Skin Basic Structure and Function

Skin is composed of three layers: the epidermis, dermis, and
subcutaneous fat (panniculus) (Fig. 1-1). The outermost layer,
the epidermis, is composed of viable keratinocytes covered by
a layer of keratin, the stratum corneum. The principal compo-
nent of the dermis is the fbrillar structural protein collagen.
The dermis lies on the panniculus, which is composed of
lobules of lipocytes separated by collagenous septae that
contain the neurovascular bundles.
There is considerable regional variation in the relative thick-
ness of these layers. The epidermis is thickest on the palms
and soles, measuring approximately 1.5 mm. It is very thin on
the eyelid, where it measures less than 0.1 mm. The dermis is
thickest on the back, where it is 30–40 times as thick as the
overlying epidermis. The amount of subcutaneous fat is gener-
ous on the abdomen and buttocks compared with the nose and
sternum, where it is meager.
Epidermis and adnexa
During the frst weeks of life, the fetus is covered by a layer
of nonkeratinizing cuboidal cells called the periderm (Fig. 1-2).
Later, the periderm is replaced by a multilayered epidermis.
Adnexal structures, particularly follicles and eccrine sweat
units, originate during the third month of fetal life as down-
growths from the developing epidermis. Later, apocrine sweat
units develop from the upper portion of the follicular epithe-
lium and sebaceous glands from the midregion of the follicle.
Adnexal structures appear frst in the cephalic portion of the
fetus and later in the caudal portions.
The adult epidermis is composed of three basic cell types:
keratinocytes, melanocytes, and Langerhans cells. An addi-
tional cell, the Merkel cell, can be found in the basal layer of
the palms and soles, oral and genital mucosa, nail bed, and
follicular infundibula. Merkel cells, located directly above the
basement membrane zone, contain intracytoplasmic dense-
core neurosecretory-like granules, and, through their associa-
tion with neurites, act as slow-adapting touch receptors. They
have direct connections with adjacent keratinocytes by desmo-
somes and contain a paranuclear whorl of intermediate keratin
flaments. Both polyclonal keratin immunostains and mono-
clonal immunostaining for keratin 20 stain this whorl of
keratin flaments in a characteristic paranuclear dot pattern.
Merkel cells also label for neuroendocrine markers such as
chromogranin and synaptophysin.
Keratinocytes
Keratinocytes, or squamous cells, are the principal cells of the
epidermis. They are of ectodermal origin and have the special-
ized function of producing keratin, a complex flamentous
protein that not only forms the surface coat (stratum corneum)
of the epidermis but also is the structural protein of hair and
nails. Multiple distinct keratin genes have been identifed and
consist of two subfamilies, acidic and basic. The product of one
basic and one acidic keratin gene combines to form the multi-
ple keratins that occur in many tissues. The presence of various
keratin types is used as a marker for the type and degree of
differentiation of a population of keratinocytes. Keratins are
critical for normal functioning of the epidermis and keratin
mutations are recognized causes of skin disease. Mutations in
the genes for keratins 5 and 14 are associated with epidermo-
lysis bullosa simplex. Keratin 1 and 10 mutations are associ-
ated with epidermolytic hyperkeratosis. Mild forms of this
disorder may represent localized or widespread expressions
of mosaicism for these gene mutations.
The epidermis may be divided into the following zones,
beginning with the innermost layer: basal layer (stratum ger-
minativum), Malpighian or prickle layer (stratum spinosum),
granular layer (stratum granulosum), and horny layer (stratum
corneum). On the palms and soles a pale clear to pink layer,
the stratum lucidum, is noted just above the granular layer.
When the skin in other sites is scratched or rubbed, the
Malpighian and granular layers thicken, a stratum lucidum
forms, and the stratum corneum becomes thick and compact.
Histones appear to regulate epidermal differentiation and
histone deacetylation suppresses expression of proflaggrin.
Slow-cycling stem cells provide a reservoir for regeneration of
the epidermis. Sites rich in stem cells include the deepest por-
tions of the rete, especially on palmoplantar skin, as well as
the hair bulge. Stem cells divide infrequently in normal skin,
but in cell culture they form active growing colonies. They can
be identifed by their high expression of β1-integrins and lack
of terminal differentiation markers. Stem cells can also be
identifed by their low levels of desmosomal proteins, such as
desmoglein 3. The basal cells divide and, as their progeny
move upward, they fatten and their nucleus disappears.
Abnormal keratinization can manifest as parakeratosis
(retained nuclei), as corps ronds (round, clear to pink, abnor-
mally keratinized cells), or as grains (elongated, basophilic,
abnormally keratinized cells).
During keratinization, the keratinocyte frst passes through
a synthetic and then a degradative phase on its way to becom-
ing a horn cell. In the synthetic phase, the keratinocyte accu-
mulates within its cytoplasm intermediate flaments composed
of a fbrous protein, keratin, arranged in an alpha-helical
coiled coil pattern. These tonoflaments are fashioned into
bundles, which converge on and terminate at the plasma
membrane, where they end in specialized attachment plates
called desmosomes. The degradative phase of keratinization
is characterized by the disappearance of cell organelles and
the consolidation of all contents into a mixture of flaments
and amorphous cell envelopes. This programmed process of
maturation resulting in death of the cell is termed terminal
differentiation. Terminal differentiation is also seen in the
involuting stage of keratoacanthomas, where the initial phase
of proliferation gives way to terminal keratinization and
involution.
Skin: Basic Structure and Function
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Bonus images for this chapter can be found online at
http://www.expertconsult.com
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Glycolipids such as ceramides contribute a water barrier func-
tion to skin and are commonly found in topical products
meant to restore the epidermal barrier. Lamellar bodies form
abnormally in the absence of critical ceramides such as gluco-
sylceramide or there is disproportion of critical lipids.
Desmosomal adhesion depends upon cadherins, including the
calcium-dependent desmogleins and desmocollins. Antibodies
to these molecules result in immunobullous diseases.
Keratinocytes of the granular zone contain, in addition to
the keratin flament system, keratohyaline granules, composed
of amorphous particulate material of high sulfur–protein
content. This material, called proflaggrin, is a precursor to
flaggrin, so named because it is thought to be responsible
for keratin flament aggregation. Conversion to flaggrin takes
place in the granular layer, and this forms the electron-dense
interflamentous protein matrix of mature epidermal keratin.
Keratohyaline is hygroscopic, and repeated cycles of hydra-
tion and dehydration contribute to normal desquamation of
the stratum corneum. Ichthyosis vulgaris is characterized by
a diminished or absent granular layer, contributing to the
retention hyperkeratosis noted in this disorder. Keratohyalin
results in the formation of soft, fexible keratin. Keratin that
forms in the absence of keratohyaline granules is typically
hard and rigid. Hair fbers and nails are composed of hard
keratin.
