Hair Follicles

The growth of hair occurs within hair follicles in a sequence of stages (Fig. 17-6). These stages include hair genesis, growth, maturation, and loss. In the anagen stage of the hair cycle, mitotic activity and growth occur. The catagen stage is a transitional phase during which cellular proliferation ceases. The follicle then enters a resting stage, telogen, after which mitotic activity and new hair production resumes. The exogen stage is the phase in which the old hair is shed. In many animals hair follicle growth occurs in cycles, resulting in periodic loss or shedding of the hair coat. The reason the hair growth occurs in cycles is not clear. Some hypotheses include that the cycle provides the ability to: (1) shed fur to cleanse the body surface, (2) adapt and change body cover in response to changing environment (winter to summer) or social conditions, or (3) protect against malignant transformation that might occur in a rapidly dividing tissue. The regulation of hair cycling is exceedingly complex and incompletely understood. Factors that play a role include genetics, photoperiod, temperature, nutrition, hormones, health status, and neural mechanisms. Genetic factors determine the hair shaft length (e.g., short-haired versus long-haired breeds of dogs). The exact signals that control the hair cycle have not been identified; however, growth factors, such as epidermal growth factor, fibroblast growth factor (FGF), hepatocyte growth factor, platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and insulin-like growth factor (ILGF), have been localized to the skin and hair follicles. These growth factors probably play a crucial role in regulation of the hair cycle and follicle growth.

Photoperiod acts via the hypothalamus, pituitary, and pineal glands, which secrete tropic hormones, such as melatonin and the gonadal, thyroid, and adrenal hormones, that also influence hair growth. Some hormones, such as thyroid and growth hormone, stimulate hair growth, whereas excessive levels of estrogen or glucocorticoids suppress hair growth. The cells in the follicular papilla (sometimes called dermal papilla) regulate epithelial growth and are probably the target of the tropic hormones. Nutrition and health status have a significant influence on hair growth and quality. Hair is largely composed of protein. Thus diets low in protein or disease states associated with severe protein loss result in poor quality hair coat. Animals in poor health have larger numbers of hair follicles in telogen, and because telogen hairs are more easily shed than anagen hairs, animals in poor health tend to shed more heavily than healthy animals. Also, in disease states, cuticle formation can be defective, resulting in a dull or dry hair coat. It is also thought that the hair cycle is influenced by the nervous system. Evidence of such is implied by the abundant nerve supply of the hair follicle, the high density of Merkel cells in the hair follicle epithelium, and facts that keratinocytes express several neurotransmitter and neuropeptide receptors whose stimulation can alter keratinocyte proliferation and differentiation. Indirect influence by autonomic nerves could also be mediated by alteration of hair follicle blood flow and thus of oxygen and nutrient supply.

Forms of hair follicles vary in different animals (Fig. 17-7). Horses and cattle have evenly distributed simple follicles with one large (i.e., primary) follicle, usually with sebaceous and apocrine glands and arrector pili muscles. Pigs have simple follicles grouped in clusters. Goats, dogs, and cats have compound follicles that consist of primary follicles and smaller secondary follicles. Sheep have simple follicles in hair-growing areas and compound follicles in wool-growing areas. Primary follicles have the hair bulb rooted more deeply in the dermis than secondary follicles. The depth of the hair bulbs varies with species. In dogs and cats, the anagen hair bulbs of primary follicles are at the dermal-subcutaneous junction, whereas in horses and cattle the anagen hair bulbs are in the mid-dermis. In all species, the bases of telogen follicles are more superficially located than the bases of anagen follicles. Typically, primary and secondary hair shafts emerge through a common follicular opening. Tactile hairs include sinus and tylotrich hairs. Sinus hairs, also termed vibrissae, arise in simple follicles with a blood-filled sinus located between the inner and outer layers of the dermal sheath. Sinus hairs generally occur on the nose, above the eyes, on the lips and throat, and on the palmar aspect of the carpus of cats. Sinus hairs function as mechanoreceptors (i.e., touch receptors). Tylotrich hairs also function as mechanoreceptors and are scattered among the regular body hairs. The arrector pili muscles extend from the connective tissue sheath of the hair follicles at the junction of the middle and inferior portion of the follicle and attach to the superficial dermis. The arrector pili smooth muscles are oriented almost perpendicularly to the wall of the follicle and are well developed on the back of animals, especially dogs. Muscle contraction causes erection of hairs and expression of the contents of sebaceous glands.

