Structure and function of the skin

The epidermis, dermis, and subcutis (subcutaneous fat). The epidermis is the outermost layer and is composed primarily of keratinocytes, or epidermal cells. Beneath the epidermis lies the dermis, which is composed primarily of collagen but also contains adnexal structures, including the hair follicles, sebaceous glands, apocrine glands, and eccrine glands. Numerous blood vessels, lymphatics, and nerves also traverse the dermis. Below the dermis lies the subcutis, or subcutaneous layer, which consists of adipose tissue, larger blood vessels, and nerves. The subcutis may also contain the base of hair follicles and sweat glands (Fig. 1-1).

The epidermis has four layers: the basal cell layer, spiny cell layer, granular cell layer, and cornified layer (Fig. 1-2). The basal cell layer (stratum basalis) is composed of columnar or cuboidal cells that are in direct contact with the basement membrane, the structure that separates the dermis from the epidermis. The basal cell layer contains the germinative cells, and, for this reason, occasional mitoses may be present.

The three layers above the basal cell layer are histologically distinct and demonstrate differentiation of the keratinocytes as they move toward the skin surface and become “cornified.” Just above the basal cell layer is the spiny cell layer (stratum spinosum), so called because of a high concentration of desmosomes and keratin filaments that give the cells a characteristic “spiny” appearance (Fig. 1-3A). Above the spiny layer is the granular cell layer (stratum granulosum). In this layer, keratohyalin granules are formed and bind to the keratin filaments (tonofilaments) to form large electron-dense masses within the cytoplasm that give this layer its “granular” appearance.

The outermost layer is the cornified layer (stratum corneum), where the keratinocytes abruptly lose all of their organelles and nuclei. The keratin filaments and keratohyalin granules form an amorphous mass within the keratinocytes, which become elongated and flattened, forming a lamellar array of “corneocytes.” The corneocytes are held together by the remnants of the desmosomes (dense bodies) and a “cementing substance” released into the intracellular space from organelles called Odland bodies.

In addition to keratinocytes, three other cells are normally found in the epidermis. The melanocyte, the most common, is a dendritic cell situated in the basal cell layer. There are approximately 36 keratinocytes for each melanocyte. This cell’s function is to synthesize and secrete melanin-containing organelles called melanosomes.

The next most common cell is the Langerhans cell, which is a bone marrow–derived, antigen-presenting cell that has very important immune surveillance functions. On light microscopy, these dendritic cells are primarily distributed in the stratum spinosum. Langerhans cells were first described by Paul Langerhans in 1868 while he was still a medical student.

Also located in the epidermis in small numbers are Merkel cells. The function of these cells is not fully established, but they are frequently in contact with nerve fibrils. Ultrastructurally, Merkel cells contain electron-dense bodies that are also found in APUD (amino acid precursor uptake and decarboxylation) cells of endocrine glands.

The BMZ is not normally visible by light microscopy in sections stained with hematoxylin-eosin but can be visualized as a homogeneous band measuring 0.5 to 1.0 mm thick on periodic acid–Schiff staining. Ultrastructural studies and immunologic mapping demonstrate that the BMZ is an extremely complex structure consisting of many components that function to attach the basal cell layer to the dermis (Fig. 1-3B). Uppermost in the BMZ are the cytoplasmic tonofilaments of the basal cells, which attach to the basal plasma membrane of the cells at the hemidesmosome. The hemidesmosome is attached to the lamina lucida and lamina densa of the BMZ via anchoring filaments. The BMZ, in turn, is anchored to the dermis by anchoring fibrils that intercalate among the collagen fibers of the dermis and secure the BMZ to the dermis. The importance of these structures in maintaining skin integrity is demonstrated by diseases such as epidermolysis bullosa, in which they are congenitally missing or damaged.

The three most important functions of the epidermis are protection from environmental insult (barrier function), prevention of desiccation, and immune surveillance. The stratum corneum is an especially important cutaneous barrier that protects the body from toxins and desiccation. Although many toxins are nonpolar compounds that can move relatively easily through the lipid-rich intracellular spaces of the cornified layer, the tortuous route among cells in this layer and the layers below effectively forms a barrier to environmental toxins. Ultraviolet light, another environmental source of damage to living cells, is effectively blocked in the stratum corneum and the melanosomes. The melanosomes are concentrated above the nucleus of the keratinocytes in an umbrella-like fashion, providing photoprotection for both epidermal nuclear DNA and the dermis.

The prevention of desiccation is another extremely important function, as extensive loss of epidermis is often fatal (e.g., toxic epidermal necrolysis). In the normal epidermis, the water content decreases as one moves from the basal layer to the surface, comprising 70% to 75% of weight at the base and decreasing to 10% to 15% at the bottom of the stratum corneum.

