The skin is the largest single organ of the body, typically

accounting for 15%-20% of total body weight and, in

adults, presenting 1.5-2 m2
of surface to the external environment. Also known as the integument (L. integumentum,
covering) or cutaneous layer, the skin is composed of the epidermis, an epithelial layer of ectodermal
origin, and the dermis, a layer of mesodermal connective tissue (Figure 18–1). At
the irregular junction between the dermis and epidermis, projections called dermal papillae interdigitate
with invaginating
epidermal ridges to strengthen adhesion of the two layers.
Epidermal derivatives include hairs, nails, and sebaceous and
sweat glands. Beneath the dermis lies the subcutaneous tissue
or hypodermis (Gr. hypo, under + derma, skin), a loose connective tissue layer usually containing pads of
adipocytes. The
subcutaneous tissue binds the skin loosely to the underlying tissues and corresponds to the superficial
fascia of gross anatomy.
The specific functions of the skin fall into several broad
categories.
■ Protective: It provides a physical barrier against thermal
and mechanical insults such as friction and against most
potential pathogens and other material. Microorganisms
that do penetrate skin alert resident lymphocytes and
antigen-presenting cells (APCs) in skin and an immune
response is mounted. The dark pigment melanin in the
epidermis protects cell nuclei from ultraviolet (UV) radiation. Skin is also a permeability barrier against
excessive
loss or uptake of water, which has allowed for terrestrial
life. Skin’s selective permeability allows some lipophilic
drugs such as certain steroid hormones and medications
to be administered via skin patches.
■ Sensory: Many types of sensory receptors allow skin to
constantly monitor the environment, and various skin
mechanoreceptors help regulate the body’s interactions
with physical objects.
■ Thermoregulatory: A constant body temperature is
normally easily maintained thanks to the skin’s insulating
components (eg, the fatty layer and hair on the head) and
its mechanisms for accelerating heat loss (sweat production and a dense superficial microvasculature).
■ Metabolic: Cells of skin synthesize vitamin D3
, needed
in calcium metabolism and proper bone formation,
through the local action of UV light on the vitamin’s
precursor. Excess electrolytes can be removed in sweat,
and the subcutaneous layer stores a significant amount of
energy in the form of fat.
■ Sexual signaling: Many features of skin, such as
pigmentation and hair, are visual indicators of health
involved in attraction between the sexes in all vertebrate
species, including humans. The effects of sex pheromones produced by the apocrine sweat glands and
other
skin glands are also important for this attraction.
The dermal-epidermal interdigitations are of the peg-andsocket variety in most skin (Figure 18–1), but
they occur as
well-formed ridges and grooves in the thick skin of the palms
and soles, which is more subject to friction. These ridges and
the intervening sulci form distinctive patterns unique for each
individual, appearing as combinations of loops, arches, and
whorls, called dermatoglyphs, also known as fingerprints and
footprints. Skin is elastic and can expand rapidly to cover swollen areas and, like the gut lining, is self-
renewing throughout
life. In healthy individuals injured skin is repaired rapidly. The
molecular basis of skin healing is increasingly well understood
and provides a basis for better understanding of repair and
regeneration in other organs.

› EPIDERMIS
The epidermis consists mainly of a stratified squamous keratinized epithelium composed of cells called
keratinocytes.
There are also three much less abundant epidermal cell types:
pigment-producing melanocytes, antigen-presenting Langerhans cells, and tactile epithelial cells called
Merkel cells
(Figure 18–2).
The epidermis forms the major distinction between
thick skin (Figure 18–2a), found on the palms and soles, and
thin skin (Figure 18–3) found elsewhere on the body. The
designations “thick” and “thin” refer to the thickness of the
epidermal layer, which alone varies from 75 to 150 μm for thin
skin and from 400 to 1400 μm (1.4 mm) for thick skin. Total
skin thickness (epidermis plus dermis) also varies according
to the site. For example, full skin on the back is about 4-mm
thick, whereas that of the scalp is about 1.5-mm thick. Like all
epithelia, the stratified squamous epidermis lacks microvasculature, its cells receiving nutrients and O2
by diffusion from
the dermis.
