OVERVIEW OF BASIC SCIENCE SECTION 1

Anatomy and Physiology
Travis W Vandergriff and Paul R Bergstresser
1 
similar in most regions of the body (Fig. 1.1). However, specialized
Key features regions of skin, including the palms (Fig. 1.2), soles, genitalia and scalp,
 The function and structure of skin is not demonstrated best by have modified forms of these structures.
diagrams and figures, but rather by presenting the diseases that As seen in Figures 1.1 and 1.2, the outer layer of skin (epidermis)
illustrate how skin can fail. Thus, function is revealed by disease, consists of a thin matrix of cells. In humans, the epidermis contains
and disease illustrates structure three major resident populations of cells1: keratinocytes (Ch. 56),
 The primary function of skin is to maintain an internal melanocytes (Ch. 65) and Langerhans cells (Chs 4 & 14). In conven-
environment that allows an organism to protect its DNA and to tional H&E-stained sections, these cells are nearly indistinguishable,
reproduce it faithfully but substantial differences become apparent when specialized immu-
nohistochemical techniques are employed. Keratinocytes, the major
 Cutaneous structures include an epidermis that serves as a barrier population, originate in bottom-most stem-cell pools; cells that leave
(e.g. to prevent fluid loss and infection) and a dermis that provides this pool then undergo maturation as they move toward the stratum
circulation and nutrition. Other functions provided by the cells corneum (Ch. 56). The human epidermis averages 50 microns in thick-
that reside in the skin include immune recognition, a capacity to ness, with a surface density of approximately 50 000 nucleated cells/
repair damage, thermoregulation and communication mm2[2]. Under basal conditions, differentiated keratinocytes require
 Evidence that skin has failed may be found in barrier disruption, about 2 weeks to exit the nucleated compartment and an additional 2
infection, autoimmunity, cancer and an undesirable appearance weeks to move through the stratum corneum3. 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
(Fig. 1.3), have the capacity to elaborate the light-absorbing pigment
melanin, which plays a major role in protecting the skin from UV
INTRODUCTION radiation (Ch. 65). Melanosomes, with their complement of melanin,
are produced by melanocytes and then transferred by excretion and
Most reviews of the anatomy and physiology of skin begin with detailed phagocytosis into nearby keratinocytes, where they assume their pre-
descriptions of cellular composition, structural proteins, and extrafibril- ferred location above the nucleus. Members of the third major resident
lar matrix (“ground substance”). Because each of these subjects, with epidermal population, Langerhans cells, have the capacity to metabolize
relevant documentation, is presented in subsequent sections of this complex antigenic materials into peptides, some of which are immu-
textbook, such aspects of cutaneous function will be introduced only nogenic (Fig. 1.4). After activation, these cells traffic out of the epider-
briefly, using references to appropriate chapters. Following this, the mis toward regional lymph nodes, where they play a critical role in
conventional approach is reversed by examining diseases that illustrate antigen presentation during the induction of immunity (Chs 4 & 14).
cutaneous function in the context of the cells and structures that Merkel cells, which contain neuroendocrine peptides within intracyto-
sustain it. This method is derived from the assertion that the structure plasmic granules, are also found in the basal layer of the epidermis.
and function of skin is revealed best through disease. The validity of The most obvious function of epidermis lies in the stratum corneum,
this alternative methodology may be seen in five short clinical vignettes a semipermeable laminated surface aggregate of differentiated (keratin­
easily recognized by those who care for patients with skin disease: ized) squamous epithelial cells, which serve as a physiologic barrier to
● an albino Native American from Panama develops numerous chemical penetration and microbiologic invasion from the environ-
squamous cell carcinomas at an early age ment, as well as a barrier to fluid and solute loss from within4 (Ch.
● a 15-year-old boy with hypohidrotic ectodermal dysplasia suffers 124).
heat stroke while competing in outdoor athletics in Texas
● toxic epidermal necrolysis leading to dehydration and sepsis
develops in a 40-year-old woman treated with phenytoin Dermis
● painful leg ulcerations incapacitate a 60-year-old woman with Beneath the epidermis, a vascularized dermis provides structural and
rheumatoid arthritis nutritional support. It is composed of a mucopolysaccharide gel held
● widespread herpes simplex virus infection occurs in a young man together by a collagen- and elastin-containing fibrous matrix (Ch. 95).
who has atopic dermatitis unrecognized by his primary care Vascular structures, accompanied by nerves and mast cells (Ch. 118),
physician. course through the dermis to provide nutrition, recirculating cells, and
These patients and their diseases illustrate at least five of the functions cutaneous sensation. Three additional cells, fibroblasts, macrophages
of skin: photoprotection, thermoregulation, barrier formation, cutane- and dermal dendritic cells, complete the list of dermal residents. In
ous circulation, and immunologic protection. Each function is sup- pathologic conditions such as acute inflammation, the functions and
ported by the cells and structural elements that reside there. 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
STRUCTURE AND FUNCTION provides students of dermatopathology useful diagnostic clues.

Conventional Concepts of the Structure of Skin Dermal–epidermal interface
The boundary between epidermis and dermis consists of a specialized
Epidermis aggregation of attachment molecules, collectively known as the base-
Consistent with conventional introductory chapters on cutaneous ment membrane5 (Ch. 28). This structure is of considerable interest,
structure and function, we begin with a histologic section through because a variety of diseases originate from genetic defects in its com- 43
normal skin. The anatomic structures observed by light microscopy are position; it also may serve as a target of autoimmune attack.

1  Normal skin: trunk. stratum spinosum and stratum basale.3  Normal melanocyte. The compact and thick stratum corneum is typical of skin on the palms and soles. First. An adjacent hair shaft passes through the specimen. dermatologists have an example. 1. thought to explain the death of male fetuses in utero. even in the absence of obvious infection. Note that the epidermis is thicker than that seen in Figure 1.4  Epon-embedded section of human epidermis. we believe that it is “barriers”. 1. possible and even likely that two or more disease processes and/or susceptibilities underlie an illness and that such simultaneous occur- rences may alter the clinical presentation. This framework is derived from the assertion that knowledge modulate the course of otherwise conventional skin diseases. stratum granulosum. Overwhelming apoptosis is neous disease. infectious and lethal in males had it not been for the survival of heterozygous females environmental factors that modify the appearance and severity of cuta- with this X chromosome-linked disease6. One corollary of this asser. In 44 deviate from the concept that physicians should invariably attempt to mammals. and more loosely arranged collagen is found deeper in the dermis. A cluster of small blood vessels and nerves is seen in the dermis. 1. Note epidermal layers from the surface: stratum corneum. these membranes. occur primarily in three organs: the lung. Lorenzo Cerroni.1. Melanocytes contain long dendritic processes that deliver protective melanosomes to nearby keratinocytes. either because giosum in patients with immunodeficiency from occult HIV infection there is no corresponding disease or because the disease is fatal. which may be described functionally as develop a single diagnosis for an illness. MD. For or from iatrogenic immuno­suppression. 1. Fig. Witness of cutaneous function begins with disease. Fig. no one would have guessed that incontinentia pigmenti was extra assignment: to find otherwise hidden genetic. which typifies melanocytes. the presence of numerous viral warts or tumors of molluscum conta- tion is that there may be unrecognized functions of skin. Note that the surrounding Overview of Basic Science keratinocytes are virtually invisible. Tightly packed dermal collagen is seen near the epidermal–dermal junction. Courtesy. which resides above the basal cell layer of the epidermis. A whole mount of epidermis has been stained for the SECTION presence of the enzyme 1 tyrosinase. gastrointestinal . Fig. In fact.7. Rather. practicing dermatolo- gists are quite aware of the unusual morphologic features of pityriasis Knowledge of the Function and Structure of Skin rosea when it occurs in a patient with underlying psoriasis or when a Begins with Skin Disease patient with atopic dermatitis improves substantially following treat- We have chosen to present in the remainder of this chapter a conceptual ment with an antibiotic. we internal space and at the same time protect against external insults. Note the pale cytoplasm and extended dendritic process of a central Langerhans cell (arrow). Fig. Thus. All plants and animals possess limiting membranes that define an Two other prejudices color the picture we choose to paint. A framework into which the other chapters of this textbook may be growing array of genetic factors and infectious agents are known to placed.2  Normal skin: palm.