Immune surveillance against foreign antigens is a function of the Langerhans cells that are dispersed among the keratinocytes. Langerhans cells internalize external antigens and process these antigens for presentation to T lymphocytes in the lymph nodes. Inflammatory cells (i.e., neutrophils, eosinophils, lymphocytes) are also capable of intercepting and destroying microorganisms in the epidermis.

In the epidermis, the keratinocytes are bound to each other by desmosomal complex. These complexes consist of the desmosome and the tonofilaments of the cytoplasm that are made of cytokeratins. In the upper stratum spinosum, the tonofilaments are composed mainly of keratins 1 and 10. Congenital abnormalities in these keratins produce structural weakness between keratinocytes, producing a disease called congenital bullous ichthyosiform erythroderma (epidermolytic hyperkeratosis). Abnormalities in keratin types 5 (KRT5) and 14 (KRT14) in the basal cell layers lead to a mild blistering disease named epidermolysis bullosa simplex (EBS) (Fig. 1-4). Pemphigus is an acquired group of blistering diseases of the epidermis in which autoantibodies directed against antidesmosomal proteins produce damage to the desmosomes.

The skin diseases associated with antibodies and damage to the desmosomes and their characteristics are listed in Table 1-1.

Yes. There is a complex group of inherited diseases in which the skin is friable and bullous lesions occur, often with subsequent scarring. The two subgroups within this group are junctional epidermolysis bullosas (JEBs) and dystrophic epidermolysis bullosas (DEBs). Like the EBS diseases, which affect the epidermal layers, these diseases occur because the vital structural elements of the BMZ and dermis are missing, causing the skin to separate easily and blister. In JEBs, the separation occurs within the lamina lucida (LL) of the BMZ. Decreased amounts or abnormalities in the LL components, such as laminins I and V, 19-DEJ-1 protein, XII collagen, plectin, XVII collagen (bullous pemphigoid antigen) and alpha 4 beta 6 integrin have been identified in this group.

Table 1-1. Diseases Associated with Antibodies and Damage to Desmosomes

DISEASE INVOLVED	CLINICAL APPEARANCE AND LOCATION	MAIN DERMOSOMAL MOLECULES
Pemphigus vulgaris	Oral and diffuse superficial flaccid blisters with ulcers	Desmogleins 1 and 3 (Dsg1 and 3) and plakoglobin
Pemphigus foliaceus	Diffuse superficial blisters and crusting	Desmoglein 1 (Dsg1)
Pemphigus vegetans	Vegetating, weeping lesions in the intertriginous areas	Desmoglein 3 (Dsg3)
Pemphigus erythematosus	Butterfly eruption with blistering in malar areas	Desmoglein 3 (Dsg3)
Paraneoplastic pemphigus	Diffuse erythema multiforme-like painful eruption	Desmoplakins 1 and 2 (Dsg1 and 2), BP antigen 1 (BP230), plectin, desmogleins 1 and 3 (Dsg1 and 3), envoplakin, periplakin
IgA pemphigus	Pustular or vesiculopustular eruption	Desmogleins 1 and 3 (Dsg1 and 3), desmocollin 1

In the DEB group, separation occurs below the BMZ in the dermal layer, and a decreased amount or absence of type VII collagen has been noted. As a rule, the deeper in the skin the separation occurs, the more severe the clinical picture with increased scarring and loss of function. DEB patients typically have severe deforming scars and decreased life span (see Fig. 1-4).

Yes. There are several diseases in which blistering occurs secondary to disruption of the structures of the BMZ and dermis. As with the epidermal blistering diseases, antibodies to the hemidesmosomes and other structures within the BMZ and dermis cause separation of the skin and blistering. In the uppermost portion of the BMZ, the LL, hemidesmosomes bind the basal keratinocytes to the basement membrane. Bullous pemphigoid (BP) is a classic example of an acquired blistering disease in which antihemidesmosomal antibodies are produced and appear to induce inflammation and subsequent damage of the hemidesmosomes, causing a blister to develop between the cells and the basement membrane.

A partial list of the skin diseases associated with antibodies and damage to the basement membrane structures and dermis are listed in Table 1-2.

The sebaceous gland is a holocrine gland that is a part of the pilosebaceous unit. Its function is to produce sebum, which is a combination of wax esters, squalene, cholesterol esters, and triglycerides. Sebum is secreted through the sebaceous duct into the hair follicle, where it covers the skin surface, possibly as a protectant. Sebum may also have antifungal properties. Sebaceous glands are located everywhere on the skin except the palms and soles.

