THE INTEGUMENT - STRUCTURE AND FUNCTION
CTS/Physiology, Lecture 29
Tuesday, December 2, 2003

For questions on this topic, contact Rick Horwitz at horwitz@virginia.edu

1. INTRODUCTION
   1. The integument is composed of skin and its associated tissues sweat glands, sebaceous glands, hair, and nails.
   2. Largest organ of the body; ~16% of the body weight
   3. Covers the entire body
   4. Continuous with the digestive system (lips and anus), respiratory system (nose), and urogenital system (urethra)
      
      
2. SKIN FUNCTION
   1. Serves as a barrier to physical, biological, and chemical agents and to radiation
   2. Prevents desiccation
   3. Regulates body temperature (thermoregulation) by evaporative cooling (perspiration), heat radiation at the surface of the body (blood circulation), and   serves as insulation (a minor function in humans)
   4. Site of excretion through sweat glands
   5. Photochemical production of vitamin D
   6. Serves as a sensory organ

3. SKIN STRUCTURE: Skin is composed of  two primary layers
   1. The epidermis is the ectodermally derived outer layer composed of keratinized stratified squamous epithelium.
   2. The dermis is the mesodermally derived layer of dense irregular collagenous connective tissue that underlies and interdigitates with the epidermis.
   3. The hypodermis is a loose connective tissue containing varying amounts of adipose that underlies and supports the skin; it is the superficial fascia that covers the entire body.
      
      
4. THE EPIDERMIS: The epidermis is an epithelium comprised of keratinocytes undergoing a program of sequential differentiation. The four major layers arise from the sequential differentiation of cells migrating from the basal layer to the surface.
   1.   The basal layer (stratum basale) is the deepest layer; it sits on the dermis.
      1. This layer is comprised of a single layer of mitotically active cuboidal or columnar epithelia.
      2. This is a major region of mitotic activity.  Roughly half of the basal cell keratinocytes are mitotically active.  The others become active after wounding.  Hyperproliferative diseases like psoriasis result from an inbalance of stimulatory and inhibitory growth factors acting on these cells.
      3. Basal cells are attached to each other by desmosomes that contain cadherins.
      4. Basal cell layers attach to the basement membrane (basal lamina) on which they reside via hemidesmosomes that contain integrins.
      5. Desmosomes and hemidesmosomes anchor intermediate filaments, which are comprised of keratins in epithelial cells, to the cell surface.
      6. Two  types of keratins, type I keratins, which are acidic and type II keratins, which are basic, are required to form an intermediate filament.
      7.  In epidermis, different pairs of keratin genes are expressed as the cells migrate upward from the basal layer and proceed through their differentiation program. For example, keratin 5 and 14 are expressed in the basal layer, while keratins 1 and 10 are found in the spinous layer.
         
         
   2.   The spinous layer (stratum spinosum) is the thickest layer of epidermis.
      1. The cells in this layer arise from the migration from the basal layer and lose their adhesion to the basement membrane and adhere to other keratinocytes.
      2. Some cells in this layer are also mitotically active.
      3. The cells in this layer attain a more flattened shape and have increased amounts of keratin containing intermediate filaments and desmosomes.
         
         
   3. The granular layer (stratum granulosum) is characterized by the presence of keratohyalin granules among the keratin filaments; it consists of 3-5 layers of flattened keratinocytes.
      1. Keratohyalin granules contain the protein filaggrin, which serves to bundle the keratin filaments together.
      2. This is the most superficial layer of the epidermis that still has nuclei.
      3. This layer (and the upper spinous layers, to a lesser degree) contain membrane coating granules (lamellar granules).
         
         
   4. The cornified layer (stratum corneum) is the most superficial layer of skin and is composed of layers of dead cells.
      1.   There is a sharp transition between the granule layer and cornified layer.
      2.   Keratin filaments are highly crosslinked by the formation of S-S bonds and the bundling activity of keratohyalin.
      3. Membrane coating granules are exocytosed into the intracellular space.  The high lipid content forms a permeability barrier for water  retention and resistence.  This layer provides 98% of the water retention ability of the epidermis.
      4. The plasma membrane becomes thick, due to the deposition and crosslinking (via transglutaminase, an enzyme that covalently links glutamine to lysine) of proteins, like involucrin, along its inner surface to form the cornified envelope.
      5. These cells lack nuclei and other organelles but have numerous keratin filaments.  Cells farther from the skin surface have desmosomes, while those nearer to the surface do not and will be sloughed.

5. Epidermis turns over about every 14-30 days depending on the region of skin.
   1. Different areas of skin show differing thickness of epidermis.
   2. 2. The epidermis thickens in response to use (abrasion).
   3. The dryness of skin serves as an inhospitable environment for growth of microorganisms.
      