which are viable and less resistant. (Langerhans cells) or dermis (dermal dendritic cells) are activated. This concept of the centrality of DNA has been devel- oped by Reg Morrison in his monograph The Spirit in the Gene: Humanity’s Proud Illusion and the Laws of Nature. Prevent infection via innate and Fungal. they have been identified humans can affect virtually any cutaneous surface. Although similar in concept. Preventing Infection: Skin as an Immunologic Organ infectious skin diseases illustrate the extent to which mechanisms of resistance to infection are lost or defective in some patients. balanced precariously. topical applica- The diagnosis and treatment of infection constitutes a substantial tions of imiquimod. Regulate temperature Hypothermia. capacity to travel to a distant location where reactive lymphocytes are rely on modulating the immune response. It is of innate and adaptive immunity. pruritus as a useful portal of entry for pharmaceutical agents. seen in this photograph. dehydration 1  or. 124). allowing these cells to travel ordinarily followed by a cytotoxic cellular response. the barrier prop- erties of these organs are fundamentally different. including the skin. motility is induced. there is no obvious benefit to skin penetration. adaptive immunity Maintain a barrier autoimmunity. For a further discussion genetic disorder epidermodysplasia verruciformis13 (Ch. The integrity of the stratum corneum. Morrison makes the striking observation that human DNA has in the last 300 years come to dominate all life on the earth. what are the requirements of skin for the protection and duplication of DNA? In fact. destruction and out of their cutaneous residence. of Skin Although we begin with the common rhetorical question: “What are the functions of skin?”. as skin has become a target of novel therapies based vasculitis. which may include genetically pro- grammed changes in the skin. A second and highly related process in a changing world is the generation of useful changes in DNA that accommodate new environmental circumstances. initial resistance depends upon the structural tive. 4). bacterial and viral infections. In addition. hyperthermia Attract attention Photoaging. other than physical destruction. cutaneous barrier. 1. is also essential for biologic success. Although the permanent repository of DNA lies in the gonads. by virtue of their internal location. while helper T lymphocytes and cytotoxic T lymphocytes begin the viral serotypes associated with squamous cell carcinoma and the to recirculate preferentially to and from skin. these residents of normal skin have the interest that many therapies for warts.5  Verrucae vulgaris (warts). the reference by Janeway is highly instructive that protective immunity against warts often appears to be useful12.5). Examples of chronic and recurrent intralesional injection of recall antigens such as Candida or mumps14. and with the possible exception of UV radiation-facilitated vitamin D3 production8. When this fails. leg ulcers be noted. we begin our survey with a listing of failures of skin (Table 1. and. We propose that the primary function of skin is to maintain an internal environment that allows an organism to protect DNA and to reproduce it faithfully. move cure. or other forms of occlusion) upon percutaneous penetration9 (Chs 124–129).15. Ultimately. example that follows. Thus. however. and at the same time they Requirement Selected failings CHAPTER promote rather than retard the transfer of gases. Prior trauma allows implantation of infectious particles among the underly- to activation. Human papillomavirus infections in logical considerations. Following this sizes and to metabolize complex proteins into small immunogenic frag. vitiligo. Courtesy. it is followed by a second and perhaps more complicated question: “What are the requirements of skin that allow it to serve those functions?”. It is of to regional lymph nodes. preservation and reproduction of DNA sustains the species. 79). immunologic recognition of infected keratinocytes is ments. larly in patients who are immunosuppressed. In each An intricate system of immunologic recognition. By contrast. It should Repair injury Cancer. the protection of DNA in all sites. Within a lymph node. structural failure. which reviews how life-form competition may be modeled as a method of protecting DNA11. at least. are both common and difficult to treat. Jr. SELECTED REQUIREMENTS AND FAILINGS OF SKIN trointestinal barriers. particu- activated helper T lymphocytes assist B lymphocytes to generate anti. so that minor shifts in responsiveness may lead to their elimination in many sites simultaneously. 1. primarily peptides derived from infectious agents. via draining lymphatics. alopecia The Central Role of Protecting DNA as a Function Table 1. Trauma to the stratum corneum interrupts a physical barrier that is Initial recognition occurs when sentinel dendritic cells in the epidermis ordinarily not susceptible to viral infection (Ch. On the other hand. few selected and then expanded greatly in number. there are as yet no recognized diseases attributed to the Anatomy and Physiology failure of any material or form of energy to penetrate the skin. rather. both innate and adap. Pulmonary and gas. . and 45 portion of dermatology (Chs 74–83). 79).1). all biologic activities serve these functions. plans are under- Provide nutrition Vitamin D deficiency way for skin to serve as a site for immunization with gene-based materi- als and as a gene-driven cutaneous factory10. these requirements have not been identified through Fig. nutrients and wastes. as through the various failures that result in skin disease. Once activated. are protected from many environmental influences. This has been Failure of immunity: infection attempted therapeutically by the use of oral cimetidine. as noted above. these cells acquire the capacity to engulf particles of many ing keratinocytes. The requirements of skin are identified in its failings So. In short. chronic infection may ensue (Fig. cancer Infection. that biomedical scientists now try to subvert the Provide circulation Infarction (due to embolization. problems are more vexing than chronic and recurrent warts. MD. Especially important are bodies. For this reason.1  Selected requirements and failings of skin. Louis A Fragola. In addition to serving Communicate Sensory neuropathy. This results in evolution of the species. Periungual infections. protects skin (and underlying tissues) from infection12 (Ch. elicitation of contact sensitivity reactions.tract and skin (Ch. cornerstone of adaptive immunity lies in recirculating lymphocytes and antibodies that are specifically recruited and “tuned” to recognize Warts “foreign” materials.

7). patients develop AIDS and thereby dem- Overview of Basic Science several individuals are chronically infected. What more evidence would one want ment may lose that resistance as the ambient humidity increases or to demonstrate the relevance of cellular immune protection of skin when occlusive military shoes are worn17. Hansen’s disease also illustrates the relevance of cutaneous sensation to protection against traumatic injury. whereas other family onstrate the relevance of effective cellular immunity to protection members. 1.6  Dermatophytosis.8  Herpes zoster. despite a panoply of relatively effective therapies. opportunistic infections in the setting of HIV infection. Warts. inasmuch as one or more serum factors (e. develop an effective immune response that is seemingly curative (Ch. 1. Courtesy. and Hansen’s disease all illustrate important aspects of Fig. 1. Obviously.9  Tzanck smear from a patient with herpes zoster. the virus has been impossible to delete. experience from tropical climates indi. On the other hand.g. Hansen’s disease is instructive in that the majority of humans exposed to its causative organism. with each patient’s clinical response falling along a spectrum from tuberculoid to lepromatous18. Perhaps this is An enormous body of biomedical knowledge has accrued during the because dermatophyte infections are almost invariably limited to the 30-year epidemic of HIV infection (Ch. dermatophytosis. Courtesy. 78). On the other hand. based on immuno- logic resistance. PAS staining for neutral mucopolysaccharides reveals branching red–purple fungal hyphae within the stratum corneum in a patient with tinea corporis. 46 Fig. . 77). immune responsiveness and environmental Hansen’s disease (leprosy) circumstances. Louis A Fragola.9) and herpes simplex viruses. a small percentage of exposed individuals develop chronic infection that may take any one of several forms.6 & 1. observations made in patients with Hansen’s disease have been important in formulating the Th1/Th2 paradigm (Ch. 75). Dermatophytosis Opportunistic infections in the setting of human The diagnosis and treatment of infections with dermatophytes remain immunodeficiency virus infection largely the responsibility of dermatologists (Ch. Pneumocystis jiroveci. Mycobacterium leprae. hair and nails. are seemingly never against infections with a wide variety of agents. Jr. Note the associated edema of the eyelid and lip. 1. that HIV penetrates through small tears in genital and rectal mucosae. As yet unidentified genetic factors protect some individuals from Once infection has occurred. MD. If diastase enzyme is not added.8 & cates that individuals who are relatively resistant in a dry environ. rium tuberculosis.7  Dermatophytosis. 4). In fact. Unilateral grouped vesicles and serous crusts on an erythematous background. in the face of obvious exposure. With the eventual infection. it appears SECTION skin. 1 transferrin) may prevent growth where serum can reach16 (Figs 1. Lorenzo Cerroni. This annular presentation of tinea corporis typifies cutaneous dermatophyte infections. as will be presented later. varicella zoster (Figs 1. As a beginning. because it is not uncommon to encounter families in which loss of immunologic integrity. Fig. glycogen within keratinocytes also stains with PAS. Note the multinucleated giant cell. dermatophyte than the diseases that are described in Chapter 78? infection and resistance include a complicated interplay among genetic susceptibilities. Fig. 1. MD. Importantly. including Mycobacte- infected.

