS The skin contains free
fatty acids as well as fatty acids bound in
triglycerides, phospholipids, glycosylceramides, and ceramides. The chain length
of free fatty acids in the epidermis ranges
from C12 to C24. The rate-limiting enzymes acetyl-CoA carboxylase and fatty
acid synthase in the epidermis are largely
autonomous (Figs. 45-7 and 45-8).13 Saturated and monounsaturated fatty acids
are synthesized in the epidermis, in contrast to di- and polyunsaturated acids.
The nomenclature of the fatty acids is determined from the position of the first
double bond in the molecule, starting
from the terminal methyl group. In particular, the essential ω-6-unsaturated acids must be obtained from food and the
circulation or can be obtained by topical
treatment. The non-essential monounsaturated fatty acid, the oleic acid, is an ω-9
fatty acid. The most important double
unsaturated fatty acid, linoleic acid, is an
ω-6 fatty acid. Also of importance is αlinoleic acid (ω-3). No skin changes due
to an ω-3 fatty acid deficiency are currently known; however, it has been proposed that these fatty acids are important
for the resolution of inflammation. ω-3
fatty acids are obtained from fish,
385
SECTION 7 ■ DISORDERS OF EPIDERMAL DIFFERENTIATION AND KERATINIZATION
386
the SC is not observed in the epidermal
stratum granulosum, stratum spinosum,
or stratum basale. This also suggests that
terminal differentiation is a key factor in
accumulating ceramide. The SC contains
at least nine different ceramides.17 In addition, there are two protein-bound ceramides, ceramide A and ceramide B (see
Fig. 45-6).7 These ceramides are covalently bound to cornified envelope proteins, most importantly to involucrin.
Ceramides are synthesized by serinepalmitoyl transferase as rate-limiting enzyme and by hydrolysis of both glucosylceramide (by β-glucocerebrosidase)18
and sphingomyelin (by acid sphingomyelinase) (Figs. 45-8 and 45-9).19 Whereas
all kinds of ceramides are derived by synthesis from serine-palmitoyl transferase
and from β-glucocerebrosidase, only ceramide 2 and ceramide 5 are obtained
from sphingomyelinase because sphingomyelin contains nonhydroxy acids.20
Lipid Transport
FIGURE 45-5 During differentiation, the upper stratum spinosum (SP) and the stratum granulosum (SG)
cells generate lamellar bodies containing preformed lipid structures and hydrolytic enzymes. Their content is extruded into the SG-stratum corneum (SC) interface and undergoes profound remodelling. SB = stratum basale.
whereas ω-6 fatty acids are obtained
from plant oils.14,15 Essential fatty acid
deficiency (EFAD) caused by unusual human diets or malabsorption or experimentally induced in rats and mice leads
to the EFAD syndrome, characterized by
profound changes in epithelia including
the epidermis.16 In this condition, the epidermis is rough, scaly, and red and shows
a severely disturbed permeability barrier
function. In addition, severe bacterial infection, impaired wound healing, and alopecia may occur. Linoleic acid is part of
phospholipids, glucosylceramides, ceramide 1, ceramide 4, and ceramide 9.17 It
has been proposed that the linoleic acid
metabolite γ-linoleic acid is of special importance for atopic eczema.
CERAMIDES Ceramide is an amide-linked
fatty acid containing a long-chain amino
alcohol called sphingoid base. The carbon
chain lengths of amide-linked fatty acids
and sphingoid bases in most mammalian
tissues are 16 to 26 and 18 to 20, respectively (see Fig. 45-6). Although sphingolipids, including glycosphingolipids and
phosphosphingolipids, are ubiquitously
distributed in mammalian tissues, tissuespecific molecular distribution has been
described. Glucosylceramide is enriched
in the epidermis and spleen whereas galactosylceramide is enriched in the brain
but is not detected in keratinocytes.
Whereas ceramide is a minor lipid component, comprising less than 10% of cholesterol or phospholipids in other mammalian tissues, ceramide is a major lipid
component in the SC, accounting for 30
to 40 percent of lipids by weight. Moreover, such a high content of ceramides in
Keratinocytes require abundant cholesterol for cutaneous permeability barrier
function. ABCA1 is a membrane transporter responsible for cholesterol efflux
and plays a pivotal role in regulating cellular cholesterol levels. It was demonstrated that ABCA1 is expressed in cultured human keratinocytes and murine
epidermis. Liver X receptor activation
and activation of peroxisome proliferatoractivated receptor (PPAR)-α, PPAR-ss/δ
and retinoid X receptor increased ABCA1
TABLE 45-2
Protective Functions of the Stratum Corneum
FUNCTIONS
STRUCTURAL BASES
BIOCHEMICAL MECHANISMS
Permeability barrier
Lamellar bilayers
Hydrophobic lipids
Mechanical integrity/
resilience
Cornified envelope, cytosolic filaments
Cross-linked peptides (e.g., involucrin,
loricrin), keratin filaments
Hydration
Lamellar bilayers; corneocyte cytosolic matrix
Sebaceous gland-derived glycerol, filaggrin break-down amino acids, natural
moisturizing factors
Cohesion/desquamation
Corneodesmosomes
Serine proteases
Antimicrobial defense
Lamellar bilayers, extracellular matrix
Free fatty acids, antimicrobial peptides
UV protection
Corneocyte cytosol
Structural proteins, trans-urocanic acid
Antioxidant defense
Corneocytes, extracellular
matrix
Keratins, sebaceous gland-derived vitamin E and other antioxidants
Waterproofing/repellence
Lamellar bilayers
Keratinocyte and sebum-derived lipids
Cytokine signalling
Corneocyte cytosol
Xenobiotic defense
Lamellar bilayers
Storage and release of pro-IL-α, serine
proteases
Lipid solubility, cytochrome p450
system (outer epidermis)
IL = interleukin; UV = ultraviolet.