Keratinocytes play an active role in the immune function of
the skin. In conditions such as allergic contact dermatitis they
participate in the induction of the immune response, rather
than acting as passive victims. Keratinocytes secrete a wide
array of cytokines and infammatory mediators, including
tumor necrosis factor (TNF)-α. They also can express mole-
cules on their surface, such as intercellular adhesion molecule-1
(ICAM-1) and major histocompatibility complex (MHC) class
II molecules, suggesting that keratinocytes actively respond to
immune effector signals.
Melanocytes
Melanocytes are the pigment-producing cells of the epidermis.
They are derived from the neural crest and by the eighth week
Premature programmed cell death, or apoptosis, appears in
hematoxylin and eosin (H&E)-stained sections as the presence
of scattered bright red cells, some of which may contain small
black pyknotic nuclei. These cells are present at various levels
of the epidermis, as this form of cell death does not represent
part of the normal process of maturation. Widespread apop-
tosis is noted in the verrucous phase of incontinentia pigmenti.
It is also a prominent fnding in catagen hairs, where apoptosis
results in the involution of the inferior segment of the hair
follicle.
In normal skin, the plasma membranes of adjacent cells are
separated by an intercellular space. Electron microscopic his-
tochemical studies have shown that this interspace contains
glycoproteins and lipids. Lamellar granules (Odland bodies or
membrane-coating granules) appear in this space, primarily at
the interface between the granular and cornifed cell layers.
Lamellar granules contribute to skin cohesion and imperme-
ability. Conditions such as lamellar ichthyosis and Flegel’s
hyperkeratosis demonstrate abnormal lamellar granules.
Fig. 1-1 Diagrammatic cross-section of the skin and panniculus.
Apocrine
unit
Straight duct
Coiled gland
Spiraled duct
Straight duct
Coiled duct
Eccrine gland
Superficial plexus
Deep plexus
Epidermis
Subcutaneous tissue
Meissner nerve
ending
papillary
reticular
Sebaceous gland
Arrector pili muscle
Hair shaft
Pacini nerve ending
Dermis
Eccrine
sweat unit
Dermal
vasculature
Fig. 1-2 Fetal periderm covering fetal mesenchyme.
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of development can be found within the fetal epidermis. In
normal, sun-protected, trunk epidermis, melanocytes reside in
the basal layer at a frequency of approximately 1 in every 10
basal keratinocytes. Areas such as the face, shins, and genitalia
have a greater density of melanocytes, and in heavily sun-
damaged facial skin, Mart-1 immunostaining can demonstrate
ratios of melanocytes to basal keratinocytes that approach 1:1.
Recognition of the variation in melanocyte to keratinocyte
ratio is critical in the interpretation of biopsies of suspected
lentigo maligna (malignant melanoma in situ) on sun-damaged
skin.
Racial differences in skin color are not caused by differences
in the number of melanocytes. It is the number, size, and dis-
tribution of the melanosomes or pigment granules within
keratinocytes that determine differences in skin color. Pale
skin has fewer melanosomes and these are smaller and pack-
aged within membrane-bound complexes. Dark skin has more
melanosomes, and these tend to be larger and singly dis-
persed. Chronic sun exposure can stimulate melanocytes to
produce larger melanosomes, thereby making the distribution
of melanosomes within keratinocytes resemble the pattern
seen in dark-skinned individuals.
In histologic sections of skin routinely stained by H&E,
the melanocyte appears as a cell with ample amphophilic
cytoplasm, or as a clear cell in the basal layer of the epidermis.
The apparent halo is an artifact formed during fxation of
the specimen. This occurs because the melanocyte, lacking
tonoflaments, cannot form desmosomal attachments with
keratinocytes. Keratinocytes also frequently demonstrate clear
spaces, but can be differentiated from melanocytes because
they demonstrate cell–cell junctions and a layer of cytoplasm
peripheral to the clear space.
The melanocyte is a dendritic cell. Its dendrites extend for
long distances within the epidermis and any one melanocyte
is therefore in contact with a great number of keratinocytes;
together they form the so-called epidermal melanin unit.
Keratinocytes actively ingest the tips of the melanocytic den-
drites, thus imbibing the melanosomes.
Melanosomes are synthesized in the Golgi zone of the cell
and pass through a series of stages in which the enzyme tyro-
sinase acts on melanin precursors to produce the densely pig-
mented granules. Melanocytes in red-heads tend to be rounder
and produce more phaeomelanin. The melanocortin 1 receptor
(MC1R) is important in the regulation of melanin production.
Loss-of-function mutations in the MC1R gene bring about a
change from eumelanin to phaeomelanin production, whereas
activating gene mutations can enhance eumelanin synthesis.
Most red-heads are compound heterozygotes or homozygotes
for a variety of loss-of-function mutations in this gene.
Eumelanin production is optimal at pH 6.8 and changes in
cellular pH also result in alterations of melanin production
and the eumelanin to phaeomelanin ratio. Within keratino-
cytes, melanin typically forms a cap over the nucleus, where
it presumably functions principally in a photoprotective
role. Evidence of keratinocyte photodamage in the form of
thymidine dimer formation can be assessed using gas
chromatography–mass spectrometry or enzyme-linked immu-
nosorbent assays. Pigment within melanocytes also serves to
protect the melanocytes themselves against photodamage,
such as ultraviolet (UV) A-induced membrane damage.
Areas of leukoderma or whitening of skin can be caused by
very different phenomena. In vitiligo, the affected skin becomes
white because of destruction of melanocytes. In albinism, the
number of melanocytes is normal, but they are unable to syn-
thesize fully pigmented melanosomes because of defects in the
enzymatic formation of melanin. Local areas of increased pig-
mentation can result from a variety of causes. The typical
freckle results from a localized increase in production of
pigment by a near-normal number of melanocytes. Black
“sunburn” or “ink spot” lentigines demonstrate basilar hyper-
pigmentation and prominent melanin within the stratum
corneum. Nevi are benign proliferations of melanocytes.
Melanomas are their malignant counterpart. Melanocytes
and keratinocytes express neurotrophins (ectodermal nerve
growth factors). Melanocytes release neurotrophin 4, but
the release is downregulated by UVB irradiation, suggesting
neurotrophins as possible targets for therapy of disorders of
pigmentation. Melanocytes express toll-like receptors (TLRs)
and stimulation by bacterial lipopolysaccharides increases
pigmentation.
Langerhans cells
Langerhans cells are normally found scattered among keratino-
cytes of the stratum spinosum. They constitute 3–5% of the
cells in this layer. Like melanocytes, they are not connected to
adjacent keratinocytes by the desmosomes. The highest density
of Langerhans cells in the oral mucosa occurs in the vestibular
region, and the lowest density in the sublingual region, sug-
gesting the latter is a relatively immunologically “privileged”
site.
At the light microscopic level, Langerhans cells are diffcult
to detect in routinely stained sections; however, they appear
as dendritic cells in sections impregnated with gold chloride,
a stain specifc for Langerhans cells. They can also be stained
with CD1α or S-100 immunostains. Ultrastructurally, they are
characterized by a folded nucleus and distinct intracytoplas-
mic organelles called Birbeck granules. In their fully devel-
oped form, the organelles are rod-shaped with a vacuole at
one end and they resemble a tennis racquet. The vacuole is an
artifact of processing.
