General organization and types of skin

The skin consists of three layers firmly attached to one another (Figure 11-1): (1) the outer epidermis—derived from ectoderm; (2) the deeper dermis—derived from mesoderm; and (3) the hypodermis or subcutaneous layer—corresponding to the superficial fascia of gross anatomy.

Figure 11-1 General organization of the skin

Skin is generally classified into two types: (1) thick skin and (2) thin skin.

Thick skin (more than 5 mm thick) covers the palms of the hands and the soles of the feet and has a thick epidermis and dermis. Thin skin (1 to 2 mm in thickness) lines the rest of the body; the epidermis is thin.

The surface of the skin of the palms and soles and digits of the hands and feet has narrow epidermal ridges separated by furrows. Each epidermal ridge corresponds to an underlying dermal papilla. Ridges and papillae are permanent, have a constant pattern, and are unique to each individual. Impressions of the ridges create fingerprint patterns, useful for forensic identification.

The epidermis and dermis display a tight fit interface at the dermal-epidermal junction, where a basal lamina and hemidesmosomes are located. A primary epidermal ridge interlocks with a subjacent primary dermal ridge (see Figure 11-1). An epidermal interpapillary peg, projecting downward from the primary epidermal ridge, interlocks with the primary dermal ridge, which is subdivided into two secondary dermal ridges. A number of dermal papillae project upward from the surface of each secondary dermal ridge into the epidermal region, interlocking with downward projections of the epidermis. This arrangement is predominant in hairless thick skin. Dermal papillae are numerous and branched. In thin skin, papillae are low and their number is reduced.

Clinical significance: Wound healing

Skin is an efficient protective barrier. If a portion of epidermis is damaged or destroyed, it must be repaired rapidly by a sequential mechanism called wound healing. This mechanism consists of four stages: (1) the formation of a fibrin-platelet clot; (2) leukocyte recruitment; (3) neovascularization and cellular proliferation; and (4) tissue remodeling.

Wound healing starts with the formation of a blood clot covering temporarily the open wound. We discussed in Chapter 6, Blood and Hematopoiesis, that the blood clot consists of platelets embedded in a fibrous mesh of cross-linked fibrin molecules formed when thrombin cleaves fibrinogen.

We discussed in Chapter 6 that platelets contain platelet-derived growth factor (PDGF) stored in alpha granules. PDGF and other growth factors are released when platelets degranulate and leukocytes arrive at the wound site. Keratinocytes and endothelial cells express cytokine CXC (for cysteine-x-cysteine) and CXC receptor, which recruit neutrophils, monocytes, and lymphocytes to the wound site. A deletion of CXC receptor gene results in delayed wound healing.

Neutrophils arrive within minutes of injury and release proinflammatory cytokines to activate local fibroblasts in the dermis and keratinocytes in the epidermis. Monocytes are recruited next and become macrophages, which produce cytokines, growth factors, and angiogenic factors. New blood vessels develop (angiogenic response) and organize granulation tissue. The pink granular appearance of the granulation tissue is determined by the formation of numerous blood capillaries.

Reepithelialization starts when keratinocytes of the stratum basale layer migrate from the edges of the wound by the formation of F-actin–containing lamellopodia. We discuss in Chapter 1, Epithelium, that hemidesmosomes anchor basal cells to the basal lamina. Leading edge keratinocytes facilitate their displacement by disrupting hemidesmosome attachment to the basal lamina and by dissolving the fibrin clot barrier. To accomplish the dissolution of the fibrin clot, keratinocytes up-regulate the expression of plasminogen activator to convert plasminogen within the clot into the fibrinolytic enzyme plasmin. Keratinocytes become free from hemidesmosome anchorage with the help of members of the matrix metalloproteinase family produced by fibroblasts in the dermis. We discussed the importance of matrix metalloproteinases in Chapter 4, Connective Tissue.

Members of the epidermal growth factor family (including epidermal growth factor, transforming growth factor-α, and heparin binding epidermal growth factor) and keratinocyte growth factor drive re-epithelialization. After the wound surface has been covered by a monolayer of keratinocytes, a new stratified squamous epithelium is established from the margin of the wound toward the center. New hemidesmosomes are formed with the inactivation of matrix metalloproteinases.