From the dermis, the epidermis consists of four layers of
keratinocytes (or five layers in thick skin, Figure 18–2):
■ The basal layer (stratum basale) is a single layer
of basophilic cuboidal or columnar cells on the basement membrane at the dermal-epidermal junction
(Figures 18–2 and 18–3). Hemidesmosomes in the basal
cell membranes join these cells to the basal lamina, and
desmosomes bind the cells of this layer together in their
lateral and upper surfaces. The stratum basale is characterized by intense mitotic activity and contains,
along
with the deepest part of the next layer, progenitor cells for
all the epidermal layers. In addition to the basal stem cells
for keratinocytes found here, a niche for such cells also occurs in the hair follicle sheaths that are
continuous with
the epidermis. The human epidermis is renewed about
every 15-30 days, depending on age, the region of the
body, and other factors. An important feature of all keratinocytes in the stratum basale is the
cytoskeletal keratins,
intermediate filaments about 10 nm in diameter. During
differentiation, the cells move upward and the amount
and types of keratin filaments increase until they represent half the total protein in the superficial
keratinocytes.■ The spinous layer (stratum spinosum) is normally
the thickest layer, especially in the epidermal ridges
(Figures 18–2 and 18–3), and consists of generally polyhedral cells having central nuclei with nucleoli and
cytoplasm actively synthesizing keratins. Just above the basal
layer, some cells may still divide and this combined zone is sometimes called the stratum germinativum.
The keratin filaments assemble here into microscopically visible
bundles called tonofibrils, which converge and terminate at the numerous desmosomes holding the cell
layers
together. The cells extend slightly around the tonofibrils on
both sides of each desmosome (and the extensions elongate if the cells shrink slightly during histologic
processing), leading to the appearance of many short “spines” or
prickles at the cell surfaces (Figure 18–4). The epidermis
of thick skin subject to continuous friction and pressure
(such as the foot soles) has a thicker stratum spinosum
with more abundant tonofibrils and desmosomes. ■ The granular layer (stratum granulosum) consists
of three to five layers of flattened cells, now undergoing
the terminal differentiation process of keratinization.
Their cytoplasm is filled with intensely basophilic masses
(Figures 18–2, 18–3, and 18–5) called keratohyaline
granules. These are dense, non-membrane-bound
masses of filaggrin and other proteins associated with
the keratins of tonofibrils, linking them further into large
cytoplasmic structures.
Characteristic features in cells of the granular layer also
include Golgi-derived lamellar granules, small ovoid
(100 × 300 nm) structures with many lamellae containing various lipids and glycolipids. Among the last
activities of the keratinocytes, the lamellar granules undergo
exocytosis, producing a lipid-rich, impermeable layer
around the cells. This material forms a major part of the
skin’s barrier against water loss. Formation of this barrier,
which appeared first in ancestral reptiles, was a key evolutionary process that permitted animals to
develop on
land. Together, keratinization and production of the lipidrich layer also have a crucial sealing effect in
skin, forming the barrier to penetration by most foreign materials.
■ The stratum lucidum, found only in thick skin, consists
of a thin, translucent layer of flattened eosinophilic keratinocytes held together by desmosomes (Figures
18–2
and 18–5). Nuclei and organelles have been lost, and the
cytoplasm consists almost exclusively of packed keratin
filaments embedded in an electron-dense matrix.
■ The stratum corneum (Figures 18–2 and 18–3) consists of 15-20 layers of squamous, keratinized cells
filled
with birefringent filamentous keratins. Keratin filaments
contain at least six different polypeptides with molecular masses ranging from 40 to 70 kDa, synthesized
during
cell differentiation in the immature layers. As they form,
keratin tonofibrils become heavily massed with filaggrin and other proteins in keratohyaline granules. By
the
end of keratinization, the cells contain only amorphous,
fibrillar proteins with plasma membranes surrounded
by the lipid-rich layer. These fully keratinized or cornified cells called squames are continuously shed at
the
epidermal surface as the desmosomes and lipid-rich cell
envelopes break down.
Important features of the epidermal strata are summarized in Table 18–1.
›››MEDICAL APPLICATION
In the chronic skin condition called psoriasis, keratocytes
are typically produced and differentiate at accelerated rates,
causing at least slight thickening of the epidermal layers
and increased keratinization and desquamation. Psoriasis is
caused by overactive T lymphocytes triggering an autoimmune reaction in the skin, which can also lead
to inflammation with redness, irritation, itching, and scaling, with a
defective skin barrier.
Melanocytes
The color of the skin is the result of several factors, the most
important of which are the keratinocytes’ content of melanin
and carotene and the number of blood vessels in the dermis.
Eumelanins are brown or black pigments produced by
the melanocyte (Figures 18–6 and 18–7), a specialized cell
of the epidermis found among the cells of the basal layer
and in hair follicles. The similar pigment found in red hair
is called pheomelanin (Gr. phaios, dusky + melas, black).
Melanocytes are neural crest derivatives that migrate into
the embryonic epidermis’ stratum basale, where eventually
one melanocyte accumulates for every five or six basal keratinocytes (600-1200/mm2
of skin). They have pale-staining,
rounded cell bodies attached by hemidesmosomes to the basal
lamina, but lacking attachments to the neighboring keratinocytes. Several long irregular cytoplasmic
extensions from
each melanocyte cell body penetrate the epidermis, running
between the cells of the basal and spinous layers and terminating in invaginations of 5-10 keratinocytes.