For all immunity. we are only now learning about how errors in recognition lead to immune responses that target self antigens inappropriately and damage indigenous structures. Fig. stratum corneum is defective in disorders of keratinization24.11). 47 . but UV radiation. autoimmunity is a misidentification and destruc. 1. i. By contrast. and we also know much about how immunity works in pro. stratum corneum and photon absorption by underlying melanin. In an attempt to treat and to prevent such infec- diseases have different sets of genetic factors and environmental insults tions.10  Pemphigus vulgaris (immuno­ fluorescence).cutaneous function. An instructive set of circumstances arose with the targets of autoimmune injury. has distinct isoforms in the skin and in the central nervous system. cutaneous cellular elements serve as both regulators and follicularis)25.21.10). without DISEASES WITH UNKNOWN OR MULTIPLE AUTOANTIGENS inflammation (Fig. 1. Having stated this. ranging from a structural barrier provided by the from within the body and. 113). Bullous pemphigoid antigen 1. electrolytes and other molecules Psoriasis Unknown 8 Table 1. 30 BPAG1* lymphatic tissues20. DISEASES WITH IDENTIFIED AUTOANTIGENS Pemphigus foliaceus Desmoglein 1 29 Failure of immunity: cancer Pemphigus vulgaris (Fig. including photon scattering in the CHAPTER We have made a case for the concept that the primary task of immunity is to recognize and destroy infectious organisms. Lorenzo Cerroni MD. Subacute cutaneous lupus Unknown 41 erythematosus Maintaining a Barrier: Skin as a Protective Organ Chronic cutaneous lupus Unknown 41 erythematosus From the outset. we include a photomicrograph of a thick melanoma.23 (Ch. reveals the in vivo This thick melanoma has deposition of antibodies virtually no associated to desmoglein 3. protection against UV radiation occurs through Faulty immunity: autoimmunity several independent phenomena. toxic materials and UV radiation22. bacterial carriage and.2  Common autoimmune skin diseases. and Target antigen Chapter patients with bullous pemphigoid have a higher incidence of dementia. epidermolytic hyperkeratosis (Fig. decades the prophylactic use of topical antibacterial agents to decrease evant elements. Autoim.e. 1  Failure of protection against toxic chemicals Anatomy and Physiology autoimmunity may then be modeled as a failure in distinguishing “self” from infection. 86).11  Melanoma. at the same time. Parkinson’s disease and multiple sclerosis19.26. 1. the stratum corneum is the central element in that function. We know a substantial amount about molecular targets in these In an article published in 1960. However. Addition. as if it were dangerous or “foreign”. for example. dermatologists and other physicians have recommended for that promote their development. 1. at the same time. Intercellular staining of epidermal keratinocytes Fig. Table 1. *Neural isoforms are referred to as dystonin. prevents penetration by stratum corneum to immunologic recognition and protective microorganisms. Cutaneous SCC is a well-known complication Epidermolysis bullosa acquisita Collagen VII 30 of immunosuppression in solid organ transplant recipients.10) Desmoglein 3 and 1 29 Data to support the concept that immune responses also protect against malignancy is strongest for those malignancies that arise in skin and Bullous pemphigoid Collagen XVII (BPAG2). Many developments in melanoma therapy are based on attempts to enhance immune responsiveness (Ch. the most obvious function of skin is to maintain a barrier that prevents the loss of fluids. the associated odor. It has also become apparent that autoimmunity to skin antigens may impact COMMON AUTOIMMUNE SKIN DISEASES other organ systems. problem that patients with these diseases commonly have recurrent mune diseases that affect the skin. The thickness and lack of a host response indicate a poor prognosis for the patient. The analysis of barrier failure begins with the observation that the tion of portions of the host. each with a different target. Dermatitis herpetiformis Transglutaminase-3 31 ally. an extraordinarily high frequency of neuropsychiatric disorders in tecting against infectious diseases.12) and Darier disease (keratosis Moreover. Subsequent chapters detail their rel. Two diseases typify this defect: membrane and desmosomes serving as important targets (Fig. 1. especially cutaneous melanoma and squamous cell carcinoma (SCC). Courtesy. These bacterial infections. 1. with components of the epidermal basement less resistant to chemical penetration. as it is mune diseases are legion. inflammatory cells histologically.2 lists several common autoim. Medansky and Woloshin27 described diseases.

the point of this Injury also occurs when there is interruption of the underlying vascular discussion is that the complications that accompany loss of the epider. be imagined that would link keratin function with CNS function. 20). Courtesy. patients with keratosis follicularis. In this drug-induced disease. it becomes apparent that melanin is located predominantly in Fig. Jean L Bolognia. however. Despite intensive treatment with similar esses that eliminate foreign objects and cover defects. 132). 1. even though no mechanism could preparations that include UV-absorbing or UV-blocking molecules. long intense exposure to sunlight. Since that time. from apoptosis signaling pathway (e. by administration of intravenous fire. immunoglobulin) may improve survival. there is a parallel high Failure to protect against dehydration and infection: frequency of skin cancer. rapidly progressive keratinocyte death leads to detachment of the epi. 87) are known complications for The most dramatic form of epidermal failure occurs in patients with these patients. there is no debate about the seen unequivocally in patients who have type 1 OCA due to an absence more recently reported enhanced absorption of topical tacrolimus in or reduction in tyrosinase activity and. (Fig. photosensitivity dis- toxic epidermal necrolysis eases and premature photoaging (Ch. There is a complete loss of barrier Mechanisms function (Figs 1. Courtesy. Our tional mechanisms are the scavenging of reactive oxygen species by antioxidants and repair of damage with DNA repair enzymes. MD. conclusion is that hexachlorophene penetrates a defective barrier in The importance of cutaneous pigment in protecting the skin against Overview of Basic Science toxic amounts. However. Full-thickness epidermal cell death leads to stripping off of the epidermis. supply. A special type of injury is caused by the penetration of UV death is not uncommon. The impact of melanin in limiting UV penetration may be to neuropsychiatric findings29. radiation. and this barrier is defective in diseases of extraordinarily high frequency of type 1 OCA and little relief from year- keratinization. toxic epidermal necrolysis (TEN. 124). In contrast. Full-thickness epidermal cell death. Fig. complications are common and can include enormous fluid and electrolyte losses leading to dehy- dration as well as infections with bacteria and yeast. in whom there is an corneum (Ch. breaks from blunt and sharp objects that are repaired almost without It has a mortality rate that depends upon the area of skin involved. Several to reflect and scatter photons. including many small fonamides. e. that heats the skin excessively (see below.12  Epidermolytic hyperkeratosis. Each episode of injury is followed by a sequence of repair proc- mis reveal all of its functions. an alternative explanation proposed by others UV damage is demonstrated in patients with oculocutaneous albinism is that dysfunction of SERCA2 within the brain may potentially lead (OCA)31. Due to its optical characteristics. with secondary bulla formation. ranging from acute toxicity and immunosuppression to carcinogenesis and prema- ture aging (Chs 86. melanin production patients with Netherton syndrome. However. Failure to protect against UV radiation: albinism UV radiation induces a myriad of changes in the skin. there is evidence that drug-induced triggering of massive immune suppression. Lorenzo Cerroni. This “wound techniques as those employed for burns. . hexachlorophene had been recommended as a damage. Marked compact orthokeratosis the epidermis. the stratum corneum tends useful antibacterial agent soon after its introduction in 1944. Ch. there have been fewer reports of neuropsychiatric findings in keratosis follicularis.13 & 1. In this African patient. the barrier for chemical penetration is invested in the stratum Cuna Indians. there is an apparent contradiction in the recommendations of dermatologists: effective ther- apies for a number of skin diseases are based on the use of UV radiation of various wavelengths (Ch. Thermoregulation). Maintaining the Integrity of Skin: Repair dermis over large areas of the body.14  Toxic epidermal necrolysis. anticonvulsants and nonsteroidal anti-inflammatory drugs. In the context of this high back- ground genetic frequency (approximately 1%). However. residents of islands near Panama. Physical injury occurs commonly in the skin. Striking amongst the evidence is the experience of the In sum.14). This includes a variety of effects that range from sunburn to However.g. 87. In addition to wearing clothing and using topical Fig. and inhibition of the injury occurs upon exposure to a hot object or radiant energy. with corneum are usually absorbed by molecules such as melanin. 1. 1. 48 overlies an epidermis showing granular and vacuolar change in its upper layers. There is as yet no specific treatment for TEN. but notice. 1. it was recognized that it was potentially neurotoxic. TEN is most often associated with sul. Likewise. and those that penetrate the stratum SECTION decades later. as a result. Thermal keratinocyte apoptosis may underlie the disease30.g. Addi- 1 use eventually curtailed in the 1970s28. 134). acute toxicity.15)31. accelerated aging and carcinogenesis. 107 & 108). In several characteristics of the skin itself limit UV radiation-induced retrospect. while protection from the sun’s rays is in general highly recommended to prevent adverse effects from UV radiation (Ch. MD.13  Toxic epidermal necrolysis.

