Skin provides a mechanical barrier against the external environment, but has further roles in thermoregulation, metabolism, and the regulation of fluid balance, as well as being socially important in contributing to physical and chemical attraction between individuals.
There are more than 1000 different skin diseases, although relatively few are commonly encountered in general medical practice. However, several skin conditions can reflect a general medical problem such as a systemic infection, or a cutaneous manifestation of internal disease (e.g. patients with underlying malignancy, endocrine disorders or chronic inflammatory diseases). An understanding of skin structure and function is also important in dealing with the common clinical scenario of ‘skin failure’ resulting from adverse drug reactions, burns, or extensive trauma.
The skin is the body’s largest organ. In a 70-kg individual the skin weighs over 5 kg and covers a surface area approaching 2 m2. Structurally, skin consists of a stratified cellular epidermis (made of keratinocytes) and an underlying dermis of connective tissue (fibroblasts, collagens, elastic tissue, and ground substance) (Fig. 23.1.1). Below the dermis is a layer of subcutaneous fat, which is separated from the rest of the body by a vestigial layer of striated muscle. The skin also contains hair follicles, sweat glands, blood vessels, autonomic and sensory nerves, as well as pigment cells (melanocytes), antigen-presenting cells (e.g. Langerhans’ cells), neuroendocrine (Merkel’s) cells, and some resident inflammatory cells (lymphocytes and mast cells).
Origin of the skin
The skin arises by the juxtaposition of two major embryological elements: the prospective epidermis, which originates from a surface area of the early gastrula, and the prospective mesoderm, which comes into contact with the inner surface of the epidermis during gastrulation. The mesoderm not only provides the dermis, but is essential for inducing differentiation of the epidermal structures, such as the hair follicle. The melanocytes are derived from the neural crest. While the skin develops in utero it is covered by a special layer, the periderm, which is unique to mammals. The periderm provides some protection to the newly forming skin, as well as having a role in the uptake of carbohydrate from the amniotic fluid.
The embryonic dermis is at first very cellular, and at 6 to 14 weeks three types of cell are present: stellate cells, phagocytic macrophages, and cells with secretory granules (either melanoblasts or mast cells). From weeks 14 to 21 fibroblasts are numerous and active, and perineural cells, pericytes, melanoblasts, Merkel’s cells, and mast cells can be individually identified. The various components of the skin that can be recognized postnatally start to appear at different embryonic time-points, e.g. hair follicles and nails (9 weeks), sweat glands (9 weeks for the palms and soles, 15 weeks for other sites), and sebaceous glands (15 weeks). Touch pads become recognizable on the hands and fingers, and on the feet and toes, by 6 weeks, and reach their greatest development at 15 weeks. After this, they flatten and become indistinct. It is these areas that determine the pattern of the dermatoglyphs (fingerprints) that take their place.
Structure of the skin
The normal epidermis is a terminally differentiated, stratified squamous epithelium composed of keratinocytes, which progressively move from attachment to the epidermal basement membrane towards the skin surface. This process normally takes about 40 days, but is accelerated in diseases such as psoriasis. The brick-like shape of keratinocytes is provided by a cytoskeleton made of keratin intermediate filaments. As the epidermis differentiates, the keratinocytes become flattened as a result of the action of filaggrin, a protein component of keratohyalin granules, on the keratin filaments. Indeed, keratin and filaggrin comprise 80 to 90% of the mass of the epidermis.
The outermost layer of the epidermis is the stratum corneum, where the cells (now called corneocytes) have lost their nuclei and cytoplasmic organelles. The corneocyte has a highly insoluble cornified envelope within the plasma membrane, formed by the cross-linking of soluble protein precursors including involucrin and loricrin. The latter contributes 70 to 85% of the mass of the cornified cell envelope, which also contains several lipids (fatty acids, sterols, and ceramides) released from lamellar bodies within the upper, living epidermis.
Melanocytes are located within the basal layer of the epidermis (closest to the dermis). These are dendritic cells that distribute packages of the pigment melanin (melanosomes) to surrounding keratinocytes, the process that gives skin its physical colour. The number of melanocytes does not differ much between white and black skin. Rather it is the nature of the melanin and the size of the melanosomes that account for the different appearance.
Another dendritic cell population within the epidermis is the Langerhans’ cell, which is of mesenchymal origin, and originates from bone marrow. Langerhans’ cells are antigen-presenting cells that process antigens encountered by the skin to local lymph nodes, and thus have a key role in adaptive immune responses in the skin.
