The integument, the largest and heaviest organ of the body, is composed of skin and its various derivatives, including sebaceous glands, sweat glands,

hair, and nails. The skin covers the entire body and is continuous with the mucous membranes at the lips, at the anus, in the nose, at the leading edges of the eyelids, and at the external orifices of the urogenital system. Some of the many functions of skin include

•protection against physical, chemical, and biologic assaults;

•providing a waterproof barrier;

•absorbing ultraviolet radiation for both vitamin D synthesis and protection;

•excretion (i.e., sweat) and thermoregulation;

•monitoring the external milieu via its various nerve endings;

•and immunologic defense of the body.

SKIN

Skin is composed of a superficial stratified squamous keratinized epithelium known as the epidermis and of a deeper connective tissue layer, the dermis (see Graphic 11-1— please note that free nerve endings are not depicted in this diagram).

•The epidermis and dermis interdigitate with each other by the formation of epidermal ridges and dermal ridges (dermal papillae), where the two are separated by a basement membrane.

Frequently, a dermal ridge is subdivided into two secondary dermal ridges with an intervening interpapillary peg from the epidermis.

•The ridges on the fingertips that imprint as fingerprints are evidence of this interdigitation.

Interposed between skin and deeper structures is a fascial sheath known as the hypodermis, which is not a part of skin.

Skin can be classified as thick or thin depending on the thickness of its epidermis and of its dermis. Since it is the thickness of the epidermis that is usually obvious when viewed with the microscope, the epidermis of thick skin is presented here. The epidermis of skin can be thick, as on the sole of the foot and the palm of the hand, or thin, as over the remainder of the body (see Table 11-1).

The epidermis of

thick skin has five well-developed layers: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum.

thin skin has three layers since the stratum granulosum and stratum lucidum are absent as welldefined layers. However, individual cells of the two absent layers are present even in thin skin.

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Epidermis of Thick Skin

The epidermis is composed of four cell types, keratinocytes, melanocytes, Langerhans cells, and Merkel cells. Approximately 95% of the cells of the epidermis are keratinocytes, and it is their morphology that is responsible for the characteristics of the five layers.

Keratinocytes and the Five Layers of the Epidermis

The deepest layer of the epidermis, the stratum basale (formerly known as stratum germinativum), is a single layer of cuboidal to columnar cells. These cells are responsible for cell renewal, via mitosis (usually at night), and the newly formed cells are pushed surfaceward, giving rise to the thickest layer, the stratum spinosum.

The cuboidal/columnar cells sit on a basement membrane, separating them from the connective tissue dermis, and form hemidesmosomes with the basal lamina and desmosomal contacts with each other and with the basal-most cells of the stratum spinosum.

These cells of the stratum basale form keratin 5 and keratin 14.

•The stratum spinosum is a number of cells in thickness and is composed of polyhedral prickle cells characterized by numerous processes (intercellular bridges) that form desmosomes with processes of surrounding prickle cells.

Cells, mostly in the deeper layer of the stratum spinosum, also display mitotic activity (usually at night).

These prickle cells form keratin 1 and keratin 10 that replace keratins 5 and 14 formed by the stratum basale. The keratins are intermediate filaments that begin to form bundles known as tonofilaments.

These prickle cells in the superficial layers of the stratum spinosum also form

-keratohyalin granules, non–membrane-bound structures that are composed of trichohyalin and filaggrin. These two proteins, associated with intermediate filaments, promote the aggregation of keratin by cross-linking the keratin filaments into thick bundles of tonofilaments.

-membrane-coating granules (Odland bodies, lamellar bodies), whose lipid-rich contents are composed of ceramides, phospholipids, and glycosphingolipids.

•Continuous migration of the cells of the stratum spinosum forms the next layer, the stratum granulosum.

Cells of this layer accumulate more keratohyalin granules, which eventually overfill the cells, destroying their nuclei and organelles.

This layer is the same in thin skin as in thick skin.

Cells of the stratum granulosum also continue to manufacture membrane-coating granules.