      
5. OTHER CELL TYPES IN THE EPIDERMIS
   1. Langerhans cells are monocyte derived dendritic cells present in the living layers of the epidermis - particularly in the spinous layer.
      1.  They do not contain intermediate filaments.
      2. In the EM, one can see a distinctive, ‘tennis racket shaped’ granules called Birbeck granules, whose function is not known.
      3.  These are antigen-presenting cells, mediating T-cell immunity, and play a role in allergic contact dermatitis.  They originate from the bone marrow.
   2. Merkel cells are present in the basal layer of thick skin of hands and soles.
      1. They are modified keratinocytes that possess keratins and form desmosomal attachments to keratinocytes.
      2. They are associated with sensory nerve terminals and function in touch sensation.
      3. They have dense core granules containing neuroendocrine components.
   3. Melanocytes are neural crest derived cells that produce melanin, the brown pigment that produces skin color.
      1.   Melanocytes reside in the basal layer of the epidermis and extend processes that contact many (usually ~30) keratinocytes in and immediately above the basal layer.  They do not form desmosomal connections.
      2. Melanocytes produce melanin from tyrosine in specialized organelles called melanosomes, which contain tryosinase, an enzyme critical for melanin production.
      3. The melanosomes are transferred to keratinocytes via a phagocytic process in which the tips of the melanocyte processes are phagocytosed by keratinocytes.
      4. The number of melanocytes differs throughout the body accounting for lighter and darker pigmentation.
      5. All humans have about the same number of melanocytes. Skin color differences arise from differences in the number, size and arrangement of melanosomes.
         1.   In dark skin, there are more melanosomes, which are larger and distributed throughout the cytoplasm rather than just in the perinuclear area as in light skin.
         2. There are two kinds of melanin, one found in people with dark hair and the other in people with red and blond hair.
      6. The epidermis responds to UV light.
         1. Melanin darkens via a photochemical reaction.
         2. Melanocytes increase production of melanin and the numbers of melanosomes.  Inactive melanocytes become active.
         3. Melanocytes increase the arborization of their cell processes.
         4. Keratinocytes increase uptake of melanosomes form melanocytes.
      7. The melanosomes in keratinocytes are degraded as the keratinocytes move upward within the epidermis.
         
         
6. PATHOLOGY OF THE EPIDERMIS
   1. Vitamin D production
      1. 7-dehydrocholesterol is concentrated in the living layers of the epidermis, where it is photochemically converted to vitamin D, which is involved in absorption of dietary calcium.
      2.   Without exposure to sunlight, vitamin D₃ must be supplied in the diet.  In its absence, bone mineralization is inhibited resulting in rickets (children) and osteomalacia (adults).
   2. Blistering diseases
      1. Bullous pemphigoid and pemphigus vulgaris are diseases that result from autoimmunity to adhesion molecules.  The former alters adhesion to the basement membrane in the basal layer, while the latter alters cell adhesion in the spinous layer.
      2. Epidermolysis bullosa simplex and epidermolytic hyperkeratosis result from mutations in keratin genes expressed in the basal and spinous cell layers.
   3. Proliferative diseases
      1. Psoriasis is caused by increased proliferation of keratinocytes and accumulation of incompletely differentiated cells in the upper epidermal layers. These cells are shed more quickly than normal (<1week vs several weeks).
      2. Warts are benign epidermal growths caused by papillomaviral infection of keratinocytes.
   4. Malignancies.  The three most common are basal cell carcinomas, which develop in the basal layer; squamous cell carcinomas, which originate in stratum spinosum; and melanomas, which develop from melanocytes, which then invade the dermis.
      
      
7. The dermis: The dermis is a dense, irregular, mesodermally derived, connective tissue, composed of collagen (mostly type I), elastin, and glycosaminoglycans.  It is much thicker than the epidermis, comprising 80-90% of the total dermis and epidermis.  It contains extensive vasculature, neurons, smooth muscle, and fibroblasts.  It is the principal mechanical barrier of skin.  Its networks of elastic fibers function to support the epidermis and bind the skin to the deeper hypodermis.
   
   
   1. The dermis contains two layers, the papillary layer and the reticular layer.
      
      1. The papillary layer is a loosely woven, superficial connective tissue region that interdigitates with the epidermal ridges and the deeper reticular layer.
         1. A key feature of this layer is the dermal ridges (dermal papillae) that extend up in ridges into the overlying epidermis and interdigitate with epidermal invaginations (epidermal ridges).
         2. The dermal ridges contain Meissner’s corpuscles, encapsulated nerve endings, and capillary loops that provide nutrients to the avascular epidermis.
         3.  A basal lamina supports the basal layer of the epidermis.
         4. Thin collagenous and elastic fibers underlie the basal lamina.
         5. Fibroblasts, mast cells, and macrophages occupy the papillary layer.
      2. The reticular layer resides below the papillary layer.  It is comprised of coarse collagenous and elastic fibers (irregular dense connective tissue) and relatively few cells.
         