expression in keratinocyte cultures. Thus
cholesterol levels for permeability barrier
function are regulated by ABCA1, liver X
receptor, and PPARs.21 The cellular fatty
acid transport and metabolism is regulated by fatty acid-binding proteins.22
EPIDERMAL PROLIFERATION
AND DIFFERENTIATION IN
SKIN BARRIER FUNCTION
CHAPTER 45 ■ SKIN AS AN ORGAN OF PROTECTION
FIGURE 45-6 The stratum corneum lipid barrier contains free fatty acids, cholesterol, and different
ceramide sub-types. Protein-bound ceramides and very-long-chain ceramides provide an anchor between the protein envelope proteins and the free intercellular lipids.
To provide this physical barrier of the SC,
not only intercellular lipids, but also the
corneocytes are of crucial importance.23,24
The epidermis undergoes keratinization
in which epidermal cells progressively
mature from basal cells with proliferative
potential to lifeless flattened squames of
the SC (see Fig. 45-2). Keratinocytes arise
from stem cells in the basal layers and
transient amplification cells and move to
a series of differentiation events until
they are finally brought to desquamation.25 Thus, in the normal epidermis,
there is a balance between the processes
of proliferation and desquamation that
results in a complete renewal approximately every 28 days (see Chap. 6). In
some of the ichthyoses, the rate of desquamation may be decreased, leading to
epidermal cell retention (retention hyperkeratosis) (see Chap. 47).26 In inflammatory skin diseases like psoriasis, there is
an increase in proliferation resulting in a
disturbance in differentiation and parakeratotic squames (hyperproliferative hyperkeratosis) (see Chap. 18).27
Keratins are major structural proteins
synthesized in keratinocytes (see Chap.
44). They assemble into a web-like pattern of intermediate filaments that emanate from a perinuclear ring, extend
throughout the cytoplasm, and terminate
at junctional desmosomes and hemidesmosomes. During the final stages of normal differentiation, keratins are aligned
into highly ordered and condensed arrays through interactions with filaggrin, a
matrix protein. In keratin disorders, the
filament networks collapse around the
nucleus, preventing attachment with the
filament-matrix complex and the inner
surface of squames and alter interaction
between neighboring cells, thereby affecting desquamation. Filaggrin aggregates the keratin filaments into tight bundles. This promotes the collapse of the
cell into a flattened shape, which is characteristic of corneocytes in the cornified
layer. Together, keratins and filaggrin
constitute 80 to 90 percent of the protein
mass of mammalian epidermis.23,24
The structural proteins involucrin, loricrin, trichohyalin, and the class of small
proline-rich proteins are synthesized and
387
Chap. 188). It consists of two parts: a protein envelope and a lipid envelope. The
protein envelope contributes to the biomechanical properties of the cornified envelope as a result of cross-linking of specialized cornified envelope structural
proteins by both disulfide bonds and
N(ε)-(γ-glutamyl)lysine isopeptide bonds
formed by transglutaminases.24,28 The
isopeptide bonds are resistant to most
common proteolytic enzymes. The corneocyte-bound lipid envelope is plasma
membrane-like structure, which replaces
the plasma membrane on the external aspect of mammalian corneocytes.29 Involucrin, envoplakin, and periplakin serve
as substrates for the covalent attachment
ω-hydroxyceramides with very long
chain N-acyl fatty acids of by ester linkage.30 These not only provide a coating to
the cell, but also interdigitate with the intercellular lipid lamellae (Table 45-3).24
SECTION 7 ■ DISORDERS OF EPIDERMAL DIFFERENTIATION AND KERATINIZATION
388
EXPERIMENTAL BARRIER
DISRUPTION AND GENE
MODIFICATION IN
EPIDERMAL DIFFERENTIATION
FIGURE 45-7 Synthetic pathways and key enzymes for stratum corneum free fatty acids and cholesterol. CoA = coenzyme A; HMG-CoA = hydroxymethylglutaryl CoA.
subsequently cross-linked by transglutaminases to reinforce the cornified envelope just beneath the plasma membrane.