Occlusion followed by cutaneous necrosis demonstrates in An important failure occurs when UV radiation-induced DNA damage vivid fashion the complete dependence of skin on arterial circulation. 141). and problem. The ulceration was preceded by coalescent purpuric papules with bulla formation and necrosis. first to draining lymph nodes and rant coagulation or cold-related “gelling” (Ch. macrophages and dendritic cells all have the cies.org) dermal vessels called lymphatic capillaries. in the elderly. and Failure to effectively repair injury arterio­venous anastomoses. The extent of necrosis depends on the size of the vessel to form hypertrophic scars and keloids. nose and ears. Fig. such as the volar surfaces of betes mellitus and aging. the survival of skin is highly dependent upon an intact circulation. via the thoracic duct. UV radiation matic skin disorders (Chs 24. and occlusion due to non-infectious cholesterol emboli is remains in its infancy. The critical element in terms of cutaneous structure is that. of blood. Thus. Only in recent years have these investigators begun to address the capacity to exit the skin via lymphatic drainage. and (2) anastomosing arteries Blockage of lymphatic drainage may also occur in certain inflammatory and veins that participate in heat regulation.woundheal. healing” response has been studied in considerable detail (Ch. the discipline of wound healing occluded. the emigration of cellular elements from the vascular space valvular incompetence contributes to the most common vascular occurs by a highly ordered sequence of signaling. Providing Circulation: Skin as a Nutritive Organ once again. They include inflammation is dangerous. the development of venous stasis ulcers of the legs (Ch. ble for a spectrum of cutaneous findings that vary depending upon the it is necessary for the skin is to protect itself against the detrimental size of vessel affected. The prototype for this deficiency is the disease xeroderma pigmentosum33. usually associated with generalized arteriosclerotic cardiovascular Xeroderma pigmentosum disease. Julie V Schaffer. Courtesy. 42 & 45). is an important part of dermatology and rehabilitation Cutaneous lymphatic drainage begins in microscopic blind-ended medicine (Ch. 1  Anatomy and Physiology Fig. which are large direct connections between Delayed wound healing arterial and venous plexuses. 1. The hematologic system includes two types of vessels: (1) nutritive Failure of circulation: lymphatic blockage vessels (arteries. industrial representation and governmental agen. The most reasonable explanation of pathogen- Embolic occlusion of arteries esis may be seen in studies showing that transforming growth factor β The most dramatic form of blood vessel occlusion occurs with emboli- (TGF-β) activity is excessively high in fibroblasts derived from keloids32. This is Despite preliminary evidence that TGF-β may play a role in the estab- followed rapidly by necrosis of all cutaneous structures distal to that lishment of an environment that favors overgrowth of dermal elements blockage. which can hold large coccal and staphylococcal infections may lead to scarring and loss of . which logic circulation. These collect both cells and is a consortium of clinical and basic science investigators that includes interstitial substances that are then directed toward regional lymph physicians. The inflammation associated with recurrent strepto. mediated blockage. associated with dermato. The high incidence of skin cancers Vasculitis of many types in these patients supports the assertion that UV radiation. The formation of hypertrophic scars and keloids may be seen as an exuberant response to injury. migratory processes that are described in Chapter 102. Stoitzner and col- issues of chronic cutaneous ulceration. The treatment of chronic leg ulcers. and thermoregulation. rheumatoid arthritis. attachment. 105). This can be precipi- then. into the central venous system. MD. Cutaneous inflammation centered in the blood vessel wall is responsi- induced injury is an important cause of skin cancer in humans. Lymphocytes. Although the movement of oxygen Venous insufficiency and solutes from blood into interstitial tissues occurs largely by passive Although listed last. leagues34 have provided an exquisite photographic description of Lang- erhans cells in their travels from epidermis to draining lymphatic Keloids vessels. erythematosus. It combines a unique mix of genetic and Failure of circulation: arteries and veins environmental factors. Vasculitis is commonly associated with rheu- effects of UV radiation.and polymyositis. 1. the delivery of leukocytes. Hemato. 1.16  Ulcers secondary to Henoch-Schönlein purpura. Patients with albinism are at CHAPTER substantially higher risk for UV radiation-induced carcinogenesis. capillaries and veins). scientists. lupus cancers arise much more quickly. and immune complex-mediated small vessel vasculitis (Fig. is not repaired effectively. These anastomoses are prominent in Delayed and incomplete wound healing have been associated with dia. and (2) a one-way lymphatic system that returns Other disorders characterized by vascular occlusion result from aber- leukocytes and interstitial fluids. 49 an extensive subcutaneous venous plexus. Note the normally pigmented fingers of the child’s mother. venous insufficiency through partial occlusion and diffusion.16). quantities of blood (to dissipate heat from the surface of the skin). especially the hands and feet. areas often exposed to maximal cooling. which can produce changes within hours. lips. The movement of cells and soluble elements to and from skin is medi- ated by two circulatory systems: (1) a two-way hematologic system that Occlusive vasculopathy conducts blood flow. tated by antibodies directed against regulators of coagulation.15  Albinism in an infant. because delays in wound healing are both incapacitating and expensive. 105). and second. The Wound Healing Society (www. serves three major functions: nutritional support. 41. when DNA repair mechanisms are defective. the most obvious because of the red and blue colors may develop in patients with rheumatic diseases. nodes. 23). This latter system includes skin conditions. This illustrates two points: first.