         
   2. Arteries and veins run through the hypodermis and branch upward to form plexuses of anastomosing vessels.  The cutaneous plexus resides at the junction of the hypodermis and dermis, and the papillary plexus resides just beneath the epidermis.
      1.   This system provides nourishment to the dermis and by diffusion to the epidermis, which is avascular.
      2. The vascular system functions in thermoregulation.  Blow flow is controlled by contraction of arterioles and venules to send blood through the capillary bed for heat radiation.  In some regions of skin, arteriovenous anastomoses, or shunts,  can send blood directly from the arterioles to venules in order to reduce heat loss.
         
         
   3. The dermis contains neuronal elements for touch, pain, itch, and temperature reception. 
      
      1. Some receptors are free nerve endings.
      2. Other nerve endings associate with Merkel cells in the epidermis.
      3. Meissner’s corpuscles reside in the dermal papillae and function as mechanoreceptors in touch perception.
      4. Pacinian corpuscles are found deep in the dermis (and in the hypodermis) and function in pressure sensation.
         
         
8. THE HYPODERMIS: The hypodermis is composed of loose connective tissue with large numbers of adipose cells.
   1. The hypodermis provides insulation, shock absorption, energy storage, and the ability of skin to slide over joints.
   2. It also contains the major blood vessels of the skin.
   3. Many epidermal appendages extend into the hypodermis.  These provide a source of keratinocytes when the epidermis is destroyed by abrasion or burns.
      
      
9. Epidermal appendages: The epidermal appendages include hair follicles, various glands, and nails.
   1. Hair is composed of dead epidermal cells that have undergone a modified epidermal keratinization including the expression of specific keratin proteins that are highly crosslinked by disulfide bonds.  It is derived from hair folicles, which are epidermal invaginations that project into the dermis or hypodermis.
      1. Two types of hair are present on humans: Vellus (fine) hair, which is short, soft, fine, and pale, and terminal (thick) hair, which is hard, large, coarse, long and dark.  The number of hairs on all primates is similar, but most is vellus on humans and terminal on other primates.
      2. Hair  functions in thermoregulation in most mammals.  Arrector pili muscles, a smooth muscle, cause hair to stand on end for better insulation (goose pimples).  In humans, touch reception is a major function of hair, which transmits deformations to sensory nerves around the hair folicle.
      3. The hair folicle undergoes a cycle of active and resting phases during which a new hair is started and then falls out, respectively. 
      4. Melanocytes are scattered throughout the hair shaft.  These impart color to the hair.  With age, tyrosinase production decreases and the hair becomes gray.
         
         
   2. Sebaceous glands are appendages of hair follicles and are embedded in the dermis and hypodermis throughout the body except on the hands and soles.  They are prominent in the face, neck and upper body.
      1. They consist of several acini that join in a short duct that empties into hair follicles.
      2.   They secrete by holocrine secretion in which the entire cell contents becomes the secretion due to autolysis.  The dead cells are replenished by mitosis at the periphery of the gland.
      3. The secretion is sebum, a wax-like mixture of triglycerides and cholesterol.  It likely functions as a protective agent and to maintain skin texture and hair flexibility.
         
         
   3.   Eccrine sweat glands are simple coiled tubular glands located in the deep dermis or underlying hypodermis and are present throughout the body.  Their primary function is evaporative cooling.
      1. They develop as invaginations of the epithelium of the epidermal ridge and grow into the dermis. The deep aspect becomes the glandular portion of the sweat gland.
      2. Eccrine sweat glands have two regions: a secretory region and a duct region. The secretory portion is comprised of simple coils of cuboidal epithelium containing two kinds of cells.
         1. Dark cells produce sialo mucins
         2. Clear cells produce water and electrolytes
      3. Myoepithelial cells support and constrict the gland in response to cholinergic stimulation. Secretion is controlled by heat stress in most of the body but is under emotional control in palms and soles.
      4. The duct portion of the sweat gland is stratified cuboidal epithelium (2 layers), whose cells resorb ions (Na+, K+, Cl-) from the glandular secretion.
      5. The final product is hypotonic (99% water) containing salts, lactate and urea.
      6. Adults produce between 0.5-10 liters/day.
         
   4. Apocrine sweat glands are simple tubular glands that empty into hair follicles in axillary and anogenital regions.  The secretion is a mixture of proteins, carbohydrates, and ferric ions that is odorless when secreted, but is acted on by commensal bacteria.  They begin to function at puberty; but their function is unknown.

Readings: Gartner and Hiatt, Chapter 14: Young and Heath, Chapter 9.