Anatomy and Physiology

Epidermis

Consistent with conventional introductory chapters on cutaneous structure and function, we begin with a schematic representation of a section through normal skin ( Fig. 1.1 ). The anatomic structures observed by light microscopy are fairly similar in most regions of the body ( Fig. 1.2 ). However, specialized regions of skin, including the palms, soles, genitalia and scalp, have modified forms that address regional functional requirements ( Fig. 1.3 ).

As seen in Fig. 1.2 , the outer layer of skin (epidermis) consists of a thin matrix of cells. In humans, the epidermis contains four major resident populations: keratinocytes ( Ch. 56 ), melanocytes ( Ch. 65 ), Langerhans cells ( Ch. 4 ), and Merkel cells ( Chs 2 & 115 ) . Keratinocytes , the major population, originate in a stem-cell pool situated in the basal layer; cells that leave this pool then undergo maturation as they migrate upward, ultimately forming the laminated stratum corneum ( Fig. 1.4 ). The human epidermis averages 50 microns in thickness, with a surface density of approximately 50 000 nucleated cells/mm ² . Under basal conditions, differentiated keratinocytes require about two weeks to exit the nucleated compartment and an additional two weeks to move through the stratum corneum . It should be noted that keratinocytes have the capacity to increase rates of proliferation and maturation to levels far greater than this, when stimulated to do so by injury, inflammation or disease ( Ch. 8 ).

Melanocytes , as noted in a DOPA-stained whole mount of epidermis (see Fig. 65.6 ), have the capacity to elaborate the light-absorbing pigment melanin, which plays a major role in protecting the skin from UV radiation ( Ch. 86 ). Melanosomes, with their complement of melanin, are produced by melanocytes and then transferred by excretion and phagocytosis into nearby keratinocytes, where they assume their preferred location above the nucleus (see Fig. 65.5 ) .

Members of the third major resident epidermal population, Langerhans cells , have the capacity to metabolize complex antigenic materials into peptides, some of which are immunogenic (see Fig. 4.4 ). After activation, these cells traffic out of the epidermis toward regional lymph nodes, where they play a critical role in antigen presentation during the induction and regulation of immunity (see Fig. 4.14 ).

Merkel cells , which contain neuroendocrine peptides within intracytoplasmic granules, are also found in the basal layer of the epidermis, although they may not be apparent in routine histologic sections. Over the past decade, there have been advances regarding their origin and pathology ( Chs 2 & 115 ) .

The most obvious function of epidermis lies in the stratum corneum (see Fig. 1.4 ), the semipermeable laminated surface aggregate of differentiated (keratinized) squamous epithelial cells, which serve as a physiologic barrier to chemical penetration and microbiologic invasion from the environment, as well as a barrier to fluid and solute loss from within ( Ch. 124 ).

Dermis

Beneath the epidermis, a vascularized dermis provides structural and nutritional support. It is composed of a glycosaminoglycan gel held together by a collagen- and elastin-containing fibrous matrix ( Fig. 1.5 ) ( Ch. 95 ). Vascular structures, accompanied by nerves and mast cells ( Ch. 118 ), course through the dermis to provide nutrition, recirculating cells, and cutaneous sensation. Three additional cells, fibroblasts, macrophages and dermal dendritic cells, complete the list of dermal residents. In pathologic conditions such as acute inflammation, the functions and types of dermal cells change substantially, with a variety of infiltrating leukocytes arriving via vascular routes. In fact, the composition of cutaneous infiltrates differs depending on the disease entity, which provides students of dermatopathology useful diagnostic clues ( Fig. 1.6 ).

Dermal–epidermal interface

The boundary between epidermis and dermis consists of a specialized aggregation of attachment molecules, collectively known as the basement membrane ( Ch. 28 ). This structure is of considerable interest, because a variety of diseases originate from genetic defects in its composition; it also may serve as a target of autoimmune attack.

The requirements of skin are identified in its failings

So, what are the requirements of skin in order to protect and replicate DNA? In fact, these requirements have not been identified through logical considerations; rather, as noted above, they have been identified through the various failures that eventuate in skin disease. For this reason, we begin our survey with a listing of failures of skin ( Table 1.1 ).