In a permanent edema may develop. example. Overview of Basic Science failure to immunize against antigens that penetrated skin affected in this way. A highly useful amounts of the biologically active cytokine interleukin-1 (IL-1)42.g. once hormones from adjacent cells (paracrine). Postherpetic neuralgia is similarly important38 (Ch. 159). In this location. vascular dilation and striae) result They envelop the pilosebaceous apparatus (Ch. in turn. a condition described as elephantiasis longstanding diabetes mellitus leads to unappreciated pressure ulcers in nostras verrucosa (Ch. mast cells produce tumor necrosis factor (TNF). at the same time. Vascular endothelial cells sensitivity produce IL-1β. The processes of activation. a loss of cutaneous sensory function in patients with change at the skin surface. touch and pain (Chs 5 & 6). which ous cells. sensitivity with the prospect of developing methods by which immunity may be The most obvious and devastating effects of altered touch and pain modulated. 12). ing’s disease (altered fat distribution. IL-8 and TGF- to a loss of facial lines for cosmetic purposes. but. injection of botulinum toxin dritic cells. which most certainly. although there is clear evidence that some small endings penetrate the Vitamin D3 (cholecalciferol) is produced in the epidermis by the action basement membrane and travel into the epidermis. which. wound healing45. larger fibers ACTH. Stemming from an improved understanding of cutaneous trauma. Although the head and distal extremities are innervated production of adrenocortical hormones causes excessive secretion of most densely. associated with widespread verrucous similar fashion. lymph nodes. With chronic infection. intercellular signaling mediated inflammatory skin disorders such as psoriasis (Ch. In both of these conditions. now being recognized. 68). uncontrolled itching. after activation. major developments in . leading fiers. Communication via hormones and cytokines Hormones Interfacing with External and Internal A relevant model for indirect hormonal influences on skin is adreno- corticotropic hormone (ACTH). although. blood vessels and from excessive secretion of corticosteroids. loss of sensation leads to unrecognized trauma to the skin. diminished sweat glands. In contrast. This. communication is as yet in its infancy. lymphatic drainage. On the other hand. therapeutic development has been the intradermal injection of botuli. Failure of cytokine and cellular communication 105). Likewise. mast cell func- and social activities. in the course of their normal function. there is no obvious structural defect in this exquisitely painful cells (endocrine) will occupy the attention of skin biologists and skin disorder. most nerve fibers appear to end in the dermis. and excessive sweating. leave the skin and traffic to regional now offers considerable potential for relief (Ch. had temporarily beneficial effects on nerve conduction via cutaneous fibers. several of the clinical signs of Cush- vascular structures. and they mediate the sensations of heat. depart from the commonly involves intertriginous areas as well as the palms and skin while in possession of information that ultimately has direct soles. We interplay between cytokines and cells is often reciprocal52. 8) and atopic der- by cytokines and hormones (endocrine. Defects in sensation and neurologic function occur commonly. which. they select and prime naive and resting T lymphocytes (Chs 4 & 14). 159). sensation may be found in patients with the peripheral neuropathies that accompany Hansen’s disease40 (Ch. a model for pathologic changes and the physical movement of “message-carrying” cells from one site induced by inappropriate secretion of hormones is seen in the effects to another. epinephrine or dopamine) in patients with vascular instability caused Skin is “wired” with afferent and efferent nerve fibers that accompany by pheochromocytomas. cold.43. Similar problems may occur in patients under the influence of Knowledge about the roles of cytokines and cell traffic in cutaneous narcotic anesthesia. and hormones from distant again. many years ago. paracrine and autocrine effects). and the Itch is a major problem for patients with skin disease (Chs 5 & 6). Likewise. injuries over months and years lead to a gradual loss of tissue. matitis (Ch. Cytokines and they may be seen in patients with chronic pain following varicella– In the last 30 years. outward Abnormality of neurologic communication: decreased migration. 83). a new field of cutaneous knowledge has evolved. This was followed in rapid succession by the recognition that cells num toxin to uncouple cholinergic nerve fibers. all skin contains nerves. For presume that modest levels of itching confer some beneficial effect. neurologic syndromes (e. and repopulation have been areas of intense investigation. Moreover. The roles and importance of these mechanisms have been of the catecholamine hormones and their precursors (norepinephrine. This technique has at within skin are able to produce an array of biological response modi- least two dermatologic applications: (1) to decrease muscle tone. where they have of UV radiation on 7-dehydrocholesterol8.53. meaning that defects are only 50 tion leads to the failure of patients to recognize. What we can learn from patients with these diseases is the exquisite vulnerability of skin to back-up of leukocytes unable to return from tissue sites as well as a traumatic injury in the absence of appropriate sensation. a profound SECTION in parasitic infections is known to cause deforming patterns of lym. with conse- 1 phatic blockage (Ch. keratinocytes produce IL-1. 67). cytokine-mediated communi- cation within the skin is an active area of research45. blockage of lymphatic drainage weight-bearing areas of the feet. Unraveling the complex rela- dence for structural abnormalities that predispose to excessive itching. In each of these settings. Skin also plays a unique hormonal role in calcium metabolism. and therefore avoid. is hydroxylated in the liver and kidneys to the active form of vitamin Nerves control vascular tone. 75) and diabetes mellitus41 (Ch. 105). Accumulated evidence favors a neurologic abnormality rather impact on the function of the skin. It is also relevant that. resulting in distal edema. zoster virus infection. but as diameters diminish. and (2) to inhibit the β44. which was recognized in classic studies Environments: Skin as a Communicating Organ as having systemic effects through the induced secretion of adrenal Communication in skin occurs by three mechanisms: conventional corticosteroids. In fact.48–51. Looking at other cutaneous cells. On the other hand. IL-6 and IL-847. as demonstrated in blushing responses. numerous the role of cytokines in keratinocyte biology. tion is regulated by other cytokines55. D (1.25-dihydroxycholecalciferol). forming an intricate network within the dermis. in turn. It then leaves the skin and the capacity to modulate immune responsiveness36. beginning with the recognition that keratinocytes contain large trigeminal trophic syndrome). gives rise to the hyperpigmentation seen in are surrounded by a myelin sheath. Chief among these cells are den- than a structural abnormality39. Frey and Wenk35 demonstrated that ligation of lymphatic drainage caused a quent ulcer formation and loss of tissue. Most prominently. Abnormality of neurologic communication: excessive Cellular communication sweating We have only recently begun to appreciate that certain resident cutane- Hyperhidrosis is a potentially debilitating disorder of sweating. but. tionships among cutaneous cells. Within the dermis. 80). For patients with Hansen’s disease. the loss of sensory func. itch. pharmacologists for the next generation. many patients with Addison’s disease (Ch. Langerhans cells produce a unique spectrum of cytokines and chemotactic factors Abnormality of neurologic communication: excessive related to their immuno­logic properties46. In fact. excessive itching can be devastating to both personal affects cutaneous immunity54. The capacity of these substances to exert important physiologic excessive sweating that characterizes disabling axillary and palmar functions is demonstrated by the beneficial effect TGF-β has on hyperhidrosis37 (Ch. revealed through various defects in their execution. fibers run free. their own hormones (autocrine). there is at present little evi.

