STRUCTURE OF THE SKIN

The skin consists of two distinct layers: the epidermis and the dermis ( Fig. 461-1 ). The skin is derived from two germinal cell lineages: the ectoderm, which gives rise to the epidermis, and the mesenchyme, which produces the dermis. These two layers are joined at a basement membrane zone termed the basal lamina.

The skin and adnexal structures

FIGURE 461-1  The skin and adnexal structures. The relationship of the epidermis and its adnexal structures (sebaceous and sweat glands and hair follicles) to the dermis and subcutaneous adipose tissue is shown. Note how these structures are associated with breaks in the barrier of the stratum corneum.

The epidermis, which is a stratified squamous epithelial layer, contains several different levels of structure and function. It is held together by distinctive adhesion structures termed desmosomes ( Fig. 461-2 ). The stratum corneum, which is the product of the dying epidermis, resists the penetration of external organisms and toxins and prevents water loss. The basal lamina is a very complex structure of epidermal and dermal-derived proteins that attach the epidermis to the dermis and resist shear stress.

  Cell attachment in the epidermis

FIGURE 461-2  Cell attachment in the epidermis. The epidermal keratinocytes, melanocytes, and Langerhans cells form a network of attachments crucial to normal epidermal function.

The papillary dermis is a collagenous matrix containing the blood vessels that feed the epidermis. The reticular dermis is a tougher cushion protecting underlying tissue and containing the epidermal adnexal structures. The blood vessels and nerves are separated into a superficial plexus in the papillary dermis and a deeper plexus that serves the adnexal structures. The dermis is separated from the fascia and underlying muscle by a layer of subcutaneous adipose tissue that allows the skin to move freely relative to deeper internal structures.

The epidermally derived adnexal structures (eccrine sweat glands, apocrine sweat glands, sebaceous glands, and hair follicles) are anchored in the dermis but penetrate the epidermis and the barrier of the stratum corneum (see Fig. 461-1 ). The hair follicle is a cycling structure containing specialized populations of epithelial cells, pigment cells, and mesenchymal cells that control the hair cycle. Eccrine sweat glands discharge sweat directly through the stratum corneum. Apocrine sweat glands discharge their products into hair follicles. Sebaceous glands drain into sebaceous hair follicles on the scalp, face, chest, back, axilla, and groin. An extensive network of blood vessels and nerves serves the skin. The superficial vascular plexus feeds the epidermis through an extensive complex of capillary loops in the papillary dermis. The deep vascular and nerve plexus serve the adnexal structures in the dermis. The hair follicles, with their apocrine and sebaceous glands, and the eccrine sweat glands are potential avenues for transepidermal absorption of drugs because they penetrate the stratum corneum.

Cells of the Epidermis and Epidermal Differentiation

The epidermis is a stratified squamous epithelium composed mostly of keratinocytes, with other resident cells in distinct locations (melanocytes, Langerhans cells, and Merkel cells). In response to various stimuli, migrating cells such as lymphocytes, dermal macrophages, neutrophils, and eosinophils enter the epidermis. Keratinocytes are attached firmly to each other through desmosomes (see Fig. 461-2 ), which connect to the rigid keratin intermediate filament network and give the epidermis strength. The basal layer of the rigid epidermis connects to the basement membrane zone by means of hemidesmosomes, which are highly organized adhesion structures linked to the basal keratin network. Adherens junctions link surrounding keratinocytes and connect them to the actin microfilament network. These junctions provide more plastic adhesions that are also involved in actin-mediated movement. Junctions on melanocytes and Langerhans cells attach through E-cadherin–containing adherens junctions to keratinocytes to maintain their dendritic structure.

Keratinocytes and Epidermal Differentiation Epidermal Differentiation

Epidermal differentiation is a genetically programmed process by which keratinocytes differentiate from proliferating cells in the germinative layer to form tightly attached “prickle” cells in the malpighian layer, dying cells in the granular layer, and corneocytes in the stratum. During this process, keratinocytes undergo tremendous changes reflecting their different functional characteristics. Keratinocytes are named for the intermediate filament protein keratin, which forms insoluble stiff filaments that give the epidermis its strength. The keratins are made of tetramers composed of two basic and two acidic keratins (K5/14 in the basal layer, K1/10 in the spinous layer, K6/16 in the hyperproliferative epidermis, K9/19 in the palms and soles). Keratin has versatile pro-perties and is the major component of hair and nails in humans and of beaks, hooves, and feathers in other animals.