The proteins of the cornified envelope
constitute approximately 7 to 10 percent
of the mass of the epidermis. These corneocytes provide the bulwark of mechanical and chemical protection, and together with their intercellular lipid
surroundings, confer water impermeability. The cornified cell envelope is a tough
protein-lipid polymer structure formed
just below the cytoplasmic membrane
and subsequently resides on the exterior
of the corneocytes (see Fig. 45-4). It is resistant to 10 percent potassium hydroxide and is the rigid structure seen on potassium hydroxide skin scrapings (see
Experimental barrier disruption leads to
changes in epidermal keratin and cornified envelope protein expression and,
vice versa, overexpression and deficiency
of these proteins in mice result in barrier
defects. A number of diseases displaying
defective epidermal barrier function are
also the result of genetic defects in the
synthesis of either keratins, cornified envelope proteins, or the transglutaminase
1 cross-linking enzyme.
Inhibition of hydroxymethylglutaryl
CoA reductase by topical application of
the lipid lowering drug lovastatin results
in a disturbed barrier function and in epidermal hyperproliferation. Therefore, the
specific relationship between barrier
function and epidermal DNA synthesis
was examined. After acute skin barrier
FIGURE 45-8 Sphingomyelin and glycosylceramides are precursor for ceramide generation, whereas phospholipids are precursors of fatty acids.
disruption (local acetone treatment or by
tape-stripping) (Fig. 45-10) and in a model
of chronic barrier disruption (EFAD diet),
an increase in DNA synthesis leading to
epidermal hyperplasia was noticed.31 The
increase in DNA and lipid synthesis was
partially prevented by occlusion.14,31,32
Also, the described acute or chronic
barrier disruption leads to specific changes
in epidermal keratin and cornified envelope protein expression (see Chap. 44). Increased expression of the basal keratins
K5 and K14 and a reduction of the differentiation-related keratins K1 and K10 was
noted. In addition, there was expression
of the proliferation-associated keratins K6
and K16 as well as the inflammation-associated keratin K17 (Fig. 45-11).33 The
importance of keratins for skin barrier
function was supported by studies in K10deficient mice. Heterozygotes and homozygotes showed a mild or severe permeability barrier disruption, respectively.
Importantly, homozygous neonatal K10-
deficient mice exhibited an extremely delicate epidermis and died a few hours after
birth. Heterozygous littermates showed a
normal skin at birth but developed increasing hyperkeratosis as they grew up.34
Barrier repair in heterozygous K10-deficient mice was delayed and skin hydration was impaired.35 Changes in ceramide
composition, a reduced amount of glucosylceramide and sphingomyelin, and reduced acid sphingomyelinase activity as
well as increased involucrin content was
also noted.36 This shows that genetically
determined changes in structural proteins
lead to an impaired skin barrier function,
changes in differentiation and lipid composition, but the detailed mechanisms remain to be determined.
The importance of keratins for skin
barrier function is further supported by
studies in diseases that are caused by
monogenetic defects of these structural
CHAPTER 45 ■ SKIN AS AN ORGAN OF PROTECTION
FIGURE 45-9 Generation and degradation of ceramides.
TABLE 45-3
Additional Protective Functions of the Nucleated Epidermis
FUNCTIONS
BIOCHEMICAL CORRELATES
Antimicrobial systems
Antioxidants
Inflammatory mediators
UV-absorbing molecules
Xenobiotic-metabolizing
enzymes
Antimicrobial peptides and lipids, iron-binding proteins, complement
Glutathione, oxidases, catalase, cytochrome P450 system, vitamins C and E
Prostaglandins, eicosanoids, leukotrienes, histamine, cytokines
Melanin, trans-urocanic acid, vitamin D, vitamin C metabolites
Glucuronidation, sulfation, hydroxylation mechanisms
UV = ultraviolet
389
Barrier Recovery
100%
50%
A
B
C
FIGURE 45-10 Three phases of barrier recovery with distinct metabolic activities occurring after
acute barrier disruption. A = Secretion of preformed pool of lamellar bodies (0 to 30 minutes). B = Increased lipid synthesis (free fatty acids, ceramide, and cholesterol) (30 minutes to 6 hours), accelerated
lamellar body formation and secretion (2 to 6 hours). C = Increased glucosylceramide processing (9 to
24 hours), increased keratinocyte proliferation and differentiation (16 to 24 hours).
SECTION 7 ■ DISORDERS OF EPIDERMAL DIFFERENTIATION AND KERATINIZATION
390
proteins. Epidermolysis bullosa simplex
shows mutation in the basal layer keratins K5 or K14 (see Chap. 60). Genetic
defects in the suprabasal keratins results
in hyperkeratosis and a mild barrier defect (see Chaps. 47 and 48). Epidermolytic hyperkeratosis has spinous layer
K1 or K10 defects, epidermolytic palmoplantar keratoderma has granular
layer K9 defects (because this keratin is
expressed only in palmar and plantar
skin the disease is restricted to that area),
and ichthyosis bullosa of Siemens has
granular layer defects K2 (formerly K2e)
defects (reviewed in ref. 23).