It is of interest that since evaporative vitiligo. The subsequent physiologic responses Virtually all attraction that occurs at a distance beyond that of touch that lower temperature to prevent injury require innervation. and. 45–50°C (113–122°F. because all heat given by both researchers and clinicians to the effect of skin disease on loss occurs through radiation. and. central heating. For humans. as death from over. considered beautiful. both may occur together. the secretory Beauty. Miss Mary Anne Bloxam. 25 by the English portrait artist Thomas Lawrence. heat therapy has been used in the ings have long been seen as expressions of self-identity. painted in 1824– The relevance of sweating to the elimination of heat. alopecia. make modifications in order to communicate with each other and to as electrocautery is a time-honored method of therapy in cutaneous display aspects of self-identity. Unfortunately. increasing attention has been effect of environmental humidity on core temperature. and consequently Thermoregulatory Organ human DNA. the defining defect is a challenged us to reconsider the relationship between appearance and nearly complete absence of sweat glands. and. core temperature is scale the Himalayan mountains and the firefighters who wear insulated maintained at approximately 37°C (98–99°F). the skin represents a “canvas” onto which individuals may The production of local heat injury may also have a beneficial side. In Figure 1. Cooling may be required under The presence of beauty. by definition. the elimination of central and condition of the skin seems to have assumed fundamental impor- heat occurs through radiation from the skin surface and from the tance. Exo­genous “sweat” may be created by spraying water over selves. eczema. increasing In contrast to heat injury. without any confirming heating. in association with other beauty. the attractiveness of the patient.e. Tattoos. individuals exposed to cold temperatures amounts of discretionary money have been diverted into procedures require heating to prevent injury. modern artists such as Andy Warhol have disorder hypohidrotic ectodermal dysplasia. direct radiation into the environment and by heat transfer to other body it should not be surprising that in every society. Ch. Under neurologic control. ultimately. to attract attention. temperature. features such as hypotrichosis and abnormal teeth (Ch. unblemished skin seems to be 51 exposure. In contrast. heat loss may be quality of life.17 we have included portraits of Mr Frederick H evaporative cooling that follows sweating. symmetric. impact of chronic skin disease. most notably psoriasis. tends two non-exclusive circumstances: (1) in response to central heating. ritual scarification. 39) and through successfully as a therapeutic tool for decades (Ch. As our understanding 199657. 88). Additionally. because high attractiveness energy is generated through muscular exertion in amounts sufficient to would seem to increase the likelihood that DNA survives and also. we are better able to treat patients with these conditions. More recently. plays a cooling role to prevent injury. preferred in the majority of societies. Dermatologists and their circumstances: (1) in response to heat loss to the environment in patients have played major roles in this transition. including psoriasis. humans have become quite adept 1  Regulating Temperature: Skin as a at creating artificial methods to prevent cold or heat injury through Anatomy and Physiology clothing and shelter. as seen in photographs or paintings. influences tend to change that temperature. During the past decade. new developments in targeted therapy tion of heat from the skin surface and shivering (or exercise) to increase will continue to expand our therapeutic armamentarium.dermatologic therapy have been achieved during the last decade in the Extreme examples of excessive core and surface cooling in association management of inflammatory skin diseases. Perhaps the most obvious are the mountain climbers who which. amounts that cool the body centrally (hypothermia). Because environmental clothing as they enter burning buildings. and (2) in response to exposure locally to sustained temperatures below freezing. when this occurs. skin ing to the development and expression of self-identity. Our question at this point . 63)56. These have enabled humans. In this patient with the X-linked genetic with interest. and (2) in response to sustained local therefore. we assert that the desire to be attractive helps to insure the selec- at which critical proteins begin to denature. and pig- patients with this disease to engage in vigorous outdoor activities in mentary disorders. much to do with the anxiety that often characterizes patients with acne. the physical appearance locations via circulating blood. However. and (2) reabsorption An important function of skin begins with the need for humans to of sodium by the duct to produce hypotonic sweat. and smell is mediated by vision. The intrinsic to survival may be found in the vignette of hyperthermia found at the “beauty” of these individuals prompts one to examine their features beginning of this chapter. which occurs when a portion of skin is heated to a temperature data. Human skin includes several million eccrine sweat glands distributed Interpersonal Communication: The Skin Conveys over most of its surface. In sum. During the last 25 years. there exists an intricate system of regulation in which skin plays a decisive role as both radiator Cold injury as therapy and insulator. including sporotrichosis and can participate in skin modification by interventions meant to improve leishmaniasis. there is virtually no skin diseases. 138). especially when the environ. 140). The skin plays an important role in interpersonal communica- Failure of thermoregulation: effects of excessive heat tion by conveying beauty to others. with the total mass of eccrine glands approxi- mately that of one kidney. cryosurgery) has been used through evaporative cooling after eccrine sweating (Ch. as well as virtually all other cooling normally plays no role in these patients. Attracts Attention and Contributes to activity of eccrine sweat glands consists of two major activities: (1) Self-Identity secretion of an ultrafiltrate of a plasma-like fluid. Having said this. and pierc- medicine (Ch. aside from vascular constriction to reduce radia- CHAPTER of cytokine biology increases. to survive successfully in geographic areas of extreme Regulation of core temperature is a characteristic of all mammals. Temperature regulation by the skin is effected primarily When properly applied. Hemming and his fiancée. It is easy to imagine which occurs when heat enters skin from an external source or when that these responses are coded genetically. which Failures to present an attractive appearance otherwise would lead to direct freezing injury (“frostbite”). are euthermic. With extreme Appropriately proportioned. there are no intrinsic cutaneous mechanisms to protect against excessive cooling. local cold injury (e. which is sometimes intense. On the other hand. aging and photoaging. with limited central heat generation were described vividly by Jon Aberrant levels of TNF-α and IL-23 have emerged as critical targets of Krakauer in his report of the Mount Everest climbing disasters of immunobiologic agents used to treat psoriasis. and contribut- Excessive heating may be local or systemic. Dispersion of local heat takes place by whelming importance as a visual target for humans. attracting attention. in the neighborhood of tive survival of human DNA. the skin assumes over- tion and successful sweating. This also occurs under two related that improve appearance (Chs 152–159). vasodilation and vasoconstriction. Dermatologists management of cutaneous infection. circula. affect the way in which patients perceive them- hot climates. Myriad reports have been published defining the extent increased substantially by a relatively simple measure that allows to which chronic skin diseases. communicate with each other so that personal and societal goals can be met. This There is not sufficient space to list the physical features that are disease demonstrates the importance of sweating. increase core temperature. that the species survives. thus. repairing a variety of defects and Failure of thermoregulation: effects of excessive cold moving fat from one site to another. As dermatologists become more aware of the psychosocial the body repeatedly throughout an exercise or event56. Many dermatologists now practice cosmetic surgery and procedures. but let us assert that the loss of these features has heating during exercise is known to occur. i. of course. Heat injury as therapy Finally.g. mental temperature is high.

the vast majority of patients who seek help for excessive hair do so primarily for cultural reasons. to our attempts at manipulation through medicine and surgery. 1. Texas. our knowledge of skin disease to patient care: the structure and func- Likewise. tion protocols. as body hair can be removed without any physiologic disadvantage. 69). with cultures in which altered pigmentation may be confused with Hansen’s the important goals of alleviating scars. Kimball Art Museum. Too much hair in the wrong place occurs in congenital and acquired forms of hypertrichosis. three diseases predominate: (1) androgenetic alopecia in men.19). Fort Worth.18. melasma has a high frequency in Hispanic individuals in tion of skin is also revealed by observing the outcomes of our specific the Americas. We could go on at length about dermabrasion for acne scars. This African-American man has vitiligo on the distal portions of his fingers. By contrast.17  Mr Frederick H Hemming and his fiancée. blepharoplasties. 1. of fat are based on psychologic needs rather than on abnormalities in the structure of the skin and subcutaneous tissues. Not In this introductory chapter. the associated function of skin is revealed through careful study of skin disease. For this reason. It interventions. Scalp hair is a major social and sexual display feature for humans. (2) female pattern alopecia in women64. once Pigmentary disorders tend to be more pronounced. is that anxiety about appearance is genetically programmed. A Fig. Inappropriate hair distribution Hair performs no vital function for humans in the twenty-first century. A discussion regarding excessive hair may be found in Chapter 70 and elsewhere63.62. Ch.18  Vitiligo. may underestimate the The next steps critical role of pigmentation throughout the world. much can be learned by studying the way skin responds to this seemingly inconsequential problem. Two phenomena predominate in concerns about hair: (1) too much hair in the wrong place. Courtesy. the psychologic contributions of hair for many humans cannot be underestimated. photoaging. An autoimmune phenomena have profound implications for melanoma important corollary to this statement becomes apparent when we apply therapy (Ch. B In terms of insufficient hair (Ch. 157). In Indian culture. and (2) not enough hair in the right place. dermatologists are playing increasingly important roles in this important. and additional information may be found in other useful references61. tion. What we propose melasma (Ch. 113). 156). 1. with an Eye to the Future cytes after physical destruction guided by autoimmune influences. The biology of hair and hair growth is detailed in Chapter 68. The defect in vitiligo is the absence of epidermal melano. 1. and thus more again. Whether the outcomes are anticipated or completely 52 is not uncommon to observe that money for necessities may be diverted unexpected. However. Fig. indications for the absolute removal and for the movement necessarily unattractive elsewhere. The intrinsic “beauty” of Overview of Basic Science these individuals prompts one to examine their features with interest. and it is often extraordinarily distressing60 (Ch. in response to therapy with minoxidil and certain immunosuppressive agents. 66)58 and effects of aging. in populations with greater amounts of natural pigmenta. Miss Mary Anne Bloxam. This . we have asserted that the structure and only is vitiligo an important disease in its own right. concerns the types of changes that are considered to be “defective”. for example. These portraits SECTION were painted in 1824–25 1 by the English artist Thomas Lawrence. Nevertheless. The disci- The preference for unblemished skin is exceedingly important in pline of cosmetic dermatology has arisen to address that anxiety. 67). hiding defects and preventing disease (Ch. and as an effect of androgen excess (Ch. An Important Corollary. arena65 (Ch. the Pigmentary turmoil movement of fat is becoming a fairly common procedure and. Pigmentary disorders of this sort are much more obvious in patients with substantial natural pigmentation. The Undesirable fat distribution defects that are most disagreeable do vary from culture to culture. rejuvena- tologists care for patients who have many different disorders of pigmen. However. Western cultures. Hair transplantation has become a popular procedure performed by dermatologists (Ch. which until recently have been derived primarily from European immigrants. 75) or viewed as hereditary. Although derma. the point has been made. so With the possible exception of hemifacial atrophy and lipodystrophy that one cannot assume that what is unattractive in one culture is syndromes. and (3) alopecia areata (Fig. 70). 67). and other techniques to reverse the tation. it is not uncommon for the discovery of vitiligo to invalidate a marriage contract59. two diseases predominate: vitiligo (Fig.