Failure of immunity: infection

The diagnosis and treatment of infection constitutes a substantial portion of dermatology ( Chapter 74, Chapter 75, Chapter 76, Chapter 77, Chapter 78, Chapter 79, Chapter 80, Chapter 81, Chapter 82, Chapter 83 ). Examples of chronic and recurrent infectious skin diseases illustrate the extent to which mechanisms of resistance to infection are lost or defective in some patients. In examples that follow, initial resistance depends upon the structural integrity of the stratum corneum.

Warts

Trauma to the stratum corneum interrupts a physical barrier that is ordinarily not susceptible to viral infection ( Ch. 79 ). In addition, trauma allows implantation of infectious particles among the underlying keratinocytes, which are viable and less resistant. Following this structural failure, immunologic recognition of infected keratinocytes is ordinarily followed by a cytotoxic cellular response, destruction, and cure. When this fails, chronic infection may ensue ( Fig. 1.7 ). It is of interest that many therapies for warts, other than physical destruction, rely on modulating the immune response. On the other hand, few problems are more vexing than chronic and recurrent warts, particularly in patients who are immunosuppressed. Especially important are the viral serotypes associated with SCC and the genetic disorder epidermodysplasia verruciformis ( Ch. 79 ). It is instructive that protective immunity against warts often appears to be balanced precariously, so that minor shifts in responsiveness may lead to their elimination in many sites simultaneously. This has been attempted therapeutically by the use of oral cimetidine, topical applications of imiquimod, elicitation of contact sensitivity reactions, and intralesional injection of recall antigens such as Candida or mumps .

Opportunistic infections in the setting of human immunodeficiency virus infection

An enormous body of biomedical knowledge has accrued during the 35-year epidemic of HIV infection ( Ch. 78 ). As a beginning, it appears that HIV penetrates through small tears in genital and rectal mucosae. Once infection has occurred, the virus has been impossible to completely delete, despite a panoply of relatively effective therapies. With loss of immunologic integrity, patients develop AIDS and thereby demonstrate the relevance of effective cellular immunity to protection against infections with a wide variety of agents, including Mycobacterium tuberculosis, Pneumocystis jirovecii , varicella–zoster ( Fig. 1.8 ), and herpes simplex viruses. What more evidence would one want to demonstrate the relevance of cellular immune protection of skin than the diseases that are described in Chapter 78 ?

Faulty immunity: autoimmunity

We have made a case for the concept that the primary task of immunity is to recognize and destroy infectious organisms. Having stated this, autoimmunity may then be modeled as a failure in distinguishing “self” from infection, i.e. autoimmunity is a misidentification and destruction of portions of the host, as if it were dangerous or “foreign”. Autoimmune diseases are legion, with components of the epidermal basement membrane and desmosomes serving as important targets ( Fig. 1.9 ). Moreover, cutaneous cellular elements serve as both regulators and targets of autoimmune injury. Table 1.2 lists several common autoimmune diseases that affect the skin, each with a different target. These diseases have different sets of genetic factors and environmental insults that promote their development. Subsequent chapters detail their relevant elements.

We know a substantial amount about molecular targets in these diseases, and we also know much about how immunity works in protecting against infectious diseases. However, we continue to learn about skin structure by observing disease states in which errors in recognition lead to immune responses that target “self” antigens inappropriately and damage residential structures. For example, in pemphigus vulgaris, autoantibodies directed against desmogleins compromise intercellular adhesion, leading to intraepithelial acantholysis and widespread erosions (see Fig. 1.9 ). It has also become apparent that autoimmunity directed against cutaneous antigens may impact other organ systems. For example, in patients with bullous pemphigoid and concomitant neurologic disease, circulating anti-basement membrane antibodies were found to recognize antigens in both the skin and brain .

Failure of immunity: cancer

Data to support the concept that immune responses also protect against malignancy are strongest for those malignancies that arise in skin and lymphatic tissues , especially cutaneous SCC, Merkel cell carcinoma, and melanoma. Cutaneous SCC is a well-known and relatively common complication of immunosuppression in solid organ transplant recipients . Many recent developments in melanoma therapy are based on attempts to enhance immune responsiveness ( Ch. 113 ).