Within 3 to 4 days after the wound injury, the underlying connective tissue of the dermis contracts, bringing the wound margins toward one another. Stimulated by local levels of PDGF and transforming growth factor-β, dermal fibroblasts begin to proliferate, infiltrate the blood clot, and deposit type III collagen and extracellular matrix. About 1 week after wounding, a number of wound fibroblasts change into myofibroblasts (resembling smooth muscle cells), wound contraction takes place, and healing with a scar occurs.

Retinol (vitamin A) is a precursor of retinoic acid, a hormone-like agent required for the differentiation of epithelia, including epidermis. Retinoids have a proliferative effect on the epidermis of normal skin. This effect is mediated at the messenger RNA (mRNA) level by inhibiting cell differentiation and stimulating cell proliferation.

Retinoic acid binds to cellular retinoic acid binding (CRAB) proteins, presumably involved in the regulation of the intracellular concentration of retinoic acid. Similar to steroid and thyroid hormones, retinoic acid binds to two types of nuclear receptors: retinoic acid receptors (RARs), and rexinoid receptors (RXRs).

The RAR/RXR heterodimer complex has binding affinity for retinoic acid–responsive elements (RAREs) on DNA and controls the expression of retinoic acid responsive genes. Retinoids are used in the prevention of acne scarring, psoriasis, and other scaling diseases of the skin.

Clinical significance: Psoriasis

Psoriasis is an inflammatory skin disorder. It is characterized by sharply demarcated plaques, called psoriatic plaques, covered by white scales commonly seen on the elbows, knees, scalp, umbilicus, and lumbar region. Physical trauma may produce psoriatic plaques at the sites of injury.

The histologic characteristics of the psoriatic plaque include excessive proliferation of epidermal keratinocytes (caused by an accelerated migration of keratinocytes from the stratum basale to the stratum corneum), presence of inflammatory cells (T cells and neutrophils) in the dermis and epidermis (microabscesses), elongation of epidermic papillae, and prominent angiogenesis (Figure 11-4).

Figure 11-4 Psoriasis

Langerhans cells initiate the psoriatic process. The role of Langerhans cells in the activation of T cells in regional lymph nodes is summarized in Figure 11-4.

Cytokines play a significant role in the trafficking and distribution of T cells in the psoriatic skin. Effector T cells are characterized by the expression of the skin homing receptor cutaneous lymphocyte-associated (CLA) antigen and CD45. CD45⁺ CLA⁺ T cells arrive at sites of cutaneous inflammation, secrete proinflammatory cytokines, and produce the psoriatic plaques. Treatment of psoriasis is targeted to the therapeutic inhibition of T cell activation (determined by Langerhans cells in the lymph node), depletion of activated T cells (by monoclonal antibodies directed to cell surface molecules expressed by Langerhans cell–activated T cells), and preventing the recruitment of CD45⁺ CLA⁺ T cells (by monoclonal antibodies blocking specific homing).

Differentiation of a keratinocyte

Keratinocytes of the stratum spinosum have a flattened polygonal shape with a distinct ovoid nucleus. The cytoplasm displays small granules with a lamellar core, called membrane-coating granules, or lamellar bodies. Bundles of intermediate filaments—tonofibrils—extend into the cytoplasmic spinous-like processes and attach to the dense plaque of a desmosome.

The stratum granulosum consists of a multilayered assembly of flattened nucleated keratinocytes with characteristic, irregularly shaped keratohyalin granules without a limiting membrane and associated with the tonofilaments. The lamellar bodies, which first appear in keratinocytes of the stratum spinosum, increase in number in the stratum granulosum, and the lamellar product, the glycolipid acylglucosylceramide, is released into the intercellular spaces (Figure 11-5). Tight junctions, containing claudin-1 and claudin-4, are found in the stratum granulosum (Figure 11-6). In the intercellular space, the lamellar lipid material forms a multilayered structure arranged in wide sheets, coating the surface of keratinocytes of the upper layer, the stratum lucidum. The glycolipid coating provides the water barrier of the epidermis.