Collagen is the major extracellular matrix protein, comprising 80 to 85% of the dry weight of the dermis. Twenty-seven different collagens have been identified in vertebrate tissue (distinguished by roman numerals in the order of their discovery, from I to XXVII), of which at least 12 are expressed in skin. The main interstitial dermal collagens are types I and III, whereas the principal basement membrane collagen (at the junction between the dermis and the epidermis, and around dermal blood vessels, nerves, and glands) is type IV. Triple-helical collagen monomers polymerize into fibrils and fibres, which then become stabilized by the formation of complex intra- and intermolecular cross-links. Collagen fibres are extremely tough and provide skin with its tensile strength.
Elastic fibres account for no more than 2 to 4% of the extracellular matrix in the dermis, and consist of two components, elastin and microfibrils, which together give skin its elasticity and resilience. Elastic microfibrils are composed of several proteins, including fibrillin, that surround the elastin and can extend throughout the dermis in a web-like configuration to the junction between the dermis and the epidermis.
The dermis also contains a number of noncollagenous glycoproteins, including fibronectins, fibulins, and integrins, which are important components of the extracellular matrix, facilitating cell adhesion and cell motility. Between the dermal collagen and elastic tissue is the ground substance, made up of glycosaminoglycan/proteoglycan macromolecules. These contribute only 0.1 to 0.3% of the total dry weight of the dermis, but play a vital role in providing hydration, mostly via the high water-binding capacity of hyaluronic acid. Indeed, about 60% of the total weight of the dermis is composed of water.
Regional variations in skin anatomy
The thickness of the living epidermis in normal human skin shows some variation with body site, and usually measures about 0.05 to 0.1 mm, although it may be thicker in regions such as the palm and sole, where the stratum corneum can be up to 10 times thicker than in nonacral sites (Fig. 23.1.2). Likewise, the thickness of the dermis may differ considerably, from less than 0.5 mm on the eyelid to more than 5 mm on the back.
There are two main types of human skin. Glabrous (nonhairy) skin is found on the palms and soles. It has a grooved surface with alternating ridges and sulci, giving rise to the fingerprints. Glabrous skin has a compact stratum corneum, encapsulated sense organs within the dermis, and a lack of hair follicles and sebaceous glands. By contrast, hair-bearing skin has both hair follicles and sebaceous glands, but lacks encapsulated sense organs. There is also wide variation between body sites. For example, the scalp has large hair follicles that may extend into the subcutaneous fat, whereas the forehead has only small vellus hair-producing follicles, although the sebaceous glands are large. The axilla is notable because it has apocrine glands in addition to the eccrine sweat glands that are found throughout the body.
The epidermis can regenerate from a heterogeneous collection of keratinocyte stem cells that are located in small clusters in the basal interfollicular epidermis and, in particular, in the bulge region and other parts of hair follicles. Although morphologically similar to other keratinocytes, stem cells are associated with particular molecular profiles. Some keratinocyte stem cells undergo symmetrical cell division to create transient amplifying cells which can proliferate and divide a small number of times before undergoing terminal differentiation. Other keratinocyte stem cells can give rise directly to terminally differentiating cells (asymmetrical division). The key signals that influence symmetrical or asymmetrical division, the distinction between stemness and transient amplification, and the precise start/stop signals for self-renewal are not known, although Wnt and BMP (bone morphogenic protein) signalling are implicated. Stem cells in the bulge region have the capacity to migrate (e.g. to the base of the hair follicle in follicular regeneration), as well as to differentiate into diverse lineages (e.g. hair, sebaceous glands, or interfollicular epidermis). Mesenchymal stem cells may also reside within the dermis, although the precise function of such cells in skin homeostasis or during wound healing has not been well established. Likewise, the renewal of many skin cells, including keratinocytes, may be possible by cellular differentiation from other stem-cell sources such as bone marrow.
Functions of the skin
Skin provides a barrier against the external environment (Fig. 23.1.3). The cornified cell envelope and the stratum corneum restrict water loss from the skin, while keratinocyte-derived endogenous antibiotics (defensins and cathelicidins) provide an innate immune defence against bacteria, viruses, and fungi. The epidermis also contains a network of about 2 × 109 Langerhans’ cells, which serve as sentinel cells whose prime function is to survey the epidermal environment and initiate an immune response against microbial threats, although they may also contribute to immune tolerance in the skin. Within the dermis, there are approximately 20 × 109 T-lymphocytes, about twice the total number in peripheral blood. Melanin in keratinocytes also provides some protection against DNA damage from ultraviolet radiation.
An important function of skin is thermoregulation, and there is both a superficial and a deep vascular plexus; vasodilatation and vasoconstriction of these blood vessels helps regulate heat loss. Eccrine sweat glands, present in densities of 100 to 600/cm2, also play a role in heat control, and may produce approximately 1 litre of sweat per hour during moderate exercise. Secretions from apocrine sweat glands, which are mainly found in the axillae, contribute to body odour (pheromones). Skin lubrication and waterproofing is provided by sebum secreted from sebaceous glands—outpouchings of hair follicles.