Functionally, Langerhans cells are of the monocyte–
macrophage lineage and originate in bone marrow. They func-
tion primarily in the afferent limb of the immune response by
providing for the recognition, uptake, processing, and presen-
tation of antigens to sensitized T lymphocytes, and are impor-
tant in the induction of delayed-type sensitivity. Once an
antigen is presented, Langerhans cells migrate to the lymph
nodes. Hyaluronan (hyaluronic acid) plays a critical role in
Langerhans cell maturation and migration. Langerhans cells
express langerin, membrane ATPase (CD39), and CCR6, while
CD1α
+
dermal dendritic cells express macrophage mannose
receptor, CD36, factor XIIIa, and chemokine receptor 5, sug-
gesting different functions for these two CD1α+ populations.
If skin is depleted of Langerhans cells by exposure to UV
radiation, it loses the ability to be sensitized until its popula-
tion of Langerhans cell is replenished. Macrophages that
present antigen in Langerhans cell-depleted skin can induce
immune tolerance. In contrast to Langerhans cells, which
make interleukin (IL)-12, the macrophages found in the epi-
dermis 72 h after UVB irradiation produce IL-10, resulting in
downregulation of the immune response. At least in mice,
viral immunity appears to require priming by CD8α+ den-
dritic cells, rather than Langerhans cells, suggesting a complex
pattern of antigen presentation in cutaneous immunity.
Ahn JH, et al: Human melanocytes express functional toll-like receptor
4. Exp Dermatol 2008 May; 17(5):412–417.
Allam JP, et al: Distribution of Langerhans cells and mast cells within
the human oral mucosa: new application sites of allergens in
sublingual immunotherapy? Allergy 2008 Jun; 63(6):720–727.
Baxter LL, et al: Networks and pathways in pigmentation, health, and
disease. Wiley Interdiscip Rev Syst Biol Med 2009 Nov 1; 1(3):359–371.
Boulais N, et al: The epidermis: a sensory tissue. Eur J Dermatol 2008
Mar–Apr; 18(2):119–127.
Dusek RL, et al: Discriminating roles of desmosomal cadherins: beyond
desmosomal adhesion. J Dermatol Sci 2007 Jan; 45(1):7–21.
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Ernfors P: Cellular origin and developmental mechanisms during the
formation of skin melanocytes. Exp Cell Res 2010 May 1;
316(8):1397–1407.
Imai Y, et al: Freshly isolated Langerhans cells negatively regulate
naïve T cell activation in response to peptide antigen through
cell-to-cell contact. J Dermatol Sci 2008 Jul; 51(1):19–29.
Jennemann R, et al: Integrity and barrier function of the epidermis
critically depend on glucosylceramide synthesis. J Biol Chem 2007
Feb 2; 282(5):3083–3094.
Le Douarin NM, et al: The stem cells of the neural crest. Cell Cycle 2008
Jan; 24:7(8).
Markova NG, et al: Inhibition of histone deacetylation promotes
abnormal epidermal differentiation and specifically suppresses the
expression of the late differentiation marker profilaggrin. J Invest
Dermatol 2007 May; 127(5):1126–1139.
Ortonne JP, et al: Latest insights into skin hyperpigmentation. J Investig
Dermatol Symp Proc 2008 Apr; 13(1):10–14.
Santegoets SJ, et al: Transcriptional profiling of human skin-resident
Langerhans cells and CD1α+ dermal dendritic cells: differential
activation states suggest distinct functions. J Leukoc Biol 2008
Apr; 24.
Schwarz T: Regulatory T cells induced by ultraviolet radiation. Int Arch
Allergy Immunol 2005; 137:187.
Dermoepidermal junction
The junction of the epidermis and dermis is formed by the
basement membrane zone (BMZ). Ultrastructurally, this zone
is composed of four components: the plasma membranes
of the basal cells with the specialized attachment plates
(hemidesmosomes); an electron-lucent zone called the lamina
lucida; the lamina densa (basal lamina); and the fbrous com-
ponents associated with the basal lamina, including anchoring
fbrils, dermal microfbrils, and collagen fbers. At the light
microscopic level, the periodic acid–Schiff (PAS)-positive
basement membrane is composed of the fbrous components.
The basal lamina is synthesized by the basal cells of the epi-
dermis. Type IV collagen is the major component of the basal
lamina. Type VII collagen is the major component of anchor-
ing fbrils. The two major hemidesmosomal proteins are the
BP230 (bullous pemphigoid antigen 1) and BP180 (bullous
pemphigoid antigen 2, type XVII collagen).
In the upper permanent portion of the anagen follicle,
plectin, BP230, BP180, α6β4-integrin, laminin 5, and type VII
collagen show essentially the same expression as that found
in the interfollicular epidermis. Staining in the lower, transient
portion of the hair follicle, however, is different. All BMZ
components diminish and may become discontinuous in the
inferior segment of the follicle. Hemidesmosomes are also not
apparent in the BMZ of the hair bulb. The lack of hemidesmo-
somes in the deep portions of the follicle may relate to the
transient nature of the inferior segment, while abundant
hemidesmosomes stabilize the upper portion of the follicle.
The BMZ is considered to be a porous semipermeable flter,
which permits exchange of cells and fuid between the epider-
mis and dermis. It further serves as a structural support for
the epidermis and holds the epidermis and dermis together,
but also helps to regulate growth, adhesion, and movement of
keratinocytes and fbroblasts, as well as apoptosis. Much of
this regulation takes place through activation of integrins and
syndecans. Extracellular matrix protein 1 demonstrates loss-
of-function mutations in lipoid proteinosis, resulting in redu-
plication of the basement membrane.
Masunaga T: Epidermal basement membrane: its molecular organiza-
tion and blistering disorders. Connect Tissue Res 2006; 47(2):55–66.
McMillan JR, et al: Epidermal basement membrane zone components:
ultrastructural distribution and molecular interactions. J Dermatol Sci
2003; 31:169.
Schéele S, et al: Laminin isoforms in development and disease. J Mol
Med 2007 Aug; 85(8):825–836.
Sercu S, et al: Interaction of extracellular matrix protein 1 with extracel-
lular matrix components: ECM1 is a basement membrane protein of
the skin. J Invest Dermatol 2008 Jun; 128(6):1397–1408.
Sugawara K, et al: Laminin-332 and 511 in skin. Exp Dermatol 2008
Jun; 17(6):473–480.
Verdolini R, et al: Autoimmune subepidermal bullous skin diseases: the
impact of recent findings for the dermatopathologist. Virchows Arch
2003; 443:184.
Epidermal appendages: adnexa
Eccrine and apocrine glands, ducts, and pilosebaceous units
constitute the skin adnexa. Embryologically, they originate as
downgrowths from the epidermis and are therefore ectoder-
mal in origin. Hedgehog signaling by the signal transducer
known as smoothened appears critical for hair development.