The attachments within the epidermis are formed by desmosomes and adherens junctions. The adherens junctions that form between keratinocytes are characterized by homophilic binding of cell surface cadherins and by binding of the adhesion structure to actin microfilaments within the cell by catenins ( Fig. 461-3A ). Desmosomes are composed of molecules called desmogleins and desmocollins, which are homologous to cadherins and form adhesion structures with keratins through numerous associated proteins such as plakoglobin and plakophilin (see Fig. 461-3B ). The basal keratinocytes are attached to the basal lamina at the hemidesmosome, a specialized adhesion structure linked to the basal cell keratin filament network (see Fig. 461-3C ). The progressive differentiation of the epidermis is associated with specific changes in protein expression and function.

Molecular aspects of key epidermal adhesion structures and connection of the epidermis to the dermis.

FIGURE 461-3  Molecular aspects of key epidermal adhesion structures and connection of the epidermis to the dermis. A–C, These structures are crucial to the normal integrity of the skin. Mutations or autoimmune damage to these structures has devastating effects on skin function. HSP = heat shock protein.

Functions of the Epidermal Layers

The germinative (basal) layer of the epidermis is responsible for cell proliferation. This layer is resistant to apoptosis because of defenses maintained by receptors for growth factors and matrix molecules. The germinative layer can become a migrating epithelial tongue to aid in wound healing.

The spinous layer produces a dense keratin filament network (keratins 1/10) that interacts with desmosomes, and it synthesizes involucrin (which is involved in protein cross-linking with the plasma membrane in the granular layer), a protective antioxidant network (glutathione reductase, peroxidases, catalases), cytokines, chemokines, lamellar bodies, and keratohyaline granules.

Cells in the granular layer undergo programmed cell death (apoptosis). Keratohyaline granule profilaggrin is activated into filaggrin, thereby inducing keratin cross-linking. Lamellar body contents are secreted into the extracellular space by fusion of the lamellar body to the cell membrane. Cross-linking of involucrin and cornifin to the cell membrane by transglutaminase produces a thickened, cornified envelope. Protein synthesis ceases as cells die to form intact corneocytes, which contain cross-linked keratin filaments and a thick cornified envelope.

Flat corneocytes surrounded by phospholipid lamellae form the impervious stratum corneum. Although the cornified layer provides a thin, flexible barrier to protect sensitive cells from the external environment, molecules can diffuse through the cornified layer. Indeed, this transepidermal route is the major route of penetration of topical medications ( Chapter 462 ). After a defined period, desquamation of superficial corneocytes occurs by enzymatic degradation of extracellular material.

Melanocytes

Melanocytes, which are dendritic cells that synthesize and secrete the pigment melanin, are derived embryonically from neural crest cells and typically migrate to the epidermal-dermal junction during development, although a few can be found in the dermis. Melanocytes are localized in the basal layer of the epidermis, with the ratio of melanocytes to keratinocytes ranging from about 1:4 to about 1:10 at different locations in the skin. The relative number of melanocytes is roughly the same for both sexes and for all races, approximately 1500 melanocytes per square millimeter of skin surface. A totally separate population of melanocytes resides in hair follicles that produce pigmented hairs. Differences in the coloration of skin are therefore determined by the relative activity of these cells, not their numbers. Epidermal melanocytes are attached to the basal lamina by integrin receptors, and they are attached to surrounding keratinocytes by E-cadherin–mediated attachments. Melanin pigment is synthesized in melanocyte-specific organelles termed melanosomes. Melanosome transfer is achieved when keratinocytes actively engulf the melanosome-containing cytoplasmic tips of the dendritic processes of the melanocytes. Exposure to ultraviolet (UV) light increases the rate of formation of melanosomes and enhances their rate of delivery to keratinocytes.