Sweat Glands

There are two basic types of sweat glands: apocrine glands and eccrine glands. Apocrine glands are located throughout haired areas of skin in domestic animals and are tubular- or saccular-coiled glands (see Fig. 17-7). The ducts of the apocrine glands open in the superficial portion of the hair follicle; thus these glands are also called epitrichial glands. The glands are lined by secretory cuboidal to low columnar epithelium surrounded by contractile myoepithelial cells. Other apocrine glands include the interdigital glands of small ruminants, glands of the external ear canal and eyelids of domestic animals, anal sac glands of dogs and cats, and the mental organ of pigs. Eccrine glands are merocrine in secretion and in contrast to ducts of apocrine glands, the ducts open directly onto the surface of the epidermis. Thus eccrine glands are also called atrichial glands. They are tubular glands lined by cuboidal epithelium surrounded by myoepithelium and are confined mainly to pawpads of dogs and cats, frog region of ungulates, carpus of pigs, and nasolabial region of ruminants and pigs.

Sebaceous Glands

Sebaceous glands are simple, branched, or compound alveolar glands that undergo holocrine secretion, with ducts opening into hair follicles except at some mucocutaneous junctions where the glands open on the surface of the skin (e.g., meibomian gland/also known as tarsal gland). Well-developed sebaceous glands are found in the supracaudal gland of dogs and cats; infraorbital, inguinal, and interdigital regions of sheep; the base of the horn of goats; the anal sac glands of cats; the preputial glands of horses; and the submental organ of cats.

Specialized Structures

Anal sacs are specialized cutaneous structures that are especially prone to develop lesions. Anal sacs are bilateral diverticula located between internal and external anal sphincter muscles in dogs and cats and have ducts that open onto the anus at the level of the anocutaneous junction. Ducts and sacs are lined by stratified squamous epithelium. In cats, the sac wall has sebaceous and apocrine glands, but in dogs, the wall has only apocrine glands. The anal sacs can become distended with secretory products, rupture after trauma, and cause bacterial infection and chronic inflammation (foreign body reaction) in contiguous tissues. Carcinomas of the apocrine gland of the anal sac in dogs are often associated with tumor cell production of parathyroid hormone-related protein (PTHrP) and humoral hypercalcemia of malignancy.

Hepatoid (i.e., circumanal or perianal) glands occur most commonly in the skin around the anus and are also present in skin near the prepuce, tail, flank, and groin. These glands are modified sebaceous gland that have nonpatent ducts and are composed of peripheral reserve cells that surround lobules of differentiated cells resembling hepatocytes, resulting in the name “hepatoid” glands. Adenomas of the perianal glands in male dogs are often testosterone dependent.

The claws of dogs and cats shield the third phalanx and consist of a wall (i.e., dorsal and lateral sides) and sole (i.e., ventral side), both of which are stratified squamous keratinizing epithelium. The wall consists of hard keratin and the sole of softer keratin. The dermis of the claw consists of dense collagen, elastic tissue, and blood vessels that can bleed profusely if the claw is trimmed too short. The claw fold is a fold of skin that covers the wall laterally and dorsally for a short distance. Hooves consist of the wall, sole, and frog in solipeds; and a wall, sole, and prominent bulb in ruminants and pigs. The hoof wall comprises three structurally distinct layers (i.e., stratum externum, stratum medium, and stratum internum), which are formed by the proliferation and downward movement of epidermal cells arising from a specialized junction of the epidermis and dermis, a region known as the coronary band or coronet. The stratum internum of the inner hoof wall interdigitates with the dermal lamina of the corium, thereby anchoring the inner hoof wall to the dermis that covers the third phalanx. If the attachment of the stratum internum to the dermal lamina fails, the shearing forces of body weight and movement lead to vascular damage in this region and ultimate damage to the corium of the sole and coronet. The separation of the third phalanx from the inner hoof wall is the primary pathologic process leading to the painful condition of laminitis most often seen in horses and cattle.

The digital pads of dogs and cats have a thick epidermis composed of all layers, including the stratum lucidum. The surface is covered by compacted layers of stratum corneum and is smooth in the cat; however, in the dog, the surface is covered by conical papillae that conform to the outline of the epidermal surface (see Fig. 17-2). The epidermis and dermis interdigitate via rete ridges and dermal papillae, thus providing resistance to shear forces. Eccrine (atrichial) glands are present in the dermis and the adipose tissue. Lobules of adipose tissue that act as a cushion are subdivided by collagenous stroma and elastic tissue.

The chestnuts and ergots of the horse are considered to be vestiges of the first, second, and fourth digits. Chestnuts are located in the supracarpal and tarsal area on the medial surface of the limbs, and the ergot is located at the flexion of the fetlocks (metacarpophalangeal articulation). Chestnuts and ergots are histologically similar and consist of compact stratum corneum covering thick cellular layers of the epidermis. The rete ridges are long and interdigitate with long dermal papillae.