1957. Neurotoxicity of expression in pig skin: incisional wound model. when wild-type BRAF is inhibited.14:719–26.   Man 4-12-2007. botulinum toxin: application in dermatology.17:621–58. Epidermolytic hyperkeratosis. Holick MF. Schmader K. 4. et al. Storey A. The dermal-epidermal human stratum corneum. The relationship 35. Elias PM. Jullien D. Gordon-Smith K. Kothny-Wilkes G.67:177–81.14(suppl. Pilgram G. 2002. How the immune system works to 29. 10. in the K1 and K10 genes of patients with   in diabetic neuropathy. iron. entrez/dispomim. Bergstresser PR. Elder HY.nih. Online Mendelian Inheritance in Man 4-3-2003. Alvord EC Jr. Sauder DN. Janeway CA Jr.118:117–25. et al.9:651–8.ncbi.nlm.2:87–93. West J. J Invest Dermatol.nih. 1):4–9. Epidermal cells. Management of warts and 1998. Yu Q-C. 2001.79:34–9. 2000. Viard I. Inhibition of toxic light and interleukin-10 modulate expression   HPV types inhibit apoptosis in response to UV damage.67. Br J 1996. 2001. 14. and type I and VI collagen and transforming growth 49. J Invest Dermatol. upregulates stromelysin-1 gene between neurological disease and bullous pemphigoid: pathogenesis of contact eczema in the guinea pig. Interactions among stratum corneum 2001. 1982. Luger TA. growth regulation in defined organotypic cultures 18.gov/entrez/dispomim. Jackson S. J Invest the ‘other’. Steyerberg EW. Wehrli P. keratin 10. 2001. Paller AS. type I. Arch Neurol. 2000. Stadler BM. Hsiao LL. 2000. Storkus WJ. J Immunol. Restifo NP. Web/URLs: http://www.11:81–100. 1999. Foye JC. Ann N Y Acad Sci. E6 proteins from diverse cutaneous 30.103:745–55.32:1481–6. 1991. epidermal necrolysis by blockade of CD95 with   of cytokines by transformed human dermal   Oncogene. Interleukin-1 53 Le Poole IC. Xeroderma pigmentosum. human intravenous immunoglobulin.nih. Nicholls PG. protect the host from infection: a personal view.145:298–301. Ditesheim JA. cell production of thymocyte activating factor (ETAF).nlm. 27. Stüssel H. Fiat F. J Lab Clin Med. 47. Epidermal ‘turnover-time’ – a reconstructed epidermis and its resemblance to native the hyperhidrotic eccrine sweat gland. Syder AJ. Niizeki H. 1975. et al. 23.19  Alopecia point has been recently illustrated by the observation that keratoacan- areata. Hartmeyer M. mesenchymal-epidermal interaction in skin.200:287–91. Quaglino D Jr. van den Wijngaard RM. Jones LA.20:569–90. Szabowski A. induction of contact hypersensitivity. Web/URLs: 43. IL-1 2001.cgi?id=124200 J Invest Dermatol Symp Proc. Burge SM. 2000. derivation of mycobacteria-reactive T cells from leprosy view of migrating Langerhans cells in the skin. Bovell DL. Clin Infect sizing of epidermal cells in normal human skin. Ultrastructure of the prediction rule for nerve-function impairment in leprosy 5. DuVivier AW. Luger TA. Fusenig NE. Burg G. molecular inhibitors of BRAF arrest melanoma growth68. et al. 52. Inheritance in Man 1-10-2005. Adolesc Med.98:7461–8.131:631–6. Corcuff P. Carter CS. Allen AL.97:  and JunB antagonistically control cytokine-regulated component definitively identified as unsaturated 240–8. Tuting T. new examination. El-Kattan AF. The with dendritic epidermal T cells. Harvey Lect.gov/entrez/dispomim. Frey JR. 2000. Taylor JR. II. complementation group A. Alard P.nih. Evidence for cgi?id=278700 through IL-1-induced keratinocyte growth factor human CD4+ T cells in the CD1-restricted repertoire: 34. Pariser RJ. human skin. gov/entrez/dispomim. 33. J Cell Dermatol. healing and modulates extracellular matrix gene immunity.3:23–8. 41. Fuchs E. DNA immunization evaluation of its neuropsychiatric component. Bergstresser PR. Minondo AM. Gibbs S. Choi EH. Dermatol. lesions. Natl Acad Sci USA. Grabbe S. junction. Curr Opin Cell Biol. Asbill CS.97:34–42. signaling pathways are enhanced and cellular prolif- 1  eration ensues66. A clinicopathological Dermatol. especially in the presence of mutated RAS. 1992. 2011. Sticherling M. cell (keratinocyte)-derived thymocyte-activating factor therapeutics.355:1603–9. gamma. In patients with the characteristic V600E activating mutation diseases such as alopecia CHAPTER in BRAF. Activation of proteins in human dermal fibroblasts. A close-up expression in resting fibroblasts. 37. Keratoacanthomas and squamous cell carcinomas Anatomy and Physiology pigmented hairs.94:47–77. 20.20:433–50. Takashima A. Science. Woloshin AA. Br J Dermatol.nlm. Groves RW. Calcium and vitamin D. Kreyden OP. Griffin JW. Br J Dermatol. Inhibitor of kappa light polypeptide gene enhancer in B location and disease severity. et al. et al. Diagnostics and http://www. 2000. Taplin D. Polydefkis M. communication by keratinocytes and Langerhans cells 12. Dis. Davidson JM. Diabetes Technol Ther. Exp Dermatol.32:320–5. which is found in approximately 40% of melano- loss in patients with mas66.96:503–9. Morrison R. Physiol. Br J Dermatol. Das PK.nlm.282:490–3. Online Mendelian Inheritance in 44. approaches. Luger TA. 17. Crit Rev Ther Drug Carrier Syst. Web/URLs: http://www.cgi?id=308300 epidermolytic hyperkeratosis: correlation between 2001.ncbi. Crit Rev Immunol. Siegfried EC. Medansky RS. URLs: http://www. 2010. Beauty is skin deep: the fascinating biology of tumour immunity: lessons from vitiligo. Barrier function in 39. Burgeson RE. areata cannot be underestimated. et al.ncbi. 1991. Our understanding of the molecular path- may consist of ways of keratinocyte biology has been expanded by observing the out- depigmented hairs. J Invest Dermatol. 36.86:204–12. Wankowicz-Kalinska A. Dermatol. Nanney LB. 1997. et al. the role of AP-1 in transcriptional activation.19:592–8. kinase of. J Invest 11. J Clin Invest. Katz SI.885:196–208. Herpes zoster in older adults. King RD. 16. and the initial cycle of regrowth are the clinical consequence. 