Abnormalities in this pathway contribute to the formation
of pilar tumors and basal cell carcinoma. In the absence of
hedghog signaling, embryonic hair germs may develop instead
into modifed sweat gland or mammary epithelium.
While the various adnexal structures serve specifc func-
tions, they all can function as reserve epidermis in that re -
epithelialization after injury to the surface epidermis occurs,
principally by virtue of the migration of keratinocytes from
the adnexal epithelium to the skin surface. It is not surprising,
therefore, that skin sites such as the face or scalp, which contain
pilosebaceous units in abundance, reepithelialize more rapidly
than do skin sites such as the back, where adnexae of all types
are comparatively scarce. Once a wound has reepithelialized,
granulation tissue is no longer produced. Deep saucerized
biopsies in an area with few adnexae will slowly fll with
granulation tissue until they are fush with the surrounding
skin. In contrast, areas rich in adnexae will quickly be covered
with epithelium. No more granulation tissue will form and the
contour defect created by the saucerization will persist.
The pseudoepitheliomatous hyperplasia noted in infections
and infammatory conditions consists almost exclusively of
adnexal epithelium. Areas of thin intervening epidermis are
generally evident between areas of massively hypertrophic
adnexal epithelium.
Eccrine sweat units
The eccrine sweat unit is composed of three sections that are
modifed from the basic tubular structure that formed during
embryogenesis as a downgrowth of surface epidermis. The
intraepidermal spiral duct, which opens directly on to the skin
surface, is called the acrosyringium. It is derived from dermal
duct cells through mitosis and upward migration. The acrosy-
ringium is composed of small polygonal cells with a central
round nucleus surrounded by ample pink cytoplasm.
Cornifcation takes place within the duct and the horn cells
become part of the stratum corneum of the epidermis. In the
stratum corneum overlying an actinic keratosis, the lamellar
spiral acrosyringeal keratin often stands out prominently
against the compact red parakeratotic keratin produced by the
actinic keratosis.
The straight dermal portion of the duct is composed of a
double layer of cuboidal epithelial cells and is lined by an
eosinophilic cuticle on its luminal side. The coiled secretory
acinar portion of the eccrine sweat gland may be found within
the superfcial panniculus. In areas of skin, such as the back,
that possess a thick dermis, the eccrine coil is found in the deep
dermis, surrounded by an extension of fat from the underlying
panniculus. An inner layer of epithelial cells, the secretory
portion of the gland, is surrounded by a layer of fattened
myoepithelial cells. The secretory cells are of two types:
glycogen-rich, large pale cells; and smaller, darker-staining
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cells. The pale glycogen-rich cells are thought to initiate the
formation of sweat. The darker cells may function in a manner
similar to that of cells of the dermal duct, which actively re -
absorb sodium, thereby modifying sweat from a basically iso-
tonic solution to a hypotonic one by the time it reaches the skin
surface. Sweat is similar in composition to plasma, containing
the same electrolytes, though in a more dilute concentration.
Physical conditioning in a hot environment results in produc-
tion of larger amounts of extremely hypotonic sweat in
response to a thermal stimulus. This adaptive response allows
greater cooling with conservation of sodium.
In humans, eccrine sweat units are found at virtually all skin
sites. Other mammals have both apocrine and eccrine glands,
but the apocrine gland is the major sweat gland, and eccrine
glands are generally restricted to areas such as the footpad.
Ringtailed lemurs have an antebrachial organ rich in sweat
glands with hybrid characteristics of eccrine and apocrine
glands.
In humans, eccrine glands are abundant and serve a thermo-
regulatory function. They are most abundant on the palms,
soles, forehead, and axillae. Some eccrine glands in the axillae,
especially in patients with hyperhidrosis, may have widely
dilated secretory coils that contain apocrine-appearing cells.
These fndings suggest the presence of hybrid glands in
humans. On friction surfaces, such as the palms and soles,
eccrine secretion is thought to assist tactile sensibility and
improve adhesion.
Physiologic secretion of sweat occurs as a result of many
factors and is mediated by cholinergic innervation. Heat is a
prime stimulus to increased sweating, but other physiologic
stimuli, including emotional stress, are important as well.
During early development, there is a switch between adrener-
gic and cholinergic innervation of sweat glands. Some respon-
siveness to both cholinergic and adrenergic stimuli persists.
Cholinergic sweating involves a biphasic response, with initial
hyperpolarization and secondary depolarization mediated
by the activation of calcium and chloride ion conductance.
Adrenergic secretion involves monophasic depolarization and
is dependent on cystic fbrosis transmembrane conductance
regulator-GCl. Cells from patients with cystic fbrosis demon-
strate no adrenergic secretion. Vasoactive intestinal polypep-
tide may also play a role in stimulating eccrine secretion.
Apocrine units
Apocrine units develop as outgrowths, not of the surface epi-
dermis, but of the infundibular or upper portion of the hair
follicle. Although immature apocrine units are found covering
the entire skin surface of the human fetus, these regress and
are absent by the time the fetus reaches term. The straight
excretory portion of the duct, which opens into the infundibu-
lar portion of the hair follicle, is composed of a double layer
of cuboidal epithelial cells.
Hidrocystomas may show focal secretory cells, but are gen-
erally composed of cuboidal cells resembling the straight
portion of the apocrine duct. Various benign cutaneous tumors
demonstrate differentiation resembling apocrine duct cells,
including hidroacanthoma simplex, poroma, dermal duct
tumor, and nodular hidradenoma. Although some of these
tumors were formerly classifed as “eccrine” in differentiation,
each may demonstrate focal apocrine decapitation secretion,
suggesting apocrine differentiation.
The coiled secretory gland is located at the junction of the
dermis and subcutaneous fat. It is lined by a single layer of
cells, which vary in appearance from columnar to cuboidal.
This layer of cells is surrounded by a layer of myoepithelial
cells. Apocrine coils appear more widely dilated than eccrine
coils, and apocrine sweat stains more deeply red in H&E sec-
tions, contrasting with the pale pink of eccrine sweat.
The apices of the columnar cells project into the lumen of
the gland and in histologic cross-section appear as if they are
being extruded (decapitation secretion). Controversy exists
about the mode of secretion in apocrine secretory cells, whether
merocrine, apocrine, holocrine, or all three. The composition
of the product of secretion is only partially understood.
Protein, carbohydrate, ammonia, lipid, and iron are all found
in apocrine secretion. It appears milky white, although lipo-
fuscin pigment may rarely produce dark shades of brown and
gray-blue (apocrine chromhidrosis). Apocrine sweat is odor-
less until it reaches the skin surface, where it is altered by
bacteria, which makes it odoriferous. Apocrine secretion is
mediated by adrenergic innervation and by circulating cate-
cholamines of adrenomedullary origin. Vasoactive intestinal
polypeptide may also play a role in stimulating apocrine
secretion. Apocrine excretion is episodic, although the actual
secretion of the gland is continuous. Apocrine gland secretion
in humans serves no known function. In other species it has a
protective as well as a sexual function, and in some species it
is important in thermoregulation as well.