Experimental permeability barrier disruption leads to a premature expression of
involucrin, but not loricrin.33 Overexpression of filaggrin in mice in the suprabasal
epidermis resulted in a delay in barrier repair.37 Loss of normal profilaggrin and filaggrin causes flaky tail (ft/ft), an autosomal recessive mutation in mice that results
in dry, flaky skin, and annular tail and paw
constrictions, in the neonatal period. Targeted ablation of the murine involucrin
gene did not show changes in skin barrier
function under basal conditions38 but did
demonstrate a reduced ability for barrier
repair. Loricrin-deficient mice did not
show a disturbed barrier function, but
demonstrated a greater susceptibility to
mechanical stress, which may alter skin
barrier function secondarily.39,40
Changes in epidermal proliferation and
differentiation are also seen in inflammatory skin diseases with a disturbed skin
barrier function (see Fig. 45-11). Increased
proliferation is one of the main characteristics of psoriasis, but also in atopic dermatitis lesional skin there is a considerable increase in epidermal proliferation.
Also, changes in keratins and cornified
envelope proteins occur in inflammatory
skin diseases.41 Overall, this shows that
there is undoubtedly a connection between epidermal proliferation, differentiation, and skin barrier function.
FUNCTIONS OF THE SUBCORNEAL EPIDERMAL LAYERS
Although the SC is recognized as the
most important physical barrier, the
lower epidermal layers are also significant in barrier function. A low to moderate increase in TEWL occurs after removal of the SC by tape stripping,
whereas loss of the entire epidermis
through suction blisters leads to a severe
disturbance in barrier function. Loss of
the SC and parts of the granular layers in
staphylococcal scalded-skin syndrome,
are not usually life-threatening (see
Chap. 178).42 In contrast, suprabasal and
sub-epidermal blistering diseases pemphigus vulgaris, toxic epidermal necrolysis (Lyell syndrome), and severe burns,
respectively, are life-threatening when
large areas of the body are involved (see
Chaps. 39 and 94). Patients die because
of extensive water loss or sepsis induced
by external bacteria infection; outcomes
directly resulting from perturbed barrier
function. Survival rates can be greatly
improved with application of an artificial
barrier in the form of a foil or a grease
ointment, often containing active antimicrobial substances. These clinical observations confirm the importance of the
nucleated epidermal layers in skin barrier
function in both directions, both in preventing excessive water loss and the entry of harmful substances into the skin.43
FIGURE 45-11 Skin diseases with a disturbed
skin barrier function show changes in epidermal differentiation. In atopic dermatitis, these changes are
already present in non-lesional and are more pronounced in lesional epidermis. The proliferation rate
is significantly increased. A premature, but reduced,
expression of involucrin occurs. The loricrin shows
gaps in the stained band. Reduced filaggrin expression is in particular noted in non-lesional skin. Basal
cytokeratin K5 expression is found in suprabasal cells
in non-lesional skin and even in the entire nucleated
epidermis in lesional atopic epidermis. Proliferationassociated K6 appears in lesional epidermis only. Expression of suprabasal cytokeratin K10 is found in
the entire suprabasal epidermis in normal and nonlesional skin, but staining was reduced in diseased
skin. K16 labelling is already found in non-lesional
skin and more pronouncedly in lesional skin in atopic
dermatitis, whereas inflammation-associated K17
shows immunostaining in lesional epidermis only.
Connexins: Intercellular
Gatekeepers
Tight junctions are cell junctions sealing
neighboring cells and controlling the
paracellular pathway of molecules, separating the apical from the basolateral
parts of a cell (fence function) (see Fig.
45-2). The most important tight junction proteins in the human epidermis
are occludin, claudins, and zonal occluding proteins. Localization of occludin is
restricted to the stratum granulosum,
zonal occluding protein-1 and claudin-4
are found in suprabasal layers, and claudins-1 and -7 are found in all epidermal
layers. In various diseases with perturbed SC barrier function, such as psoriasis vulgaris, lichen planus, acute and
chronic eczema, and ichthyosis vulgaris,
tight junction proteins that were formerly restricted to the stratum granulosum and upper stratum spinosum were
also found in deeper layers of the epidermis. Claudin-1–deficient mice die
within 1 day of birth due to tremendous
water loss.44 Altered barrier function of
the skin has also been demonstrated in
mice overexpressing claudin-6 in the
epidermis.45,46
Connexins are transmembrane proteins
that homo- or heteromerize on the plasma
membrane to form a connexon. Connexons on adjoining cells associate to form
gap junctions and allow the passage of
ions and small molecules between cells.
Connexin-26 is one of the most highly upregulated genes in psoriatic plaques. Missense mutations in connexin-26 result in
five distinct ichthyosis-like skin disorders
(see Chap. 47). In mice overexpressing
connexin-26, a hyperproliferative state, infiltration of immunocells, and a delayed
epidermal barrier recovery were noted.51
Desmosomal and Adherence
Junction Proteins: Structural
Cell-Cell Interfaces
A perturbation in SC barrier function
has also been found after the alteration
of desmosomal proteins. Desmogleins
are desmosomal cadherins that play a
major role in stabilizing cell-cell adhesion in the living layers of the epidermis
(see Fig. 45-2; see Chap. 51). Autoantibodies against these transmembrane
glycoproteins cause blisters in pemphigus vulgaris due to loss of keratinocyte
adhesion. In acute eczema, which
shows disturbed skin barrier function,
a reduction in keratinocyte membrane
E-cadherin in areas of spongiosis has
been found.47,48 In transgenic mice in
which the distribution of desmoglein 3
in epidermis was similar to that in mucous membrane, a highly increased
TEWL resulted in lethality during the
first week of life due to dehydration.49
Mice conditionally inactivated in Ecadherin in the epidermis died perinatally due to the inability to retain a
functional epidermal water barrier.