28. Christiano AM. Katz SI. et al. REFERENCES 1. Langan SM.gov/ melanocyte-stimulating hormone in cutaneous biology. Cell.144:2223–32. microvascular endothelial cells. Cytokine-mediated University Press. Croft RP. Ochoa MT.cgi?id=203100 three NAP-1/IL-8-related neutrophil chemotactic contact sensitizers in benign dermatoses. Ponec M. 51.50:53–61. Shuman RM.67. Proc neuropsychiatric phenotype in Darier disease. Fig. Bullani R. 32. 1978. The detrimental thomas may erupt in patients being treated with molecular inhibitors social impact of hair   of mutated BRAF. Maas-Szabowski N. Skin Pharmacol Appl Skin Physiol. Oppenheim JJ. The disease process targets However. transferrin. Arch expression in human dermal fibroblasts: evidence for a population-based case-control study. Lancet. 40. 1. Leukoregulin. Wenk P. Streilein JW. collagen gene expression in keloids: co-localization of 1990.145:385–405. Fastrich M. et al. 1998. Revival of the use of the epidermis and its appendages. Kurkinen M. 1):63–71. Overwijk WW.127:1493–8. Keratinocyte 1976. Henneicke HH. Maas-Szabowski N. A symbiotic concept of autoimmunity and 1999. 1977. 2001. I. Stark HJ. Pfaller K. Oculocutaneous albinism. Semin Immunol.nih.163:515–22. Darier’s disease: an 45. 1998. 25. Online J Invest Dermatol. protects transformed keratinocytes from tumor necrosis . J Invest 2000. Trends Immunol. Andrecht S. Transferrin. c-Jun dermatophytes. Oppenheim JJ. et al. Superficial mycoses. Skin Pharmacol Appl Skin patients. Autoimmunity and the Dermatology. Genetic mutations   biopsy as a tool to assess distal small fiber innervation Man 5-20-2003. Romani N. et al. 1981. Dermatol. Arch Transforming growth factor-beta stimulates wound targeting the skin: molecular control of adaptive Dermatol. Skin 6. Michniak B. Web/ 50.111:183–8. 31. cgi?id=148080 (ETAF). Leech RW.ncbi.ncbi. Ultraviolet 13. Khan HA.70:280–4. J Immunol. Falo LD Jr. Buckley DA. 9. J Immunol. 2000.93:1533–42.8:333–9. Scholzen T.gov/entrez/dispomim. gov/entrez/dispomim. Taylor JR. 46. 1975. J Invest Dermatol.84:482–4. 1960. J Invest Allergy Appl Immunol. Many more such observations are bound to follow as we continue to develop new ways of treating skin disease. Jaakkola S.cgi?id=300248 Mendelian Inheritance in Man 3-6-2003. 2001. Clunes MT. 2000. The Spirit in the Gene: Humanity’s Proud hexachlorophene in humans.14(suppl. Online Mendelian 48. Peltonen J. Scholzen T. 2001.nih. New York: Cornell study of 46 premature infants. Web/URLs: http:// alpha or tumor necrosis factor-alpha stimulate release of 15. Stoitzner P. 21. Neural influences on Biochem. Ultrastructure of 3. J Invest Dermatol. A clinical defensive functions. Hauer P. comes of our intervention on melanoma.nlm.ncbi. Schrüder JM. The therapeutic use of topical www. Web/URLs: http://www. Clin Lab Med. Darier-White disease. Online Mendelian Inheritance in 24. molluscum in adolescents. 2001. Kulms D. 22. The role of alpha- transdermal drug delivery: chemical and physical Man 4-4-2001. Illusion and the Laws of Nature.114:1075–84. Counting and immunotherapy of cancer: targeting the ‘self’ to destroy 38.nlm. Enhancement of 26.164:4790–6.111:50–6. Online Mendelian Inheritance in 1994.12:229–42. Epidermal 8. Serum dermatophyte inhibitory factor-beta-1 mRNA. Bergstresser PR. 2.22:130–6. Experimental studies on the T-cell derived cytokine. et al. Sieling PA. McArthur JC. 2005. 42. 1997. Mauviel A. Incontinentia pigmenti. Kahari VM. 7. a 19. Boni R. et al.

gov/entrez/dispomim. Kothny-Wilkes G.nih. Henz BM.464:431–5.   stimulating hormone acts as a selective inducer of 62. et al. RAF   through tumor necrosis factor and macrophage 60. Trends Mol with BRAF V600E mutation.nlm. Shaffrali F. cell-mediated delayed-type hypersensitivity reactions McGraw-Hill. Eisen AZ.273:29247–53.26:3–5. Clin SECTION Interleukin-1 protects transformed keratinocytes from 58. 2000. Cell. Gawkrodger D. In: Fitzpatrick TB. 54 . Chapman PB.   to drive tumor progression through CRAF. Ectodermal dysplasia-1. Sinclair RD. Biedermann T. 1998. Poppelmann B. Clin Dermatol. New York: Random House. Kneilling M. Markey AC. Mechanisms of disease: the biology 2010. 67. New York: 2010. Wolff K. Millar SE. Cotsarelis G. 1441–52. Krakauer J. Hatzivassiliou G. Med. Liposuction in cosmetic dermatology. Nature. 65. Web/URLs: http:// 2001. Song K. J Exp Med. Disorders 66. et al. Hirsuties. Mailhammer R. Milagre C.and 56.140:209–21. Dawber RP. Kulms D. Hori Y. 2001. Pandya AG. J Biol Chem. www. radiation-induced apoptosis. Mount Everest Disaster.364:2507–16.19:189–99. 1999. Cotsarelis G. 2011. Disorders of hyperpigmentation. Grutzkau A. 53. 1 tumor necrosis factor-related apoptosis-inducing ligand. 68. Clin Exp Dermatol. α-Melanocyte of hair follicles. 61. et al. 59. et al.341:491–7. N Engl J Med.274:28916–21. Exp Dermatol. N Engl J Med. Paus R. Whittaker S. Mosher DB. 2000.ncbi. 2000. Towards a molecular Improved survival with vemurafenib in melanoma   secretory functions in human mast cells. Ortonne JP. 1999. 55. Into Thin Air. 57.278:14–9. Dermatology in General Medicine. J Am Acad Dermatol. factor-related apoptosis-inducing ligand. MAPK pathway and enhance growth.7:293–301. CD95-induced apoptosis but not from ultraviolet Man 4-22-2004.   Kinase-dead BRAF and oncogenic RAS cooperate   54. J Biol Chem. et al. Yen I. Heidorn SJ. Female pattern hair loss. 1987:794–876. 2000. Management of vitiligo.192:  Dermatol Clin.25:575–9. et al. Kirchhof L.cgi?id=305100 64. 1997. of pigmentation. Biophys Res Commun. 2001. Guevara IL.18:91–8. Online Mendelian Inheritance in 63.45:570–80. Hauschild A. Overview of Basic Science Mast cells control neutrophil recruitment during T et al (eds). 2000. A Personal Account of the 2001. Biochem understanding of hair loss and its treatment. inhibitors prime wild-type RAF to activate the   inflammatory protein 2. Olsen EA. Robert C. Fitzpatrick TB.