Subcutaneous fat has an important role in cushioning trauma, as well as in providing insulation and a calorie reserve. Nails provide protection to the ends of the fingers and toes, and are important in pinching and prizing objects. Skin also has a key function in synthesizing various metabolic products, such as vitamin D.
Skin also contains motor and sensory nerves. The motor innervation of the skin is autonomic, and includes a cholinergic component to the eccrine sweat glands, and adrenergic components to both the eccrine and apocrine glands, to the smooth muscle and the arterioles, and to the arrector pili muscle (attached to hair follicles). The sensory nerve endings are of several kinds; some are free, some terminate in hair follicles, and others have expanded tips.
Failure of the skin
Loss of a functional epidermis has profound biological and clinical consequences involving the loss of water and electrolytes, cutaneous and systemic infection, and impaired thermoregulation. The clinical importance of an intact skin barrier has recently been highlighted by the discovery that a large number of people with atopic dermatitis (and atopic dermatitis associated with asthma) have loss-of-function mutations in filaggrin (see OMIM 135 940), an important component of the cornified cell envelope. Loss of filaggrin leads to a defective skin barrier with increased transepidermal water loss (leading to skin dryness and itching) and an increased susceptibility to allergic sensitization and infection. Loss-of-function mutations in filaggrin, which may occur in up to 10% of the population, are also a major risk factor for systemic allergies and for nut allergy, emphasizing the importance of the skin as a portal for allergen presentation.
As far as acquired epidermal failure is concerned, burns, trauma, and adverse drug reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis (TEN, Lyell’s syndrome) can all lead to significant skin detachment and major metabolic imbalances. Stevens–Johnson syndrome can be considered a minor form of TEN, and involves less than 10% of body surface area skin detachment, with an average reported mortality of 1 to 5%, whereas TEN is characterized by more than 30% skin detachment, and an average reported mortality of 25 to 35%. Both conditions are characterized histologically by a rapid onset of keratinocyte cell death by apoptosis, a process that results in the separation of the epidermis from the dermis. Recent evidence supports a role for inflammatory cytokines and the death receptor Fas (TNF receptor superfamily, member 6) and its ligand in the pathogenesis of keratinocyte apoptosis during TEN. Fas-mediated keratinocyte apoptosis can be inhibited in vitro by antagonistic monoclonal antibodies to Fas, and by intravenous immunoglobulins, which have been shown to contain natural anti-Fas antibodies. Other explanations of the pathophysiology of TEN involve the drug interacting with major histocompatibility complex class I-expressing cells to generate drug-specific CD8+ cytotoxic T cells, which accumulate locally and release granzymes and perforin to kill keratinocytes. CD8+ T cells, natural killer (NK) cells and NKT cells may also release granulysin, leading to keratinocyte death without the need for direct cell contact. Early recognition of TEN leading to skin failure is, however, vital for optimal patient management.
In normal skin ageing, and in photoageing (skin changes resulting from chronic sun exposure), there is reduced synthesis of interstitial collagens (type I and III), and increased synthesis of enzymes (matrix metalloproteinases) that break down dermal fibres. Paradoxically, there is an increase in elastin synthesis, although this functions poorly and contributes to the wrinkled, sagging appearance of aged skin.
More specific insight into the consequences of the failure of particular dermal components, however, has recently been determined from the molecular characterization of genetic disorders such as Ehlers–Danlos syndrome (EDS) and cutis laxa. EDS represents a collection of six major disease subtypes associated with varying degrees of hyperextensible fragile skin and loose joints. There are several rarer variants of EDS, with pathogenic mutations reported in at least 13 different genes. Some subtypes may also be associated with catastrophic rupture of arterial blood vessels, the bowel, or the uterus. Although the cause of the major forms of EDS is unknown, in some forms of EDS abnormalities have been detected in type V collagen (OMIM 120 190) and tenascin X (a molecular organizer of connective tissue; OMIM 600 985), and in the vascular type of EDS, in type III collagen (OMIM 120 180). Further pathology has also been demonstrated in type I procollagen (OMIM 120 160) and in two enzymes, lysyl hydroxylase (EC 22.214.171.124; OMIM 153 454) and procollagen N-endopeptidase (EC 126.96.36.199; OMIM 604 539), involved in the formation of collagen fibres.
Cutis laxa is clinically characterized by loose, sagging skin and, in some subtypes, by extracutaneous abnormalities such as emphysema, and inguinal or umbilical hernias. Mutations in the gene encoding fibulin 5 (OMIM 604 580), a protein involved in elastin fibrillogenesis, have been shown to underlie some, but not all cases of this disease. Collectively, these rare genetic diseases highlight the significant clinical consequences of the failure of specific components of the dermis, and provide evidence for their important roles in the maintenance of normal, healthy skin.
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