Figure 11-5 Differentiation of keratinocytes: Expression of keratins

Figure 11-6 Components of the epidermal permeability barrier

The stratum lucidum is recognized by some histologists as an intermediate layer above the stratum granulosum and beneath the stratum corneum. However, no distinctive cytologic features are significantly apparent.

Both the stratum lucidum and stratum corneum consist of several layers of keratinocytes without nuclei and a cytoplasm containing aggregated intermediate filaments of keratin cross-linked with filaggrin (see Figure 11-6) by a process catalyzed by transglutaminases. Filaggrin aggregates keratin intermediate filaments into tight bundles, leading to cell flattening, a characteristic of the stratum corneum.

The keratin-filaggrin complex is deposited on the inside of the plasma membrane forming a structure called the cornified cell envelope (Figure 11-7). Additional proteins—involucrin, small proline–rich proteins (SPRs), and loricrin—are cross-linked by several transglutaminases and reinforce the cornified cell envelope just beneath the plasma membrane. On the outside of the cell, a complex of lipids extruded from lamellar bodies cross-link the cell envelope, forming the compound cornified cell envelope.

Figure 11-7 Keratinocytes

In summary, keratinocytes of the stratum corneum consist of a keratin-filaggrin matrix surrounded by a reinforcing involucrin–SPRs–loricrin complex that provides elasticity and mechanical resistance. Extracellular insoluble lipids, cross-linked to involucrin, make the cell membrane impermeable to fluids (permeability barrier). See Box 11-A.

The terminally differentiated keratinocytes of the stratum corneum consist of flattened squames with a highly resistant compound cell envelope. Squames are sloughed from the surface of the epidermis and are continually replaced by keratinocytes of the inner strata.

Two additional characteristics of the epidermis are (1) the cell layer–specific expression of keratins observed during differentiation of keratinocytes (see Figure 11-5) and (2) the presence of tight junctions and desmosomes in the epidermis. The maintenance of a three-dimensional lattice of tightly attached keratinocytes is essential for the protective nature of the permeability barrier.

In Chapter 1, Epithelium, we discussed the structure and components of tight junctions, desmosomes, and intermediate filament keratins, including pathologic conditions such as blistering, epidermolytic, and proliferative diseases (Box 11-B).

Melanocytes

Melanocytes are branching cells located in the stratum basale of the epidermis (Figure 11-8; see Figure 11-3). Melanocytes derive from melanoblasts, a cell precursor migrating from the neural crest.

Figure 11-8 Melanocytes, derived from the neural crest, pigment and protect the skin

The development of the melanoblast into melanocytes is under the control of the ligand stem cell factor interacting with the c-kit receptor, a membrane-bound tyrosine kinase. The development of mast cells, primordial germinal cells, and hematopoietic stem cells is also dependent on the interaction of stem cell factor with the c-kit receptor.

Melanocytes enter the developing epidermis and remain as independent cells without desmosome attachment to the differentiating keratinocytes. The turnover of melanocytes is slower than that of keratinocytes.

Melanocytes produce melanin, contained in melanosomes, which are transferred to neighboring keratinocytes through their branching cell processes, called melanocyte dendrites, and released by cytocrine secretion (Figure 11-9; Box 11-C).

Figure 11-9 Synthesis and transport of melanin from melanocytes to keratinocytes

Melanin is initially stored in a membrane-bound premelanosome derived from the Golgi apparatus. Melanin is produced by oxidation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) by the enzyme tyrosinase. DOPA is then transformed to melanin, which accumulates in melanosomes, the mature melanin granules that are distributed along the melanocyte dendrites.

Cytocrine secretion is preceded by the transport of melanosomes along cytoplasmic microtubules by the motor protein kinesin. Melanosomes are then transferred to a network of F-actin tracks located beneath the plasma membrane. Melanosome transfer occurs when melanophilin, an adapter protein, binds to Rab27a, a protein inserted in the melanosome membrane. The F-actin–based molecular motor myosin Va binds to the Rab27a-melanophilin complex and transports the melanosome to the plasma membrane. Extruded melanin by exocytosis is captured by adjacent keratinocytes and internalized by endocytosis. The molecular characteristics of the unconventional myosin V are discussed in Chapter 1, Epithelium.