Although occasionally found in an ectopic location, apocrine
units of the human body are generally confned to the follow-
ing sites: axillae, areolae, anogenital region, external auditory
canal (ceruminous glands), and eyelids (glands of Moll). They
are also generally prominent in the stroma of nevus sebaceous
of Jadassohn. Apocrine glands do not begin to function until
puberty.
Hair follicles
During embryogenesis, mesenchymal cells in the fetal dermis
collect immediately below the basal layer of the epidermis.
Epidermal buds grow down into the dermis at these sites. The
developing follicle forms at an angle to the skin surface and
continues its downward growth. At this base, the column of
cells widens, forming the bulb, and surrounds small collec-
tions of mesenchymal cells. These papillary mesenchymal
bodies contain mesenchymal stem cells with broad functional-
ity. At least in mice, they demonstrate extramedullary hemato-
poietic stem cell activity, and represent a potential therapeutic
source of hematopoietic stem cells and a possible source of
extramedullary hematopoiesis in vivo.
Along one side of the fetal follicle, two buds are formed: an
upper, which develops into the sebaceous gland, and a lower,
which becomes the attachment for the arrector pili muscle. A
third epithelial bud develops from the opposite side of the
follicle above the level of the sebaceous gland anlage, and
gives rise to the apocrine gland. The uppermost portion of the
follicle, which extends from its surface opening to the entrance
of the sebaceous duct, is called the infundibular segment. It
resembles the surface epidermis and its keratinocytes may be
of epidermal origin. The portion of the follicle between the
sebaceous duct and the insertion of the arrector pili muscle is
the isthmus. The inner root sheath fully keratinizes and sheds
within this isthmic portion. The inferior portion includes the
lowermost part of the follicle and the hair bulb. Throughout
life, the inferior portion undergoes cycles of involution and
regeneration.
Hair follicles develop sequentially in rows of three. Primary
follicles are surrounded by the appearance of two secondary
follicles; other secondary follicles subsequently develop
around the principal units. The density of pilosebaceous units
decreases throughout life, possibly because of dropout of the
secondary follicles. In mouse models, signaling by molecules
designated as ectodysplasin A and noggin is essential for the
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development of primary hair follicles and induction of second-
ary follicles. Arrector pili muscles contained within the follicu-
lar unit interconnect at the level of the isthmus.
The actual hair shaft, as well as an inner and an outer root
sheath, is produced by the matrix portion of the hair bulb (Fig.
1-3). The sheaths and contained hair form concentric cylindri-
cal layers. The hair shaft and inner root sheath move together
as the hair grows upwards until the fully keratinized inner
root sheath sheds at the level of the isthmus. The epidermis
of the upper part of the follicular canal is contiguous with
the outer root sheath. The upper two portions of the follicle
(infundibulum and isthmus) are permanent; the inferior
segment is completely replaced with each new cycle of hair
growth. On the scalp, anagen, the active growth phase, lasts
about 3–5 years. Normally, approximately 85–90% of all scalp
hairs are in the anagen phase, a fgure that decreases with age
and decreases faster in individuals with male-pattern baldness
(as the length of anagen decreases dramatically). Scalp anagen
hairs grow at a rate of about 0.37 mm/day. Catagen, or involu-
tion, lasts about 2 weeks. Telogen, the resting phase, lasts
about 3–5 months. Most sites on the body have a much shorter
anagen phase and much longer telogen, resulting in short
hairs that stay in place for long periods of time without
growing longer. Prolongation of the anagen phase results in
long eyelashes in patients with acquired immunodefciency
syndrome (AIDS).
Human hair growth is cyclical, but each follicle functions as
an independent unit (Fig. 1-4). Therefore, humans do not shed
hair synchronously, as most animals do. Each hair follicle
undergoes intermittent stages of activity and quiescence.
Synchronous termination of anagen or telogen results in
telogen effuvium. Most commonly, telogen effuvium is the
result of early release from anagen, such as that induced by a
febrile illness, surgery, or weight loss.
Various exogenous and endogenous physiologic factors can
modulate the hair cycle. The hair papilla and the connective
tissue sheath form a communicating network through gap
junctions. This network may play a role in controlling hair
cycling. Pregnancy is typically accompanied by retention of an
increased number of scalp hairs in the anagen phase, as well
as a prolongation of telogen. Soon after delivery, telogen loss
can be detected as abnormally prolonged telogen hairs are
released. At the same time, abnormally prolonged anagen
hairs are converted synchronously to telogen. Between 3 and
5 months later, a more profound effuvium is noted. Patients
on chemotherapy often have hair loss because the drugs inter-
fere with the mitotic activity of the hair matrix, leading to the
formation of a tapered fracture. Only anagen hairs are affected,
leaving a sparse coat of telogen hairs on the scalp. As the
matrix recovers, anagen hairs resume growth without having
to cycle through catagen and telogen.
The growing anagen hair is characterized by a pigmented
bulb (Fig. 1-5) and an inner root sheath (Fig. 1-6). Histologically,
catagen hairs are best identifed by the presence of many apop-
totic cells in the outer root sheath (Fig. 1-7). Telogen club hairs
have a nonpigmented bulb with a shaggy lower border. The
presence of bright red trichilemmal keratin bordering the club
hair results in a fame thrower-like appearance in vertical H&E
sections (Fig. 1-8). As the new anagen hair grows, the old
telogen hair is shed.
Fig. 1-3 Anatomy of the hair follicle.
Outer root sheath
Inner root sheath
Hair cuticle
Cortex
Medulla
Bulb with matrix cells
Dermal papilla
Hair shaft
Cross-
section
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Fig. 1-4 Phases of the growth cycle of a hair.
Growing
hair
Growing
hair
Sebaceous
gland
Dermal
papilla
Club hair
Anagen Catagen Telogen Anagen
Fig. 1-5 Cross-section of anagen bulb demonstrating pigment within
matrix.
Fig. 1-6 Cross-section of isthmus of anagen follicle demonstrating
glycogenated outer root sheath and keratinized inner root sheath.
The scalp hair of white people is round; pubic hair, beard
hair, and eyelashes are oval. The scalp hair of black people is
also oval, and it is this, plus a curvature of the follicle just
above the bulb, that causes black hair to be curly. Uncombable
hair is triangular with a central canal.
Hair color depends on the degree of melanization and dis-
tribution of melanosomes within the hair shaft. Melanocytes
of the hair bulb synthesize melanosomes and transfer them to
the keratinocytes of the bulb matrix. Larger melanosomes are
found in the hair of black persons; smaller melanosomes,
which are aggregated within membrane-bound complexes,
are found in the hair of white persons. Red hair is character-
ized by spherical melanosomes. Graying of hair is a result of
a decreased number of melanocytes, which produce fewer
melanosomes. Repetitive oxidative stress causes apoptosis of
hair follicle melanocytes, resulting in normal hair graying.
