Page 292 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Host Defenses in Skin

Hui Xu, Laura Timares, Craig A. Elmets

Skin, which is the largest organ in the body, is the major interface in the dermal layer that lies under the epidermis. Approximately
between the individual and the environment. It comprises 12–16% 95% of cells within the epidermis are keratinocytes. These form
of the body’s weight and chiefly functions to protect against a self-renewing stratified squamous epithelium, which differenti-
environmental threats. It also plays an important homeostatic role ates from bottom to top from a regenerating basal layer containing
in maintaining body temperature, water and electrolyte balance, cuboidal cells to the outer most superficial layer, called the stratum
and vitamin D production. It acts as a barrier against invading corneum, composed of flat, anucleate, compact scales. Keratin
pathogens, exogenous chemicals, and the destructive effects of intermediate filaments are the major proteins produced by
physical agents, such as the sun, wind, and heat. To perform keratinocytes. The type of heterodimer keratins that are made
these various functions, skin consists of three self-regenerating during differentiation impacts the cytoskeletal structure and cell
specialized compartments that are layered on top of each other morphology.
(Fig. 19.1). Adnexal tissues, which include hair, nails, sebaceous Keratinocytes bind to one another through specialized adher-
glands, and eccrine and apocrine sweat glands, are embedded ence junctions called desmosomes. Keratin filaments attach to
within these tissues to provide specialized protective functions. desmosomal proteins to provide structural, tensile strength.
During the differentiation process, the composition of the keratin
and desmosomal proteins changes. For example, basal layer
KEY CONCEPT keratinocytes synthesize keratins 5 and 14, and the desmosomal
Primary Functions of Skin protein desmoglein 3 is more abundant than desmoglein 1. In
the stratum corneum, keratins 1 and 10 and desmoglein 1 are
• It is the body’s largest organ representing 12–15% of body weight, all highly expressed, but keratins 5 and 14 and desmoglein 3 are
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and spans a surface area of ≈2 m .
• Because of skin’s large surface area, it serves as the principal organ absent. Finally, the compact tough outer scales (squames) of the
for homeostatic thermoregulation and regulation of fluid retention and stratum corneum are cross-linked with keratin filaments.
evaporation. The differences in protein localization between the epidermal
• It provides a tactile interface with our environment through an array of layers have consequences for immunologically mediated skin
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specialized sensory cells, which are distributed at very high densities diseases. Pemphigus vulgaris, a disease in which autoantibodies
at critical points of the skin surface (e.g., finger tips have up to 2500 are formed against desmogleins 1 and 3, presents with blisters
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sensory cells/cm ). that originate in the suprabasal layer of the epidermis. Conversely,
• It serves as a photosynthetic surface, utilizing the energy of ultraviolet
radiation (UVR) to transform 7-dehydrocholesterol to cholecalciferol the closely related disease pemphigus foliaceus, in which auto-
(vitamin D3), vitamin D 3 , an essential step in the biosynthetic pathway antibodies recognize only desmoglein 1, results in blisters located
of vitamin D. exclusively in the upper epidermis.
• It provides a strong physical barrier to withstand physical stresses The remaining cells located in the epidermis are pigment-
engendered by exposure to the forces of nature. These include shear producing melanocytes, neuroendocrine Merkel cells (important
forces, extreme temperatures, wind, water, and solar radiation. Granular for mechanoreception), and Langerhans cells (LCs) (specialized
layer keratinocytes are bound together through tight junctions, providing
an effective seal that blocks entry of small molecules and microbes. epidermal antigen presenting cells). Melanocytes are derived
• It provides a pharmacological barrier by means of enzymes that detoxify from the neural crest, and progenitors seed the epidermis early
or repair damage caused by chemicals and other carcinogens, such in development. They synthesize melanin pigment in organelles
as UVR and ionizing radiation. called melanosomes, which mature into the melanin-filled granules,
• It serves as a regenerative organ that continuously replaces older, which are then transferred and internalized by keratinocytes.
damaged skin cells, which are eliminated and shed from skin as Melanin absorbs the damaging effects of ultraviolet radiation
anucleated squames.
• It provides an immunological barrier by means of a complex integration (UVR) and protects skin keratinocytes. When stimulated by
of innate and adaptive immune mechanisms that serve to protect against cytokines, melanocytes may express several immunologically
entry by microbial pathogens and to neutralize or eliminate potentially relevant proteins, including intracellular adhesion molecule 1
harmful exogenous antigens and endogenous neoplastic cells. (ICAM-1; CD54), costimulatory receptor CD40, and major
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histocompatibility complex (MHC) class I and II molecules
(Chapter 5).
The outermost layer of skin is the epidermis. Blood and Malignant melanomas arise from melanocytes. These tumors
lymphatic vessels are absent. However, oxygen and nutrients evade the host immune response, at least in part, through expres-
diffuse to epidermal cells from the microvasculature that is housed sion of programmed death ligand 1 (PD-L1). PD-L1 is an immune

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