Cells of the stratum granulosum contact each other via desmosomes and, in their superficial layers, also form claudin-containing occluding junctions with each other as well as with cells of the stratum lucidum (or, in the absence of the stratum lucidum, with the stratum corneum).

In the superficial layers, cells of the stratum granulosum release the contents of their membrane-coating granules into the extracellular space. These cells no longer contain organelles or a nucleus and are considered to be dead having undergone apoptosis.

The stratum spinosum and stratum granulosum together are frequently referred to as the stratum

Malpighii.

•The fourth layer, the stratum lucidum, is relatively thin and is usually absent in thin skin. When evident in thick skin, palmar and plantar skin, it usually appears as a thin, translucent region, interposed between the strata granulosum and the corneum.

The cells of the stratum lucidum have no nuclei or organelles but contain a large amount of tonofibrils embedded in keratohyalin.

•The surface-most layer is the stratum corneum, composed of preferentially arranged stacks of dead hulls known as squames.

The squames, similar to the cells of the stratum lucidum, are filled with the keratohyalin-keratin complex, which deposits on the internal aspect of the cell membrane, forming a cornified cell envelope.

The cornified cell envelope is further buttressed by at least three proteins, involucrin, loricrin, and small proline-rich protein.

The contents of the Odland bodies, released by cells of the strata spinosum and granulosum, form a lipid envelope that provides a waterproof barrier.

The cornified cell envelope and the lipid envelope form a structure known as the compound cornified cell envelope.

The superficial layers of the stratum corneum are desquamated at the same rate as they are being replaced by the mitotic activity of the strata basale and spinosum while maintaining the integrity of the compound cornified cell envelope.

Recent investigations indicate that keratinocytes produce immunogenic molecules and are probably active in the immune process. Evidence also shows that these cells are capable of producing several interleukins, colony-stimulating factors, interferons, tumor necrosis factors, as well as plateletand fibroblast-stimulating growth factors.

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Nonkeratinocytes of the Epidermis

There are three types of nonkeratinocytes in the epidermis: melanocytes, Langerhans cells, and Merkel cells (see Table 11-2).

Melanocytes

Melanoblasts, derived from neural crest cells, differentiate into melanocytes under the influence of the signaling molecule stem cell factor. Melanocytes manufacture a dark melanin pigment.

•Melanocytes and premelanocytes migrate into the epidermis during embryonic development and establish residence in the forming stratum basale and may establish hemidesmosomes with the basal lamina. Some of the premelanocytes differentiate into melanocytes, whereas other remain in an undifferentiated state even in the adult.

•Once there, they do not make desmosomal contact with other cells in their vicinity but form long processes, dendrites, that penetrate the stratum spinosum.

•Each melanocyte forms an association, via its dendrites, with a number of keratinocytes, referred to as epidermal-melanin unit.

•The number of keratinocytes per melanocyte varies with regions of the body but is relatively constant across the races, and approximately 3% of the cells of the epidermis consist of melanocytes.

In the adult premelanocytes enter into the cell cycle to maintain their population as well as to differentiate into melanocytes.

•The hormone a-MSH binds to melanocortin receptors on the melanocyte cell membrane that activates a cAMP pathway prompting the melanocyte to express microphthalmia-associated transcription factor (MITF).

MITF not only regulates the mitotic activity of the premelanocytes but also induces the formation of melanin, in specialized organelles of melanocytes known as melanosomes.

There are two types of melanin, eumelanin, a dark brown to black pigment composed of polymers of hydroxyindole, and pheomelanin, a red to rust-colored compound composed of cysteinyl dopa polymers.

•Eumelanin is present in individuals with dark hair.

•Pheomelanin is found in individuals with red and blond hair.

Both types of melanin are derived from the amino acid tyrosine, which is transported into specialized tyrosinase- containing vesicles derived from the trans-Golgi network, known as premelanosomes.