Ultrastructurally a
melanocyte has numerous small mitochondria, short cisternae
of RER, and a well-developed Golgi apparatus (Figure 18–6).
The first step in melanin synthesis is catalyzed by tyrosinase, a transmembrane enzyme in Golgi-derived
vesicles
(Figure 18–7). Tyrosinase activity converts tyrosine into
3,4-dihydroxyphenylalanine (DOPA), which is then further transformed and polymerized into the
different forms
of melanin. Melanin pigment is linked to a matrix of structural proteins and accumulates in the vesicles
until they form
mature elliptical granules about 1-μm long called melanosomes (Figure 18–7).
Melanosomes are then transported via kinesin to the tips
of the cytoplasmic extensions. The neighboring keratinocytes
phagocytose the tips of these dendrites, take in the melanosomes, and transport them by dynein toward
their nuclei. The
melanosomes accumulate within keratinocytes as a supranuclear cap that prior to keratinization absorbs
and scatters
sunlight, protecting DNA of the living cells from the ionizing,
mutagenic effects of UV radiation.
Although melanocytes produce melanosomes, the keratinocytes are the melanin depot and contain
more of this pigment than the cells that make it. One melanocyte plus the
keratinocytes into which it transfers melanosomes make up an
epidermal-melanin unit. The density of such units in skin is
similar in all individuals. Melanocytes of people with ancestral
origins near the equator, where the need for protection against
the sun is greatest, produce melanin granules more rapidly
and accumulate them more abundantly in keratinocytes. In regions with much less sunlight such as
Northern
Europe, the small amount of UV radiation penetrating dark
skin barely sustains adequate vitamin D3
synthesis. Individuals
with ancestry there have one or more genetic polymorphisms
affecting steps in melanin formation and causing more lightly
pigmented keratinocytes, which allow increased UV penetration and vitamin D3
synthesis.
Darkening of the skin, or tanning, after exposure to solar
radiation at wavelengths of 290-320 nm is a two-step process.
A physicochemical reaction darkens preexisting melanin. At
the same time, paracrine factors secreted by keratinocytes
experiencing increased UV radiation accelerate melanin synthesis and its accumulation in the epidermis.
Langerhans Cells
Antigen-presenting cells called Langerhans cells, derived from
monocytes, represent 2%-8% of the cells in epidermis and are
usually most clearly seen in the spinous layer. Cytoplasmic processes extend from these dendritic cells
between keratinocytes
of all the layers, forming a fairly dense network in the epidermis
(Figure 18–8). Langerhans cells bind, process, and present antigens to T lymphocytes in the same
manner as immune dendritic
cells in other organs (see Chapter 14). Microorganisms cannot
penetrate the epidermis without alerting these dendritic cells and
triggering an immune response. Langerhans cells, along with more
scattered epidermal lymphocytes and other APCs in the dermis,
comprise a major component of the skin’s adaptive immunity.
Because of its location, the skin is continuously in close
contact with many antigenic molecules. Various epidermal
features participate in both innate and adaptive immunity (see
Chapter 14), providing an important immunologic component to the skin’s overall protective function.
Merkel Cells
Merkel cells, or epithelial tactile cells, are low-threshold
mechanoreceptors essential for sensing gentle touch. They are
abundant in highly sensitive skin like that of fingertips and at the
bases of some hair follicles. Joined by desmosomes to keratinocytes of the basal epidermal layer, present
in both thick and thin
skin Merkel cells resemble the surrounding keratinocytes, with
which they share a stem cell origin, but contain few, if any, melanosomes. Instead, they are characterized
by small, Golgi-derived dense-core granules concentrated in areas near the basolateral
surface where the cells have synaptic contacts with the expanded
terminal discs of unmyelinated afferent fibers penetrating the
basal lamina (Figure 18–9). Light touch to the skin initiates
release of neurotransmitters and sensation from that location.
›››MEDICAL APPLICATION
Merkel cells are of clinical importance because Merkel cell carcinomas, though uncommon, are very
aggressive and difficult to
treat. Merkel cell carcinoma is 40 times less common than malignant melanoma but has twice the
mortality of that disease.
› DERMIS
The dermis is the layer of connective tissue (Figures 18–1
and 18–2) that supports the epidermis and binds it to the
subcutaneous tissue (hypodermis). The thickness of the dermis varies with the region of the body and
reaches its maximum of 4 mm on the back. The surface of the dermis is very
irregular and has many projections (dermal papillae) that
interdigitate with projections (epidermal pegs or ridges) of
the epidermis (Figure 18–1), especially in skin subject to frequent pressure, where they reinforce the
dermal-epidermal
junction.A basement membrane always occurs between the
stratum basale and the dermis, and follows the contour of the
interdigitations between these layers. Nutrients for keratinocytes diffuse into the avascular epidermis
from the dermal
vasculature through the basement membrane.