Absence of E-cadherin leads to improper localization of key tight junctional proteins and in permeable tight
junctions and thus altered epidermal
barrier function.50
Proteases
Proteases are important for epidermal differentiation. The characteristic resistance
of the cornified envelope is based on the
formation of very stable isopeptide bonds
that are catalyzed by transglutaminase 1,
3, and 5. Transglutaminase 1-deficient
mice showed a defective SC and early
neonatal death.52 Mutations in transglutaminases 1 have been found to be the
defect in lamellar ichthyosis (see Chap.
47).53 Cathepsin D is involved in the processing of transglutaminase 1. Cathepsin
D-deficient mice expressed a defect in
barrier function and hyperproliferation.54
Netherton syndrome, a severe autosomal recessive genodermatosis, is
caused by mutations in SPINK5, encoding the serine protease inhibitor LEKTI
(see Chap. 47). In Netherton syndrome,
often an atopic eczema-like skin disease
with a disrupted permeability barrier is
found. SPINK 5-/- mice replicate key
features of Netherton syndrome, including altered desquamation, impaired
keratinization, hair malformation, and a
skin barrier defect. LEKTI deficiency
causes abnormal desmosome cleavage
in the upper granular layer through degradation of desmoglein 1 due to SC chymotryptic enzyme-like hyperactivity.
This leads to defective SC adhesion and
results in loss of skin barrier function.55
Cytokine Signaling: Regulation of
Epidermal Homeostasis and Repair
Cytokines are very important for the regulation of wound healing in which reepithelization and differentiation to form
a competent barrier is the last step (see
Chap. 249). Besides the immune cells, keratinocytes are able to produce a large variety and amount of cytokines (Fig. 45-12;
see Chap. 11). Of special importance are
the so-called primary cytokines tumor necrosis factor (TNF), interleukin (IL)-1,
and IL-6. The cytokines IL-1α and IL-1β
are among the few that are present in the
SC under basal conditions. In response to
all forms of acute barrier disruption, the
preformed pool of IL-1α is released.57 IL1, TNF, and IL-6 are potent mitogens and
stimulators of lipid synthesis in cutaneous
and extracutaneous tissues. After acute
permeability barrier disruption an increase in the expression of TNF, IL-1, and
IL-6 on the messenger RNA and the protein level occurs.19,58,59 There is a delay in
barrier repair in several genetically engineered mice, including those deficient in
TNF-α receptor 1, IL-1 receptor 1 TNF-α
receptor 1-double knock-out mice, and in
IL-6.19,59 Moreover, topical application of
TNF enhances permeability barrier repair,
and topical application of IL-6 in IL-6-deficient mice restores the normal speed in
permeability barrier (see Fig. 45-12). In
TNF receptor 1-deficient mice, the generation of lipids for skin barrier repair is delayed and the activity of acid sphingomyelinase, which generates ceramides for
skin barrier repair, is reduced.19 STAT3 tyrosine phosphorylation was induced after
barrier disruption in wild type, but markedly reduced in IL-6-deficient mice. The
acute increase in TNF, IL-1, and IL-6 after
barrier disruption is crucial for skin barrier
repair. However, if barrier disruption is
prolonged and a chronic increase in cytokine production occurs, it could have a
harmful effect leading to inflammation and
epidermal proliferation. Disrupted permeability barrier, epidermal hyperproliferation, and inflammation is well known in
several diseases like irritant and allergic
contact dermatitis, atopic dermatitis, and
psoriasis, and could aggravate the disease.
CHAPTER 45 ■ SKIN AS AN ORGAN OF PROTECTION
Tight Junctions: A Second Line
Epidermal Barrier
Ionic Modulations: Epidermal
Calcium and Potassium Levels
A perturbed barrier recovers normally
when exposed to an isotonic, hyper- or
hypotonic external solution instead of air.
If the solution contains both calcium and
potassium the barrier recovery is inhibited. There is a calcium gradient in the
epidermis with a relatively low calcium
concentration in the basal epidermis, and
an even lower concentration in the spinous layers, while the highest calcium
concentrations are found in the granular
layers. Calcium in the SC is very low because the relatively dry SC with extracellular lipids is not able to solve the high polar ions. After disruption of the
permeability barrier there is influx of water into the SC and the ion gradient is lost
391
SECTION 7 ■ DISORDERS OF EPIDERMAL DIFFERENTIATION AND KERATINIZATION
FIGURE 45-12 A barrier insult from the outside results not only in the release of cytokines for epidermal cell signaling, but also interacts with dermal processes, which may result in inflammation and ultimately scar tissue formation in case of destruction of the dermis. GAG = glycosaminoglycan; GM-CSF = granulocyte macrophage-colony stimulating factor; IL = interleukin; TNF = tumor necrosis factor.