In addition to melanocytes, melanin-producing cells are present in the choroid plexus, retina, and ciliary body of the eye. Albinism results from the inability of cells to form melanin. Griscelli syndrome is determined by mutations of the myosin Va gene. Patients with Griscelli syndrome have silvery hair, partial albinism, occasional neurologic defects, and immunodeficiency (due to a defective vesicular transport and secretion in cytolytic T cells). Similar pigmentation disorders are determined by mutations in the Rab27a and melanophilin genes.

Langerhans cells (dendritic cells)

Langerhans cells are bone marrow–derived cells present in the epidermis as immunologic sentinels, involved in immune responses, in particular the presentation of antigens to T cells (Figure 11-10).

Figure 11-10 Langerhans cell, an antigen-presenting dendritic cell of the epidermis

Langerhans cells, containing an epidermal antigen, enter a lymphatic vessel in the dermis and migrate to a regional lymph node where they interact with T cells in the deep cortex (T cell zone). T cells, activated by the epidermal antigen, reenter the blood circulation, reach the site where the epidermal antigen is present, and release proinflammatory cytokines in an attempt to neutralize the antigen.

Similar to melanocytes, Langerhans cells have cytoplasmic processes (dendritic cells) extending among keratinocytes of the stratum spinosum without establishing desmosomal contact but associating with keratinocytes through E-cadherin. Langerhans cells express CD1a, a cell surface marker. CD1a mediates the presentation of nonpeptide antigens (for example, α-galactosylceramide) to T cells.

The nucleus of a Langerhans cell is indented, and the cytoplasm contains characteristic tennis racket–shaped inclusions (Birbeck granules) associated with the protein langerin. Langerin is a transmembrane C-type lectin (calcium-dependent) that facilitates the uptake of mannose-containing microbial fragments for their delivery to the endosomal compartment.

Langerhans cells use CD1a and langerin to trigger cellular immune responses to Mycobacterium leprae, the causative agent of leprosy, also known as Hansen’s disease, a neurologic disease affecting the extremities. Myelin-producing Schwann cells are the primary target. In the early stages, infected individuals have skin nodules on the face and all over the body, followed by paralysis or loss of sensation in the affected areas, and eventually loss of fingers and toes. Blindness occurs in advanced stages of the disease. Multidrug therapy, consisting of rifampicin, clofazimine, and dapsone, is used to treat all cases of leprosy.

Merkel cells

Merkel cells resemble modified keratinocytes, are found in the stratum basale, and are numerous in the fingertips. Merkel cells are mechanoreceptor cells linked to adjacent keratinocytes by desmosomes and in contact with an afferent myelinated nerve fiber projecting from the dermis into the epidermis. The nerve fiber becomes unmyelinated after passing through the basal lamina of the epidermis and expands into a platelike sensory ending, the nerve plate, in contact with the Merkel cell (see Figure 11-3).

The nucleus is irregularly shaped and the cytoplasm contains abundant granules, presumably neurotransmitters.

Clinical significance: Vascular diseases

Local and generalized vascular diseases affect the cutaneous vascular network. Noninflammatory purpuras (extravasation of blood in the dermis from small vessels) can be small (petechiae; less than 3 mm in diameter), or large (ecchymoses). Coagulation disorders, red blood cell diseases (sickle cell disease), and trauma are common causes.

Acute urticaria is a transient reaction caused by increased vascular permeability associated with edema in the dermis. In Chapter 4, Connective Tissue, we discussed the mechanism of degranulation of mast cells and release of histamine as determinants. Vasculitis includes a group of disorders in which there is inflammation of and damage to blood vessel walls. Most cases of cutaneous vasculitis affect small vessels, predominantly venules.

Keratinocyte stem cells and the hair follicle

The epidermis is contiguous with the external root sheath of the hair follicle, a structure responsible for developing the hair shaft. When the epidermis is lost in severely burned patients, keratinocyte stem cells migrate upward from the follicular bulb to reestablish the epidermis by populating the highly proliferative and self-renewing cells of the stratum basale (see Figure 11-14). These stem cells can also give rise to hair follicles and sebaceous glands.