›››MEDICAL APPLICATION
Abnormalities of the dermal-epidermal junction can lead
to one type of blistering disorder (bullous pemphigoid).
Another type of blistering disorder (pemphigus) is caused
by autoimmune damage to intercellular junctions between
keratinocytes.
The dermis contains two sublayers with indistinct boundaries (Figure 18–1; Table 18–1):
■ The thin papillary layer, which includes the dermal
papillae, consists of loose connective tissue, with types
I and III collagen fibers, fibroblasts and scattered
mast cells, dendritic cells, and leukocytes. From this
layer, anchoring fibrils of type VII collagen insert into
the basal lamina, helping to bind the dermis to the
epidermis.
■ The underlying reticular layer is much thicker, consists
of dense irregular connective tissue (mainly bundles of
type I collagen), with more fibers and fewer cells than the
papillary layer. A network of elastic fibers is also present
(Figure 18–10), providing elasticity to the skin. Between
the collagen and elastic fibers are abundant proteoglycans rich in dermatan sulfate.
›››MEDICAL APPLICATION
With age changes in the dermal ECM are normal: thickening
of collagen fibers, less collagen synthesis, and loss of hyaluronan and other GAGs. In old age, extensive
cross-linking of
collagen fibers and the loss of elastic fibers, especially after
excessive exposure to the sun (solar elastosis), cause the skin
to become more fragile, lose its suppleness, and develop
wrinkles. The epidermis also normally thins and becomes
more transparent during aging. In several disorders, such as
cutis laxa and Ehlers-Danlos syndromes, there is a considerable increase in skin and ligament extensibility
caused by
defective collagen fibril processing.
Both dermal regions contain a rich network of blood and
lymphatic vessels. Nutritive vessels form two major plexuses
(Table 18–1):
■ Between the papillary and reticular dermal layers lies
the microvascular subpapillary plexus, from which
capillary branches extend into the dermal papillae and
form a rich, nutritive capillary network just below the ■ A deep plexus with larger blood and lymphatic
vessels
lies near the interface of the dermis and the subcutaneous layer.
In addition to the nutritive function, dermal vasculature has a thermoregulatory function, which involves
numerous arteriovenous anastomoses or shunts (see
Chapter 11) located between the two major plexuses. The
shunts decrease blood flow in the papillary layer to minimize heat loss in cold conditions and increase
this flow to
facilitate heat loss when it is hot, thus helping maintain a
constant body temperature. Lymphatic vessels begin in the
dermal papillae and converge to form two plexuses located
with the blood vessels.
The dermis is also richly innervated. Sensory afferent nerve fibers form a network in the papillary dermis
and
around hair follicles, ending at epithelial and dermal receptors
shown in Figure 18–11. Autonomic effector nerves to dermal
sweat glands and smooth muscle fibers in the skin of some areas are postganglionic fibers of
sympathetic ganglia; no
parasympathetic innervation is present.
› SUBCUTANEOUS TISSUE
The subcutaneous layer (see Figure 18–1) consists of loose
connective tissue that binds the skin loosely to the subjacent
organs, making it possible for the skin to slide over them. This
layer, also called the hypodermis or superficial fascia, contains adipocytes that vary in number in
different body regions
and vary in size according to nutritional state. The extensive
vascular supply at the subcutaneous layer promotes rapid
uptake of insulin or drugs injected into this tissue.
› SENSORY RECEPTORS
With its large surface and external location, the skin functions as an extensive receiver for various stimuli
from the
environment. Diverse sensory receptors are present in skin,
including both simple nerve endings with no Schwann cell

382 CHAPTER 18 ■ Skin

or collagenous coverings and more complex structures with
sensory fibers enclosed by glia and delicate connective tissue capsules (Figure 18–11). The
unencapsulated receptors
include the following:
■ The Merkel cells, each associated with expanded nerve
endings (Figure 18–9), which function as tonic receptors for sustained light touch and for sensing an
object’s
texture.
■ Free nerve endings in the papillary dermis and extending into lower epidermal layers, which respond
primarily
to high and low temperatures, pain, and itching, but also
function as tactile receptors.
■ Root hair plexuses, a web of sensory fibers surrounding the bases of hair follicles in the reticular
dermis that
detects movements of the hairs.
The encapsulated receptors are all phasic mechanoreceptors, responding rapidly to stimuli on the skin.
Four are recognized in human skin, although only the first two are seen in
routine preparations:
■ Meissner corpuscles are elliptical structures, 30-75
μm by 50-150 μm, consisting of sensory axons winding
among flattened Schwann cells arranged perpendicular
to the epidermis in the dermal papillae (Figure 18–12a).