392
(Fig. 45-13). This depletion of calcium regulates lamellar body exocytosis.60-62 Calcium is a very important regulator of protein synthesis in the epidermis, including
regulation of transglutaminase 1 activity.63
Furthermore, extracellular calcium ions
are important for cell to cell adhesion and
epidermal differentiation. Intracellular calcium is controlled by more than one
mechanism as demonstrated by two
genetic diseases: Disturbed regulation
of calcium metabolism and increased
TEWL64 occur in Darier disease, characterized by loss of adhesion between suprabasal epidermal cells associated with
abnormal keratinization, and in HaileyHailey disease, which shows loss of epidermal cell to cell adhesion. The gene
for Darier disease (ATP2A2) encodes a
calcium transport adenosine triphosphatase of the sarco (endo)plasmic reticulum
(SERCA2),65,66 whereas the gene for
Hailey-Hailey (ATP2C1) codes for a secretory pathway for calcium and manganese
transport adenosine triphosphatase of the
Golgi apparatus (SPCA1).67
Neurotransmitters in the
Keratinocytes: Common
Origins of the Brain and Skin
Neurotransmitters are found in keratinocytes and may regulate skin permeability
barrier function. The receptors can be categorized in two groups, that is, ionotro-
inflammation or whether inflammation
leads to epidermal changes including barrier dysfunction. The vast majority of reports on the pathogenesis of atopic dermatitis and even more on psoriasis
focused on the primary role of abnormalities in the immune system.70 However,
others have proposed an “outside-inside”
pathogenesis for atopic dermatitis and
other inflammatory dermatoses with barrier abnormalities,71,72 as an alternative to
the current “inside-outside” paradigm.
Atopic Dermatitis: Consequence
of a Chronically Disturbed Barrier
pic (calcium or chloride ion) receptors and
G protein-coupled receptors. Topical application of calcium channel agonists delays the barrier recovery whereas antagonists accelerate barrier repair.
The G protein-coupled receptors modulate intracellular cyclic adenosine
monophosphatase (cAMP) level, increase
of intracellular cAMP in epidermal keratinocytes delays barrier recovery, whereas
cAMP antagonists accelerate the barrier
recovery. Activation of dopamine 2–like
receptors, melatonin receptors, or serotonin receptor (type 5-HT 1) decreases
intracellular cAMP and consequently accelerates barrier recovery, whereas activation of adrenergic β2 receptors increases intracellular cAMP and delays the
barrier repair. Many agonists or antagonists of neurotransmitter receptors are
used clinically to treat nervous disorders.
Some of them might also be effective for
treating skin diseases.68
PATHOLOGIC SKIN BARRIERS:
SKIN BARRIER FUNCTION
IN DERMATOSES
A mild impairment of the skin barrier is
found in monogenetic diseases expressing an impaired epidermal differentiation
or lipid composition without inflammation, such as ichthyosis vulgaris, X-linked
recessive ichthyosis (see Chap. 47), and
Darier disease (see Chap. 49). 64 The diseases with a more pronounced barrier
disruption are inflammatory diseases,
such as irritant and allergic contact dermatitis (see Chaps. 211 and 13), atopic
dermatitis (see Chap. 14), seborrheic dermatitis (see Chap. 22), psoriasis (see
Chap. 18), and T-cell lymphoma (see
Chap. 146). Also, blistering diseases,
most of them inflammatory-related,
show an increase in TEWL especially after loosening of the blister roof and the
development of erosions (Table 45-4).
Most inflammatory skin lesions are
covered with dry scales or scale-crusts
due to the disturbed epidermal differentiation and an SC with poor water-holding
capacity. Inflammatory skin diseases can
be produced by either exogenous or endogenous causes. In contact dermatitis,
disruption of the barrier by irritants and
allergens is the primary event, followed
by sensitization, inflammation, increased
epidermal proliferation, and changes in
differentiation. In T-cell lymphoma (mycosis fungoides), an endogenous cause for
barrier disruption, changes in epidermal
proliferation, and differentiation, by expansion of clonal malignant CD4+ T cells
is obvious.69 In atopic dermatitis and in
psoriasis, it is debatable whether permeability barrier disruption is followed by
TABLE 45-4
Potential Role of the Cutaneous Barrier in
the Pathophysiology of Skin Disorders
• Barrier abnormality represents a primary or
intrinsic process:
• Irritant contact dermatitis
• Allergic contact dermatitis
• Burns
• Ulcers (ischemic, vascular, diabetic)
• Bullous disorders by friction or keratin
abnormalities
• Premature infant’s skin
• Ichthyosis, Gaucher disease (II), NiemannPick disease (I)
• A primary barrier abnormality triggers
immunologic reactions, but vice versa primary immunologic reactions may trigger
barrier abnormalities in yet unknown subgroups of the diseases
• Atopic dermatitis
• Psoriasis
• Immunologic abnormality triggers barrier
abnormality
• T-cell lymphoma (mycosis fungoides)
• Autoimmune bullous diseases
• Lichen planus
CHAPTER 45 ■ SKIN AS AN ORGAN OF PROTECTION
FIGURE 45-13 Changes in calcium gradient after barrier disruption regulates lamellar body secretion and epidermal differentiation.