Melanin is a complex heteropolymer that absorbs light across the entire UV and visible spectrum; it is the principal protection of the skin against solar radiation. Melanization is a complex biochemical process controlled largely by three genes: tyrosinase (rate-limiting step), which oxidizes tyrosine to 3,4-dihydroxyphenylalanine (dopa); tyrosinase-related protein 1 (TyRP-1); and tyrosinase-related protein 2 (TyRP-2). Control of melanization is a complex genetic and environmental process. One important level of control is binding of melanocyte-stimulating hormone to the melanocortin-1 receptor (MC-1R) on melanocytes. The enzymes that control melanization are transported into the melanosome, where the biochemical processes occur in a protected organelle-bound environment. The whole organelle is then transported to keratinocytes, where it resides in a “helmet” location above the nucleus. Polymorphisms in MC-1R control the relative amounts of the three key enzymes. Decreases in TyRP-1 and TyRP-2 lead to the production of pheomelanin, a brown-red pigment with inferior photoprotective properties. This type of pigment is seen in red-haired individuals and is associated with decreased sun protection, increased photoaging, and a higher rate of melanoma and nonmelanoma skin cancer. UV light can transform melanocytes into malignant melanoma, the most deadly form of skin cancer ( Chapter 214 ).

Melanocytes are terminally differentiated cells with no stem cell population to repopulate interfollicular melanocytes. A melanocyte precursor population in the outer root sheath of the hair follicle can be mobilized to repopulate lost interfollicular melanocytes—an approach to repigmentation that is used for vitiligo. However, melanocyte stem cell populations are believed to exist in the hair follicle, where they replenish the melanocytes of the hair bulb during each cycle of hair regeneration in the transition from telogen to anagen (see Hair).

Langerhans Cells

Dendritic Langerhans cells are an important subset of antigen-presenting cells located in the midportion of the epidermis. These cells become more abundant at sites of inflammatory skin disorders, including allergic reactions such as contact dermatitis ( Chapter 464 ). Langerhans cells are migratory, and they contain characteristic striated, rodlike structures known as Birbeck granules. They also bear several important immunologic cell surface receptors (DC1, major histocompatibility complex [MHC] class II, IgG receptor, C3 receptor). In contact sensitization (contact dermatitis), Langerhans cells internalize and process antigen, migrate to regional lymph nodes, and present the antigen to naive lymphocytes. When the antigen is reapplied to skin (challenge), the Langerhans cells again process and present the antigen to sensitized lymphocytes in the skin or in lymph nodes.

Merkel Cells

Merkel cells are scattered among the basal keratinocytes and are more abundant in some areas than others. These cells are often found near or in contact with very fine, unmyelinated nerves, and they form synapses with peripheral nerve fiber endings. Merkel cells are present singly or in clusters called tactile corpuscles. They are attached to adjacent epidermal cells by numerous desmosome connections, but their tonofilaments, unlike those of keratinocytes, are not grouped into bundles. In the cytoplasm of Merkel cells are numerous membrane-bounded dense granules that contain catecholamines. It is believed that Merkel cells serve as adapting mechanoreceptors. Merkel cell tumors are uncommon but are among the most deadly of skin cancers.

The Dermal-Epidermal Junction

The dermal-epidermal junction is a transitional zone in which the basal layer of the epithelium is connected to penetrating deep collagenous anchors that originate in the papillary dermis. The connection is composed of collagenous rods, globular domains, and cruciate protein complexes that form a firm attachment that resists friction and tangential stress. This junction, which is the weakest structure point in the skin, is the site of blistering induced by cold, heat, and immunologically and genetically mediated blistering disorders.

Downgrowths of the epidermis form tiny ridges, called rete pegs, that add bonding surface area between the dermis and epidermis ( Table 461-1 ). The sandwiched basal lamina follows the ridges, which are more pronounced in areas of high abrasion. The lamina has three zones: the lamina lucida, the lamina densa, and the fibroreticular lamina. Keratin filaments in the basal cells anchor in the hemidesmosomes, which connect to anchoring filaments of the lamina lucida and then to the dense collagen and heparan sulfate proteoglycan matrix of the lamina densa. Anchoring fibrils of type VII collagen form the fibroreticular lamina and end in the anchoring plaques that intercalate with type III and VI collagen in the papillary dermis.