Premature graying is related to exhaustion of the melanocyte
stem cell pool.
Sebaceous glands
Sebaceous glands are formed embryologically as an outgrowth
from the upper portion of the hair follicle. They are composed
of lobules of pale-staining cells with abundant lipid droplets
in their cytoplasm. At the periphery of the lobules basaloid
germinative cells are noted. These germinative cells give rise
to the lipid-flled pale cells, which are continuously being
extruded through the short sebaceous duct into the infundibu-
lar portion of the hair follicle. The sebaceous duct is lined by
a red cuticle that undulates sharply in a pattern resembling
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Although sebaceous glands are independent miniorgans in
their own right, they are anatomically and functionally related
to the hair follicle. Cutaneous disorders attributed to seba-
ceous glands, such as acne vulgaris, are really disorders of the
entire pilosebaceous unit. The clinical manifestations of acne,
namely the comedo, papule, pustule, and cyst, would not
form, regardless of increased sebaceous gland activity, as long
as the sebaceous duct and infundibular portion of the hair
follicle remained patent, and lipid and cell debris (sebum)
were able to reach the skin surface.
Most lipids produced by the sebaceous gland are also pro-
duced elsewhere in the body. Wax esters and squalene are
unique secretory products of sebaceous glands. Sebocytes
express histamine receptors and antihistamines can reduce
squalene levels, suggesting that antihistamines could play a
role in modulating sebum production. Skin lipids contribute
to the barrier function and some have antimicrobial properties.
Antimicrobial lipids include free sphingoid bases derived
from epidermal ceramides and fatty acids like sapienic acid
derived from sebaceous triglycerides.
Drake DR, et al: Thematic review series: skin lipids. Antimicrobial lipids
at the skin surface. J Lipid Res 2008 Jan; 49(1):4–11.
Gritli-Linde A, et al: Abnormal hair development and apparent follicular
transformation to mammary gland in the absence of hedgehog
signaling. Dev Cell 2007 Jan; 12(1):99–112.
Kizawa K, et al: Specific citrullination causes assembly of a globular
S100A3 homotetramer: a putative Ca2
+
modulator matures human hair
cuticle. J Biol Chem 2008 Feb 22; 283(8):5004–5013.
Novotný J, et al: Synthesis and structure-activity relationships of skin
ceramides. Curr Med Chem 2010; 17(21):2301–2324.
Pelle E, et al: Identification of histamine receptors and reduction of
squalene levels by an antihistamine in sebocytes. J Invest Dermatol
2008 May; 128(5):1280–1285.
Saga K: Structure and function of human sweat glands studied with
histochemistry and cytochemistry. Prog Histochem Cytochem 2002;
37:323.
Smith KR, et al: Thematic review series: skin lipids. Sebaceous gland
lipids: friend or foe? J Lipid Res 2008 Feb; 49(2):271–281.
Spatz KR, et al: Increased melanocyte apoptosis under stress-mediator
substance P-elucidating pathways involved in stress-induced prema-
ture graying. Exp Dermatol 2008 Jul; 17(7):632.
Xu X, et al: Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal
homeostasis and maintenance of hair follicle stem cells. Dev Biol 2007
Dec 15; 312(2):484–500.
Nails
Nails act to assist in grasping small objects and in protecting
the fngertip from trauma. Matrix keratinization leads to the
formation of the nail plate. Fingernails grow an average of 0.1
mm/day, requiring about 4–6 months to replace a complete
nail plate. The growth rate is much slower for toenails, with
12–18 months required to replace the great toenail.
Abnormalities of the nail may serve as important clues to
cutaneous and systemic disease, and may provide the astute
clinician with information about disease or toxic exposures
that occurred several months in the past.
The keratin types found in the nail are a mixture of epider-
mal and hair types, with the hair types predominating. Nail
isthmus keratinization differs from that of the nail bed in that
K10 is only present in nail isthmus. Brittle nails demonstrate
widening of the intercellular space between nail keratinocytes
on electron microscopy.
Whereas most of the skin is characterized by rete pegs that
resemble an egg crate, the nail bed has true parallel rete ridges.
These ridges result in the formation of splinter hemorrhages
when small quantities of extravasated red cells mark their
path. The nail cuticle is formed by keratinocytes of the
proximal nailfold, whereas the nail plate is formed by matrix
Fig. 1-7 Catagen hair with many apoptotic keratinocytes within the
outer root sheath.
Fig. 1-8 Vertical section of telogen hair demonstrating “flame
thrower” appearance of club hair.
shark’s teeth. This same undulating cuticle is seen in steato-
cystoma and some dermoid cysts.
Sebaceous glands are found in greatest abundance on the
face and scalp, though they are distributed throughout all skin
sites except the palms and soles. They are always associated
with hair follicles except at the following sites: tarsal plate of
the eyelids (meibomian glands), buccal mucosa and vermilion
border of the lip (Fordyce spots), prepuce and mucosa lateral
to the penile frenulum (Tyson glands), labia minora, and
female areola (Montgomery tubercles).
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Type IV collagen is found in the BMZ. Type VII collagen is
the major structural component of anchoring fbrils and is
produced predominately by keratinocytes. Abnormalities in
type VII collagen are seen in dystrophic epidermolysis bullosa,
and autoantibodies to this collagen type characterize acquired
epidermolysis bullosa. Collagen fbers are continuously being
degraded by proteolytic enzymes called spare collagenases,
and replaced by newly synthesized fbers. Additional informa-
tion on collagen types and diseases can be found in Chapter 25.
The fbroblast also synthesizes elastic fbers and the ground
substance of the dermis, which is composed of glycosaminogly-
cans or acid mucopolysaccharides. Elastic fbers differ both
structurally and chemically from collagen. They consist of
aggregates of two components: protein flaments and elastin,
an amorphous protein. The amino acids desmosine and iso-
desmosine are unique to elastic fbers. Elastic fbers in the
papillary dermis are fne, whereas those in the reticular dermis
are coarse. The extracellular matrix or ground substance of the
dermis is composed of sulfated acid mucopolysaccharide,
principally chondroitin sulfate and dermatan sulfate, neutral
mucopolysaccharides, and electrolytes. Sulfated acid muco-
polysaccharides stain with colloidal iron and with alcian blue
at both pH 2.5 and 0.5. They stain metachromatically with
toluidine blue at both pH 3.0 and 1.5. Hyaluronan (hyaluronic
acid) is a minor component of normal dermis, but is the major
mucopolysaccharide that accumulates in pathologic states. It
stains with colloidal iron, and with both alcian blue and tolui-
dine blue (metachromatically), but only at the higher pH for
each stain.
Collagen is the major stress-resistant material of the skin.
Elastic fbers contribute very little to resisting deformation and
tearing of skin, but have a role in maintaining elasticity.