258 I N T E G U M E N T

•Within these oval (1.0 by 0.5 mm) premelanosomes, tyrosinase converts tyrosine into 3,4-dihydroxy- phenylalanine (DOPA), which is transformed into dopaquinone and, eventually, into filamentous melanin (melanofilaments).

•As the amount of melanin increases within the premelanosomes, its filamentous structure is no longer evident, and the organelles mature into much darker structures known as melanosomes.

•Melanosomes possess the transmembrane protein Rab27a in their membranes.

•Melanosomes travel, along microtubules powered by kinesin, into the dendrites of melanocytes.

•The Rab27a binds a cytoplasmic molecule, melanophilin, which

permits a detachment of the melanosome from the kinesin and

facilitates its attachment to myosin Va, which transfers the melanosome to F-actin

melanosomes are transported to the immediate vicinity of the dendrite plasmalemma along the F-actin pathway.

Myosin Va detaches from the F-actin and permits the exocytosis of the melanosome into the extracellular space.

Once melanosomes enter the extracellular space, keratinocytes of the stratum spinosum phagocytose them. The melanosomes migrate to the nuclear region of the keratinocyte and form a protective umbrella, shielding the nucleus (and its chromosomes) from the ultraviolet rays of the sun. Soon thereafter, lysosomes attack and destroy the melanosomes.

•Ultraviolet rays not only increase the rates of darkening of melanin and endocytosis of the melanosomes but also enhance tyrosinase activity and thus melanin production.

•Fewer melanocytes are located on the insides of the thighs and undersides of the arms and face. Skin pigmentation is related to the location of melanin rather than to the numbers of melanocytes.

•Melanosomes are fewer and congregate around the keratinocyte nucleus in Caucasians, whereas in darkskinned individuals they are larger and are more dispersed throughout the keratinocyte cytoplasm. The destruction of the melanosomes occurs at a slower rate in darker than in lighter skin.

Langerhans Cells

Langerhans cells (also known as dendritic cells because of their long processes) are derived from bone marrow and located mostly in the stratum spinosum. They function

as antigen-presenting cells in immune responses. The nucleus of these cells possesses numerous indentations, and their cytoplasm contain, in addition to the usual organelles, Birbeck granules, elongated vesicles whose end is ballooned. Langerhans cells:

•do not make desmosomal contact with the cells of the stratum spinosum.

•express CD1a surface marker and MHC I, MHC II, Fc receptors for IgG, C3b receptors, and the transmembrane protein langerin that is associated with Birbeck granules. Langerin and CD1a facilitate the immune defense against Mycobacterium leprae, the microorganism responsible for leprosy

•phagocytose antigens entering the epidermis, including nonprotein antigens.

When a Langerhans cell phagocytoses an antigen, the cell migrates into a lymph vessel of the dermis to enter the paracortex of a nearby lymph node. Here, the Langerhans cell presents its antigen to T cells to activate a delayed-type hypersensitivity response.

Merkel Cells

Merkel cells, whose origin is uncertain, although most authors believe them to be a modified type of keratinocyte, are interspersed among the cells of the stratum basale and are most abundant in the fingertips. Afferent nerve terminals approximate these cells, forming complexes, known as Merkel discs that are believed to function as mechanoreceptors (touch receptors). There is some evidence that Merkel cells may also have a neurosecretory function.

Dermis

The dermis of the skin, lying directly deep to the epidermis, is derived from mesoderm. It is composed of dense, irregular collagenous connective tissue containing mostly type I collagen and numerous elastic fibers that assist in securing the skin to the underlying hypodermis.

•The dermis is subdivided into a loosely woven papillary layer (composed of primary and secondary dermal ridges), a superficial region that interdigitates with the epidermal ridges (and interpapillary pegs) of the epidermis, and

•a deeper, coarser, and denser reticular layer. The interface between the papillary and reticular layers is indistinct.

•Dermal ridges (as well as secondary dermal ridges) display encapsulated nerve endings, such as Meissner’s corpuscles, as well as capillary loops that bring nourishment to the avascular epidermis.

T N E M U G E T N I