TABLE 461-1   -- COMPONENTS OF THE DERMAL-EPIDERMAL JUNCTION

Location Structure Macromolecules
Basal keratinocytes Hemidesmosomes BPAg 230 (BPAg1)
Plasma membrane   BPAg 180 (BPAg2)
    Plectin
    Integrins α6β4 and α3β1
Lamina lucida Anchoring filaments Laminin isoforms
    Part of BPAg2
Lamina densa Electron-dense band Type IV collagen
    Entactin
    Heparan sulfate
    proteoglycan
Sublamina densa fibrillar zone Anchoring fibrils Type VII collagen
  Microfibrils Fibrillin 1 and 2
  Collagen fibers Collagen types I, III, and VI
  Microthread-like fibers Linkin

The Dermis

The thickness of the dermis varies considerably in different parts of the body. For descriptive purposes, the dermis is divided into the papillary layer, which is the thinner inner layer next to the epidermis, and the reticular layer, which is composed of denser connective tissue and constitutes the bulk of the dermis. The papillary layer, which forms the dermal papillary ridges, is composed of collagen and reticular and elastic fibers that are woven into a loose network. The extracellular matrix consists of mucopolysaccharides. The dermis contains many different cell types, including fibroblasts, fibrocytes, macrophages, leukocytes, and plasma cells. The vascular supply to the skin is confined to the dermis, where small arteries enter from the subcutaneous tissue and form deep and superficial sheetlike plexus. Capillary loops ascend into the dermal papillae and return via venous plexus. The postcapillary venule portion of the vascular network, which is where leukocytes enter the tissue, is an important target of damage in allergic vasculitis. The nerve supply to the skin is very profuse and consists of both myelinated and nonmyelinated fibers. Specialized sensory structures such as pacinian and Meissner's corpuscles are located prominently in the hands and feet. Because up to 4 to 5% of the total blood volume can be stored in the dermis, it plays an important role in thermal regulation; sympathetic nerve fibers control blood flow to and from the skin.

Epidermal Appendages of the Skin Sebaceous Glands

Sebaceous glands, or oil glands, are found throughout the dermis except for the palms of the hands and the soles of the feet. Most of these glands, which are greatly activated at the onset of puberty, discharge their contents via a single duct into the lumen of hair follicles. Where these glands occur independently of hairs (e.g., the glans penis, lips, labia minora, and eyelids), they open directly onto the surface of the skin. The sebaceous glands are holocrine in their secretion; that is, the entire cell is discharged as a secretory body. Mature cells filled with triglycerides, waxy esters, squalene, cholesterol, and fatty acids degenerate and disintegrate (necrosis); the entire debris is discharged as sebum. Contraction of the erector pili muscles aids in discharging the contents of these glands.

Eccrine Sweat Glands

Sweat glands are merocrine in secretion; that is, they discharge components of cytoplasm into the sweat duct. Eccrine sweat glands are positioned over the entire skin but are concentrated most densely in the palms, the soles, and the head. Eccrine sweat glands, which number about 3 million, are innervated by postganglionic, cholinergic sympathetic nerves. Excess heat causes sweating to begin on the forehead and to spread elsewhere over the body. Eccrine sweat glands secrete a watery solution that is high in sodium chloride but also contains urea, uric acid, potassium, and immunoglobulins. Histologically, these glands are simple tubular structures composed of a coiled glandular portion and a straight duct, which on entry into the epidermis is continuous with a spiral cleft opening to the surface of the skin. On the outside of the secretory epithelium are myoepithelial cells.

Apocrine Sweat Glands

Apocrine glands remain small until early puberty, when they enlarge and begin to secrete. Histologically, these glands consist of two portions: the coiled secretory gland, which is situated in the dermis and subcutaneous tissue, and a straight excretory duct, which is composed of two layers of epithelial cells. Apocrine release can be secretion or excretion. Secretion is a continuous process, but excretion is episodic. Excretion occurs when there is actual propulsion, presumably provided by the myoepithelial sheath, which is innervated by adrenergic sympathetic fibers. Apocrine glands are scent glands whose secretion is increased by fear, sexual excitement, and other forms of heightened tension. Apocrine glands are present in the axilla, the external genitalia, the areolar skin around nipples, and the perianal area. Specialized apocrine glands include Moll's glands on the eyelid and ceruminous (wax) glands in the auditory canal.