Connective tissue disease is a term generally used to refer to
a clinically heterogeneous group of autoimmune diseases,
including lupus erythematosus, scleroderma, and dermato-
myositis. Scleroderma involves the most visible collagen
abnormalities, as collagen bundles become hyalinized and the
space between collagen bundles diminishes. Both lupus and
dermatomyositis produce increased dermal mucin, mostly
hyaluronic acid. Bullous lupus has autoantibodies directed
against type VII collagen.
Defects in collagen synthesis have been described in a
number of inheritable diseases, including Ehlers–Danlos syn-
drome, X-linked cutis laxa, and osteogenesis imperfecta.
Defects in elastic tissue are seen in Marfan syndrome and
pseudoxanthoma elasticum.
Vasculature
The dermal vasculature consists principally of two intercom-
municating plexuses. The subpapillary plexus, or upper hori-
zontal network, contains the postcapillary venules and courses
at the junction of the papillary and reticular dermis. This
plexus furnishes a rich supply of capillaries, end arterioles,
and venules to the dermal papillae. The deeper, lower hori-
zontal plexus is found at the dermal–subcutaneous interface
and is composed of larger blood vessels than those of the
superfcial plexus. Nodular lymphoid infltrates surrounding
this lower plexus are typical of early infammatory morphea.
The vasculature of the dermis is particularly well developed
at sites of adnexal structures. Associated with the vascular
plexus are dermal lymphatics and nerves.
Muscles
Smooth muscle occurs in the skin as arrectores pilorum (erec-
tors of the hairs), as the tunica dartos (or dartos) of the scrotum,
keratinocytes. Endogenous pigments tend to follow the
contour of the lunula (the distal portion of the matrix), whereas
exogenous pigments tend to follow the contour of the cuticle.
The dorsal nail plate is formed by the proximal matrix, and
the ventral nail plate is formed by the distal matrix with some
contribution from the nail bed. The location of a melanocytic
lesion within the matrix can be assessed by the presence of
pigment within the dorsal or ventral nail plate.
Kitamori K, et al: Weakness in intercellular association of keratinocytes
in severely brittle nails. Arch Histol Cytol 2006 Dec; 69(5):323–328.
McCarthy DJ: Anatomic considerations of the human nail. Clin Podiatr
Med Surg 2004; 21:477.
Perrin C: Expression of follicular sheath keratins in the normal nail with
special reference to the morphological analysis of the distal nail unit.
Am J Dermatopathol 2007 Dec; 29(6):543–550.
Dermis
The constituents of the dermis are mesodermal in origin except
for nerves, which, like melanocytes, derive from the neural
crest. Until the sixth week of fetal life, the dermis is merely
a pool of acid mucopolysaccharide-containing, scattered
dendritic-shaped cells, which are the precursors of fbroblasts.
By the 12th week, fbroblasts are actively synthesizing
reticulum fbers, elastic fbers, and collagen. A vascular
network develops, and by the 24th week, fat cells have
appeared beneath the dermis. During fetal development,
Wnt/beta-catenin signaling is critical for differentiation of
ventral versus dorsal dermis, and the dermis then serves as a
scaffold for the adnexal structures identifed with ventral or
dorsal sites.
Infant dermis is composed of small collagen bundles that
stain deeply red. Many fbroblasts are present. In adult dermis,
few fbroblasts persist; collagen bundles are thick and stain
pale red.
Two populations of dermal dendritic cells are noted in the
adult dermis. Factor XIIIa-positive dermal dendrocytes appear
to give rise to dermatofbromas, angiofbromas, acquired
digital fbrokeratomas, pleomorphic fbromas, and fbrous
papules. CD34+ dermal dendroctyes are accentuated around
hair follicles, but exist throughout the dermis. They disappear
from the dermis early in the course of morphea. Their loss can
be diagnostic in subtle cases. CD34+ dermal dendrocytes re -
appear in the dermis when morphea responds to UVA1 light
treatment.
The principal component of the dermis is collagen, a family
of fbrous proteins comprising at least 15 genetically distinct
types in human skin. Collagen serves as the major structural
protein for the entire body; it is found in tendons, ligaments,
and the lining of bones, as well as in the dermis. It represents
70% of the dry weight of skin. The fbroblast synthesizes
the procollagen molecule, a helical arrangement of specifc
polypeptide chains that are subsequently secreted by the cell
and assembled into collagen fbrils. Collagen is rich in the
amino acids hydroxyproline, hydroxylysine, and glycine. The
fbrillar collagens are the major group found in the skin. Type
I collagen is the major component of the dermis. The structure
of type I collagen is uniform in width and each fber displays
characteristic cross-striations with a periodicity of 68 nm.
Collagen fbers are loosely arranged in the papillary and
adventitial (periadnexal) dermis. Large collagen bundles are
noted in the reticular dermis (the dermis below the level of the
postcapillary venule). Collagen I mRNA and collagen III
mRNA are both expressed in the reticular and papillary
dermis, and are downregulated by UV light, as is the collagen
regulatory proteoglycan decorin. This downregulation may
play a role in photoaging.
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Mast cell granules stain metachromatically with toluidine
blue and methylene blue (in the Giemsa stain) because of their
high content of heparin. They also contain histamine, neu-
trophil chemotactic factor, eosinophil chemotactic factor of
anaphylaxis, tryptase, kininogenase, and β-glucosaminidase.
Slow-reacting substance of anaphylaxis (leukotrienes C4 and
D4), leukotriene B4, platelet activating factor, and prostaglan-
din D2 are formed only after IgE-mediated release of granules.
Mast cells stain reliably with the Leder ASD-chloracetase este-
rase stain. Because this stain does not rely on the presence of
mast cell granules, it is particularly useful in situations when
mast cells have degranulated. In forensic medicine, fuorescent
labeling of mast cells with antibodies to the mast cell enzymes
chymase and tryptase is useful in determining the timing of
skin lesions in regard to death. Lesions sustained while living
show an initial increase, then decline in mast cells. Lesions
sustained postmortem demonstrate few mast cells.
Cutaneous mast cells respond to environmental changes.
Dry environments result in an increase in mast cell number
and cutaneous histamine content. In mastocytosis, mast cells
accumulate in skin because of abnormal proliferation, migra-
tion, and failure of apoptosis. The terminal deoxynucleotidyl
transferase-mediated deoxyuridine triphosphate-biotin nick
end labeling (TUNEL) method is commonly used to assess
apoptosis, and demonstrates decreased staining in mastocyto-
mas. Proliferation is usually only moderately enhanced.
Abraham SN, et al: Mast cell-orchestrated immunity to pathogens. Nat
Rev Immunol 2010 Jun; 10(6):440–452.
Charkoudian N: Skin blood flow in adult human thermoregulation: how it
works, when it does not, and why. Mayo Clin Proc 2003; 78:603.
Galli SJ, et al: Mast cells: versatile regulators of inflammation, tissue
remodeling, host defense and homeostasis. J Dermatol Sci 2008 Jan;
49(1):7–19.
Hendrix S, et al: Skin and hair follicle innervation in experimental
models: a guide for the exact and reproducible evaluation of neuronal
plasticity. Exp Dermatol 2008 Mar; 17(3):214–227.