Table 1-2. Skin Diseases Associated with Antibodies and Damage to Basement Membrane Structures and Dermis

DISEASE	CLINICAL APPEARANCE AND LOCATION	BASEMENT MEMBRANE MOLECULE INVOLVED
Bullous pemphigoid	Tense blisters diffusely	BP antigens 1 (BP230) and 2 (BP180)
Pemphigoid (herpes) gestationis	Urticarial blisters with pruritus in late pregnancy	BP antigen 2 (BP180 or collagen XVII antigen)
Epidermolysis bullosa acquisita	Friable skin and blistering knees, elbows, and sites of increased pressure	Type VII dermal collagen (anchoring fibril antigen)
Bullous lupus erythematosus	Blistering face and trunk with flairs of systemic lupus erythematosus (SLE)	Type VII dermal collagen and lamins 5 and 6
Linear IgA bullous disease (LIBD)	Tense vesicles in annular and target-like patterns on the trunk	BP antigen 2 (BP180 or collagen XVII antigen) and 97 kDa

Embryologically, eccrine glands derive from the epidermis and are not part of the pilosebaceous unit. The eccrine sweat glands function in temperature regulation via secretion of sweat, a combination of mostly water and electrolytes, which evaporates and cools the skin. Their ducts pass through the dermis and epidermis to empty directly onto the skin surface. Eccrine glands are located everywhere on the skin surface except on modified skin areas, such as the lips, nail beds, and glans penis. Eccrine sweat glands are found only in higher primates and horses.

Apocrine glands originate from the same hair germ that gives rise to the hair follicle and sebaceous gland. The apocrine duct empties into the follicle above the sebaceous gland. Their anachronistic function is to produce scent. They are located primarily in the axillae and perineum, and their activity is sex hormone–dependent. The breast and cerumen glands are both modified apocrine sweat glands.

The dermis is organized into two distinct areas: the papillary dermis and the reticular dermis. The superficial papillary dermis is a relatively thin zone beneath the epidermis. On light microscopy, it is composed of thin, delicate collagen fibers and is highly vascularized. The hair follicles are enveloped by a perifollicular dermis that is contiguous with, and morphologically resembles, the papillary dermis. Collectively, the papillary dermis and perifollicular dermis are called the adventitial dermis, although this term is rarely used in dermatology texts.

The deeper zone is the reticular dermis, which comprises the bulk of the dermis. It is less vascular than the papillary dermis and demonstrates thick, well-organized collagen bundles.

Collagen. Antibodies against type VII collagen, which makes up the anchoring filaments within the dermis, are found in the autoimmune diseases bullous systemic lupus erythematosus (SLE) and acquired epidermolysis bullosa. Antibodies to laminins 5 and 6, which are also located in the anchoring filaments, are found in bullous SLE patients. The anchoring filaments function to bind the basement membrane to the dermis, and damage to this collagen results in blister formation below the basement membrane. Clinically, blistering damage beneath the basement membrane causes significant scarring in contrast to blisters in the epidermis or above the basement membrane that do not cause scarring. Congenital epidermolysis bullosa (EB), in which there is a congenital paucity or absence of type VII collagen and anchoring fibers, can result in severe scarring. The most severe form of this disease, recessive dystrophic EB, is associated with “mitten” deformities of the hands and feet, severe scarring of the upper respiratory and gastrointestinal tracts, and early death (Fig. 1-5A).

Congenital abnormalities in the various collagens in the dermis, especially types I and III, are found in several of the Ehlers-Danlos syndromes. The cutaneous manifestations of these syndromes are hyperextensibility of the skin, easy bruising, and poor healing with resultant wide scar formation (Fig. 1-5B).

Body temperature is regulated, in part, through control of dermal blood flow. Lowering body temperature is accomplished through increased blood flow in the vascular plexus in the high papillary dermis, allowing heat to be removed through radiation from the skin. The dermal vasculature is composed of a superficial and deep plexus of arterioles and venules that are interconnected by communicating vessels (Fig. 1-6). The incoming blood flow to the superficial capillary plexus in the upper dermis can be decreased by increased smooth muscle tone in the ascending arterioles, or it can be shunted directly from the arterioles to the venous channels in the deeper plexus systems via glomus bodies, which are modified arterioles surrounded by multiple layers of muscle cells. During cold temperatures, decreased papillary blood flow to the papillary dermis, in essence, shunts the blood away from the skin surface and decreases heat loss from the body. The hot flashes that typically occur in menopausal women are caused by an instability of this system. Periodic dilation of the skin capillaries allows increased blood flow to the skin, which is perceived as heat.