Nails

The nail is composed of a proximal germinative epithelium that is called the nail matrix, a keratinized product that is called the nail plate or body, an underlying specialized epithelium that is called the nail bed and is attached to the undersurface of the nail, and a protective loop of skin that is called the proximal nail fold. Underlying the proximal part of the body of the nail is a collection of germinal cells that form an opaque spot on the nail, the lunula. The lunula is white because the papillary dermis in this region is less vascular, and the stratum germinativum is thick and opaque; this is the site of the proliferating nail matrix that is responsible for growth of the nail. As these epidermal cells are formed, they become tightly packed and keratinized, but they do not desquamate. Nails grow at a rate of 0.5 to 1.5 mm/wk, with toenails growing much more slowly than fingernails.

Hair

There are three types of hair follicles: vellus hair follicles located over most of the body; terminal hair follicles located on the scalp, beard area, axilla, groin, and other hairy areas; and sebaceous hair follicles located on the scalp, face, beard, chest, back, axilla, and groin. Sebaceous hair follicles have a minimal hair shaft but hypertrophied sebaceous glands. Terminal hairs form the long hairs of the scalp and beard. The hair follicles of the eyelashes and eyebrows also have specialized characteristics determined by local mesenchymal factors. Hair follicle growth is determined by influences of the dermis and is strongly stimulated by androgens by means of the type II androgen receptor.

Hairs are dead shafts composed of fused plates of keratin that project from the surface of the epidermis. Hair does not grow continuously but rather passes through a cycle ( Fig. 461-4 ). Anagen is the growth phase. Then comes a short catagen stage in which portions of the hair follicle involute and growth ceases. Next is the telogen, or resting, phase. Near the end of the telogen phase, the hair falls out or is easily pulled out. A shed hair is called a club hair because of the shape of the root. This overall cycle varies depending on the hair and the location on the body. For scalp hairs, the anagen phase can last 3 to 10 years, but it may be as short as 4 months in other areas of the body. The hair growth cycle can be synchronized during pregnancy so that a larger number of hair follicles will enter the telogen phase together and therefore be shed together after delivery of the fetus, thereby causing temporary thinning of the hair 3 to 4 months after pregnancy (telogen effluvium). Hair is pigmented by melanocytes situated in the hair bulb close to the papillae. Keratinocytes in the papillary region engulf the pigment granules, much as they do in the skin.

Hair follicle cycle

FIGURE 461-4  Hair follicle cycle. Communications between the dermal papilla, the matrix, the follicle sheath, and the stem cells control the hair cycle through its anagen, catagen, and telogen phases.

The hair cycle depends on synchronized cooperation among four major components of the hair follicle: the dermal papilla, the hair matrix, the outer root sheaths, and the stem cells in the bulge region. During the actively growing anagen phase of the hair cycle, signals from the dermal papilla maintain the proliferating hair matrix. When these signals terminate, the follicle enters the catagen phase in which the matrix and root sheaths of the lower follicle die by apoptosis. The follicle then enters a resting telogen phase. When the follicle re-enters the anagen phase, signals from the dermal papilla stimulate stem cells in the bulge region of the follicle, and these cells migrate to form the new matrix, initiate a new hair shaft, and cause the old hair to fall out. In normal follicles in young healthy adults, the anagen phase is almost 3 years and the telogen phase is about 3 months. At any time, 10 to 15% of the hairs are in telogen on a healthy young scalp.

In “telogen effluvium,” the shift to telogen is abrupt, and hairs fall from the scalp precipitously in 3 months when new anagen hairs are formed in the follicles. This pattern is commonly seen 3 to 4 months after a severe systemic illness or at the termination of pregnancy. A gradual shift to the telogen phase occurs with age and is even greater in androgenic alopecia.