The existence of a defective permeability barrier function in atopic dermatitis
is now widely accepted. A genetically
impaired skin barrier function is already
present in non-lesional and more pronounced in lesional skin in atopic dermatitis. Increased epidermal proliferation and disturbed differentiation,
including changes in keratins and cornified envelope proteins involucrin, loricrin, and filaggrin, and in lipid composition, cause impaired barrier function in
atopic dermatitis (see Figs. 45-11 and
45-14).73 Recently, two mutations in the
filaggrin gene have been described74 and
immediately confirmed.75,76 Two lossof-function genetic variants in the gene
encoding filaggrin are strong predispos-
393
SECTION 7 ■ DISORDERS OF EPIDERMAL DIFFERENTIATION AND KERATINIZATION
394
TEWL
50
Hydration
100
*
90
80
30
20
*
Hydration (units)
40
TEWL (g/m2/h)
ing factors for atopic dermatitis in atopic
kindreds of European origin.77 These mutations were also significantly associated
with asthma, independent of atopic dermatitis, that means that genetic factors
that compromise the epidermal barrier
could also underlie mucosal atopic diseases (filaggrin is a protein that is unique
to keratinizing epithelia). The atopic syndrome represents a genetically impaired
skin barrier function as well as impaired
nasal, bronchial, and intestinal mucous
membranes leading to atopic dermatitis,
allergic rhinitis, bronchial asthma, or aggravation of atopic dermatitis. Defective
permeability barrier function enables penetration of environmental allergens into
the skin and initiates immunological reactions and inflammation (Fig. 45-15). Filaggrin mutation is the first strong genetic
factor identified in this complex disease.
Filaggrin hydrolysis generates amino acids
in their deaminated products, which serve
as endogenous humectants.78 This may
explain the dry skin well known in atopic
dermatitis. Also, gene polymorphisms in
the gene for SPINK5, which encodes the
serine protease inhibitor LEKTI, have
been reported79 and variations within two
serine proteases of the kallikrein family,
the SC chymotryptic enzyme which degrades corneodesmosomal proteins, involved in the cohesion between the corneocytes of the SC, have been found in
some cohorts with atopic dermatitis.
The impaired skin barrier function in
atopic dermatitis is also caused by reduced lipid content or impaired lipid composition in atopic dermatitis. In particular,
a decreased content for the total amount
and for certain types of ceramides has
been described.72 A decrease in covalently
bound ceramides80 and a reduced sphingomyelinase activity has been found in
atopic dermatitis. Also, decreased secretion of lamellar bodies, which are predominantly composed of lipids, with subsequent entombment of lamellar bodies
within corneocytes, has been reported.81
70
*
*
60
50
40
30
10
20
10
0
A
0
■ Healthy
■ Non-lesional
■ Lesional
B
FIGURE 45-14 Transepidermal water loss (TEWL) (A) and stratum corneum hydration (B) are impaired in atopic dermatitis. Reduced stratum corneum hydration and enhanced TEWL are already seen in
non-lesional and are more pronounced in lesional skin in atopic dermatitis.
Psoriasis: Epidermal
Hyperproliferation and the
Skin Barrier (See Chap. 18)
Psoriasis is a chronic, generalized, and
scaly erythematous dermatosis that is primarily localized in the epidermis, showing highly enhanced proliferation and disturbed differentiation, which leads to
hyperkeratosis and parakeratosis. In addition, there is a neutrophilic infiltrate in the
beginning and in particular in severe cases
of psoriasis; later a moderate T-lymphocytic infiltrate is present. Because of this
FIGURE 45-15 Endogenous and exogenous insults lead to a disturbance in skin barrier function,
thus inducing or maintaining inflammatory skin diseases in atopic dermatitis.
severely disturbed proliferation and epidermal differentiation, there is an impaired barrier function.82 The level of
TEWL is directly related to the clinical severity of the lesion: high TEWL in acute
exanthematous psoriasis; a moderate increase in TEWL in the chronic plaque type
of the disease. Abnormalities in the SC intercellular lipids, especially a significant reduction in ceramide 1 have been found.83
Electron microscopy studies disclosed severe structural alteration of the intercellular lipid lamellae.84 A genetic linkage of
psoriasis to the epidermal differentiation
complex 1q21 has been found. Within the
epidermal differentiation complex the
small proline-rich proteins are highly upregulated in psoriasis plaques.85 Also, the
association of psoriasis with cytokeratin
K17 has been discussed.