Hoffmann T, et al: Sensory transduction in peripheral nerve axons elicits
ectopic action potentials. J Neurosci 2008 Jun 11; 28(24):6281–6284.
Metz M, et al: Mast cell functions in the innate skin immune system.
Immunobiology 2008; 213(3–4):251–260.
Norman MU, et al: Mast cells regulate the magnitude and the cytokine
microenvironment of the contact hypersensitivity response. Am J
Pathol 2008 Jun; 172(6):1638–1649.
Ohtola J, et al: β-Catenin has sequential roles in the survival and
specification of ventral dermis. Development 2008 Jul;
135(13):2321–2329.
Subcutaneous tissue (fat)
Beneath the dermis lies the panniculus, lobules of fat cells or
lipocytes separated by fbrous septa composed of collagen and
large blood vessels. The collagen in the septa is continuous
with the collagen in the dermis. Just as the epidermis and
dermis vary in thickness according to skin site, so does the
subcutaneous tissue. The panniculus provides buoyancy, and
functions as a repository of energy and an endocrine organ. It
is an important site of hormone conversions, such as that of
androstenedione into estrone by aromatase. Leptin, a hormone
produced in lipocytes, regulates body weight via the hypotha-
lamus and infuences how we react to favors in food. Various
substances can affect lipid accumulation within lipocytes.
Obestatin is a polypeptide that reduces feed intake and weight
gain in rodents. (–)-ternatin, a highly N-methylated cyclic
heptapeptide that inhibits fat accumulation, produced by the
mushroom Coriolus versicolor, has similar effects in mice. Study
of these molecules provides insight into the molecular basis of
weight gain and obesity. Abnormal fat distribution and insulin
resistance are seen in Cushing syndrome and as a result of
antiretroviral therapy. In obese children and adolescents
and in the areolas around the nipples. The arrectores pilorum
are attached to the hair follicles below the sebaceous glands
and, in contracting, pull the hair follicle upward, producing
goosefesh. The presence of scattered smooth muscle through-
out the dermis is typical of anogenital skin.
Smooth muscle also comprises the muscularis of dermal and
subcutaneous blood vessels. The muscularis of veins is com-
posed of small bundles of smooth muscle that criss-cross
at right angles. Arterial smooth muscle forms a concentric
wreath-like ring. Specialized aggregates of smooth muscle
cells (glomus bodies) are found between arterioles and venules,
and are especially prominent on the digits and at the lateral
margins of the palms and soles. Glomus bodies serve to
shunt blood and regulate temperature. Most smooth muscle
expresses desmin intermediate flaments, but vascular smooth
muscle expresses vimentin instead. Smooth muscle actin is
consistently expressed by all types of smooth muscle.
Striated (voluntary) muscle occurs in the skin of the neck as
the platysma muscle and in the skin of the face as the muscles
of expression. This complex network of striated muscle, fascia,
and aponeuroses is known as the superfcial muscular aponeu-
rotic system (SMAS).
Nerves
In the dermis, nerve bundles are found together with arterioles
and venules as part of the neurovascular bundle. In the deep
dermis, nerves travel parallel to the surface, and the presence
of long sausage-like granulomas following this path is an
important clue to the diagnosis of Hansen’s disease.
Touch and pressure are mediated by Meissner corpuscles
found in the dermal papillae, particularly on the digits, palms,
and soles, and by Vater–Pacini corpuscles located in the deeper
portion of the dermis of weight-bearing surfaces and genitalia.
Mucocutaneous end organs are found in the papillary dermis
of modifed hairless skin at the mucocutaneous junctions:
namely, the glans, prepuce, clitoris, labia minora, perianal
region, and vermilion border of the lips. Temperature, pain,
and itch sensation are transmitted by unmyelinated nerve
fbers which terminate in the papillary dermis and around hair
follicles. Impulses pass to the central nervous system by way
of the dorsal root ganglia. Histamine-evoked itch is transmit-
ted by slow-conducting unmyelinated C-polymodal neurons.
Signal transduction differs for sensations of heat and cold, and
in peripheral nerve axons.
Postganglionic adrenergic fbers of the autonomic nervous
system regulate vasoconstriction, apocrine gland secretions,
and contraction of arrector pili muscles of hair follicles.
Cholinergic fbers mediate eccrine sweat secretion.
Mast cells
Mast cells play an important role in the normal immune
response, as well as immediate-type sensitivity, contact allergy,
and fbrosis. Measuring 6–12 microns in diameter, with ample
amphophilic cytoplasm and a small round central nucleus,
normal mast cells resemble fried eggs in histologic sections. In
telangiectasia macularis eruptiva perstans (TMEP mastocyto-
sis), they are spindle-shaped and hyperchromatic, resembling
large, dark fbroblasts. Mast cells are distinguished by contain-
ing up to 1000 granules, each measuring 0.6–0.7 microns in
diameter. Coarse particulate granules, crystalline granules,
and granules containing scrolls may be seen. On the cell’s
surface are 100 000–500 000 glycoprotein receptor sites for
immunoglobulin E (IgE). There is heterogeneity to mast cells
with type I or connective tissue mast cells found in the dermis
and submucosa, and type II or mucosal mast cells found in the
bowel and respiratory tract mucosa.
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developing diabetes, severe peripheral insulin resistance is
associated with intramyocellular and intra-abdominal lipocyte
lipid accumulation.
Certain infammatory dermatoses, known as the pannicu-
litides, principally affect this level of the skin, producing sub-
cutaneous nodules. The pattern of the infammation, specifcally
whether it primarily affects the septa or the fat lobules, serves
to distinguish various conditions which may resemble one
another clinically.
Nagaraj S, et al: Fragments of obestatin as modulators of feed intake,
circulating lipids, and stored fat. Biochem Biophys Res Commun 2008
Feb 15; 366(3):731–737.
Shimokawa K, et al: Biological activity, structural features, and synthetic
studies of (-)-ternatin, a potent fat-accumulation inhibitor of 3T3-L1
adipocytes. Chem Asian J 2008 Feb 1; 3(2):438–446.
Weiss R, et al: Prediabetes in obese youth: a syndrome of impaired
glucose tolerance, severe insulin resistance, and altered myocellular
and abdominal fat partitioning. Lancet 2003; 362:951.
Fig. 1-1 Electron micrograph illustrating the three basic cell types in
the epidermis and their relationships.
Fig. 1-2 Ultrastructural appearance of the desmosome specialized
attachment plate between adjacent keratinocytes.
Fig. 1-3 Upper portion of the epidermis.
Fig. 1-4 Portion of a melanocyte from dark skin.
Fig. 1-5 Relationship between melanocytes (M) and basal
keratinocytes (K) in light skin.
Fig. 1-6 Ultrastructural appearance of the Langerhans cell.
Fig. 1-7 Ultrastructural appearance of the basement membrane zone
at the junction of the epidermis and dermis.
Bonus images for this chapter can be found online at
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