There are two signaling pathways that stimulate stem cells to enter the epidermal differentiation pathway: (1) the Wnt (winglesss related) signaling pathway and (2) the Notch signaling pathway. The Wnt signaling pathway is important for the morphogenesis of the hair follicle. The Notch signaling pathway stimulates epidermal differentiation in the postnatal epidermis.

During embryogenesis, the bone morphogenetic protein (BMP) pathway promotes ectodermal differentiation to an epidermal cell fate.

Sweat glands

There are two types of sweat glands: (1) eccrine (merocrine) sweat glands (see Figure 11-17) and (2) apocrine sweat glands (see Figure 11-18).

The eccrine sweat gland is a simple coiled tubular gland with a role in the control of body temperature. Eccrine sweat glands are innervated by cholinergic nerves. The secretory portion of the eccrine sweat gland (see Figure 11-17) is a convoluted tube composed of three cell types: (1) clear cells, (2) dark cells, and (3) myoepithelial cells.

The clear cells are separated from each other by intercellular canaliculi, show an infolded basal domain with abundant mitochondria, rest on a basal lamina, and secrete most of the water and electrolytes (mainly Na⁺ and Cl⁻) of sweat.

The dark cells rest on top of the clear cells. Dark cells secrete glycoproteins.

Myoepithelial cells are found between the basal lamina and the clear cells.

The excretory portion of the eccrine sweat gland is lined by a bilayer of cuboid cells that partially reabsorb NaCl and water under the influence of aldosterone. The reabsorption of NaCl by the excretory duct is deficient in patients with cystic fibrosis (see next section). The duct follows a helical path when it approaches the epidermis and opens on its surface at a sweat pore. Within the epidermis, the excretory duct loses its epithelial wall and is surrounded by keratinocytes.

Apocrine sweat glands (see Figure 11-18) are coiled and occur in the axilla, mons pubis, and circumanal area. Apocrine sweat glands contain secretory acini larger than those in the eccrine sweat glands. The secretory portion is located in the dermis and hypodermis. The excretory duct opens into the hair follicle (instead of into the epidermis as in the eccrine sweat glands). Apocrine sweat glands are functional after puberty and are supplied by adrenergic nerves.

Two special examples of apocrine sweat glands are the ceruminous glands in the external auditory meatus and the glands of Moll of the margins of the eyelids.

The ceruminous glands produce cerumen, a pigmented lipid; the excretory duct opens, together with the ducts of sebaceous glands, into the hair follicles of the external auditory meatus.

The excretory duct of the glands of Moll opens into the free surface of the epidermis of the eyelid, or the eyelashes.

Clinical significance: Sweat glands and cystic fibrosis

Cystic fibrosis is a genetic disorder of epithelial transport of Cl⁻ by the channel protein CFTR (cystic fibrosis transmembrane conductance regulator), encoded by the cystic fibrosis gene located on chromosome 7.

Exocrine glands and the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts are affected by a mutation of CFTR. Recurrent pulmonary infections, pancreatic insufficiency, steatorrhea, hepatic cirrhosis, intestinal obstruction, and male infertility are clinical features of cystic fibrosis.

The excretory ducts of sweat glands are lined by epithelial cells containing CFTR involved in the transport of Cl⁻ (Figure 11-19). The CFTR channel opens when an agonist, such as acetylcholine, induces an increase in cyclic adenosine monophosphate (cAMP), followed by activation of protein kinase A, production of adenosine triphosphate (ATP) (see Chapter 3, Cell Signaling), and binding of ATP to two ATP-binding domains of CFTR.

Figure 11-19 Cystic fibrosis and sweat glands

A defect in CFTR in sweat gland ducts leads to a decrease in the reabsorption of sodium chloride from the lumen, resulting in increased concentrations of chloride in sweat.

In the respiratory epithelium (see Chapter 13, Respiratory System), a defect in CFTR results in a reduction or loss of chloride secretion into the airways, active reabsorption of sodium and water, and a consequent decrease in the water content of the protective mucus blanket. Dehydrated mucus causes defective mucociliary action and predisposes to recurrent pulmonary infections.