Ichthyosis comprises a group of monogenetic diseases expressing a disturbed
desquamation resulting in scales and a
mild to moderate barrier defect. They
are caused either by changes in epidermal lipids or by changes in epidermal
differentiation. X-linked recessive ichthyosis is relative mild noncongenital
ichthyosis, consisting of a generalized
desquamation of large, adherent, and
dark brown scales. The metabolic basis
of XLRI is an enzymatic lysosomal deficiency of steroid sulfatase or arylsulfatase C. Complete deletions of the STS
gene mapped to the Xp22.3-pter region
have been found in up to 90 percent of
patients. The reduced cholesterol sulfatase activity leads to accumulation of
cholesterol sulfate and a reduction of
CHAPTER 46
Irritant Contact
Dermatitis
Antoine Amado
James S. Taylor
Apra Sood
Dermatitis or eczema is a pattern of
cutaneous inflammation that presents
TREATMENT IMPLICATIONS AND
APPROACHES: RESTORING THE
SKIN’S PROTECTIVE FUNCTION
Treatment strategies in inflammatory diseases often address immunogenic abnormalities and barrier function. Treatment
with corticosteroids, cyclosporin, tacrolimus, pimecrolimus, and UV light has been
shown to reduce cell inflammation as well
as to improve barrier function, thus helping to normalize proliferation and differentiation. However, because of side effects, these treatments should be used for
a short time only. In contrast, application
of bland creams and ointments containing
lipids and lipid-like substances, hydrocarbons, fatty acids, cholesterol esters, and
triglycerides can be used without side effects for long-term treatment of mild to
moderate inflammatory diseases. Creams
with erythema, vesiculation, and pruritus in its acute phase. Its chronic phase
is characterized by dryness, scaling, and
fissuring. Irritant contact dermatitis
(ICD) is a cutaneous response to contact
with an external chemical, physical, or
biologic agent; endogenous factors such
as skin barrier function and pre-existing
dermatitis also play a role. The spectrum of presentation after contact with
an irritant varies from overt dermatitis
to subjective contact reaction, contact
urticaria, caustic and necrotic reactions
as well as pigmentary changes and other
dermatoses.
and ointments partially correct or stimulate barrier repair and increase SC hydration,41,90–92 thus influencing epidermal
proliferation and differentiation.14 It has
been proposed that a lipid mixture containing the three key lipid groups (ceramides, cholesterol, and free fatty acids) is
able to improve skin barrier function and
SC hydration in atopic dermatitis.93 Also,
the efficacy of ceramide 3 in a nanoparticle
cream in atopic dermatitis has been described.94 However, because several research groups and companies report that
creams containing ceramides and a mixture of the three key lipids are not superior
to “classical” cream or ointment preparations, such preparations have not yet been
widely used. More research is necessary to
determine the significance of ceramides
and the composition of creams and ointments with the most therapeutic benefit.
KEY REFERENCES
The full reference list for all chapters
is available at www.digm7.com.
7. Bouwstra JA, Pilgrim K, Ponec M: Structure of the skin barrier, in Skin Barrier,
edited by PM Elias, KR Feingold. New
York, Taylor and Francis, 2006, p 65
23. Roop D: Defects in the barrier. Science
267:474, 1995
28. Candi E, Schmidt R, Melino G: The
cornified envelope: A model of cell
death in the skin. Nat Rev Mol Cell Biol
6:328, 2005
46. Brandner JM, Proksch E: Epidermal barrier
function: Role of tight junctions, in Skin
Barrier, edited by PM Elias, KR Feingold.
New York, Taylor and Francis, 2006, p 191
73. Proksch E, Foelster-Holst R, Jensen JM:
Skin barrier function, epidermal proliferation and differentiation in eczema. J
Dermatol Science 43:159-169, 2006
77. Irvine AD, McLean WH: Breaking the
(un)sound barrier: Filaggrin is a major
gene for atopic dermatitis. J Invest Dermatol 126:1200, 2006
CHAPTER 46 ■ IRRITANT CONTACT DERMATITIS
Ichthyosis: Pathologic
Lack of Moisture in the
Epidermis (See Chap. 47)
cholesterol and consequent abnormality
in the structural organization of the intercorneocyte lipid lamellae.86-88
Ichthyosis vulgaris is the most common
monogenetic skin disease. Recently, lossof-function mutations in the gene encoding filaggrin that cause ichthyosis vulgaris
have been described. During terminal differentiation, profilaggrin is cleaved into
multiple filaggrin peptides that aggregate
keratin filaments. The resultant matrix is
cross-linked to form a major component
of the cornified cell envelope. Reduction
of this major structural protein leads to an
impaired keratinization and to a moderate
defect in skin barrier function.89
Transglutaminase 1 is responsible for
the cross-link of several cornified envelope proteins. Therefore, deficiency in
transglutaminase 153 leads to lamellar
ichthyosis, which is a more severe disease than ichthyosis vulgaris with a defect in filaggrin only.
EPIDEMIOLOGY
In contrast to allergic contact dermatitis
(ACD), no previous exposure to the irritant is necessary in eliciting irritant reactions.1 ICD accounts for 80 percent of all
cases of contact dermatitis,2,3 and is often
occupation-related. ICD caused by personal-care products and cosmetics is also
common; however, very few of these patients with these irritant reactions seek
medical help because they manage by
avoiding the offending agent.4
The incidence of ICD is difficult to
determine because the accuracy of the
395