Barrier Functions

Barriers of the skin against physical injury are listed in Box 17-3. The hair coat, particularly the long dense hair coat of some dogs and cats, serves as a physical barrier to temperature extremes, UVR, and minor trauma. The hair coat also sheds water as a result of the lipids provided by sebaceous gland secretion. Vibrissae, or tactile hairs, and sensory neurons provide awareness of the physical environment, allowing the animal to make appropriate reactions for survival such as reflex responses to heat and other noxious stimuli. Claws, especially on cats, serve as a quite effective barrier against predators by providing traction for climbing and serve as weapons to be used against aggressors. Horns of cattle, sheep, and goats also provide some physical defense capabilities.

The stratum corneum is an exceedingly important component of the barrier, imparting protection from the exterior and preventing water loss from the interior. The stratum corneum is composed largely of keratins, a family of proteins called intermediate filaments. Keratin proteins are the major structural proteins of the skin, hair, and claws. The stratum corneum is considered to be the “bricks and mortar” of the barrier. The bricks are the flattened cornified cells (corneocytes) with their resistant cell envelopes and keratin microfibrils, and the mortar consists of intercorneocyte lipids.

The bricks are formed at the level of the stratum granulosum when the keratinocytes are transformed into the flattened corneocytes. The transformation occurs when (1) the nucleus is digested, (2) the keratin intermediate filaments aggregate into microfibrils oriented parallel to the skin surface, (3) the lipids are released into the intercellular space, and (4) the cell membrane is replaced by a resilient cell envelope consisting of cross-linked protein with lipids covalently bound to its surface. Filaggrin (which is an acronym for filament-aggregating protein) from the keratohyalin granules in the stratum granulosum plays a significant role in formation of the bricks by participating in the aggregation of keratin filaments into tight bundles. The keratin intermediate filaments and filaggrin compose 80% to 90% of the protein mass of the epidermis. Later, filaggrin is digested by proteolytic enzymes to produce components of amino acids that form the “natural moisturizing factor” of the stratum corneum, which serves to help maintain hydration, flexibility, and proper desquamation. Concurrent with the aggregation of the keratin filaments, the resistant cornified envelope is transformed from the water-permeable phospholipid cell membrane of the keratinocyte when the membrane-bound enzymes (e.g., transglutaminases), cross-link proteins from the keratohyalin granules (e.g., loricrin) and the cytoplasm (e.g., involucrin) in isopeptide bonds. Other proteins (including trichohyalin and small proline-rich proteins) are similarly cross-linked and eventually the entire cell membrane consists of cross-linked proteins. The proteins of the cornified envelope compose 7% to 10% of the protein mass of the epidermis. The corneocytes are joined together by desmosomes that are modified from those joining keratinocytes in lower layers of the epidermis by the addition of a protein called corneodesmosine. These stratum corneum desmosomes are referred to as corneodesmosomes.

The mortar is formed when lipids, from the lamellar bodies in the stratum granulosum, are released into the intercellular space. These intercorneocyte lipids (glycosyl ceramides, cholesterol, cholesterol esters, and long-chain fatty acids) are hydrophobic and prevent transepidermal water loss. Lamellar bodies have other important functions: (1) they provide enzymes that generate ceramides and free fatty acids that are incorporated into the lipid membranes; (2) they provide proteases and antiproteases that regulate digestion of corneodesmosomes and shedding of cornified cells to the exterior; and (3) they secrete antimicrobial peptides including defensins into the intercellular compartment of the stratum corneum. The lipid component of the stratum corneum surrounds the protein component to which it is covalently bound and provides adhesion of the cornified cells (i.e., bricks) to the intercellular lipids (i.e., mortar). Layers of the corneocytes and their corneocyte envelope (i.e., bricks), and intercellular lipids (i.e., mortar) form a tough and resilient protective barrier. The waterproofing and repellency of the stratum corneum is in part provided by the keratinocyte and sebum-derived lipids.

Other barrier functions of the skin include defense against antioxidant injury provided by vitamin E in sebaceous gland secretion and defense against UV light provided by the hair coat and also by melanin pigment in keratinocytes. The cap of melanin pigment over the nucleus helps protect the nucleus (and its nucleic acid) against UV light–induced injury by scattering and absorbing UV light rays. The basement membrane zone serves as an initial barrier to invasion of the dermis by neoplastic epidermal cells. The panniculus through its insulating properties serves as a barrier against cold temperatures. Secretion from apocrine glands in cattle and horses provides defense against excessive heat.

Resistance to Mechanical Forces

Anatomic features of the skin that provide resistance to physical injury are listed in Box 17-3. Hair follicles help anchor the epidermis to the dermis, as do epidermal-dermal interdigitations, thus these interdigitations are most numerous in nasal planum and pawpad where hair follicles are absent and resistance to shearing force is necessary. Host defense against mechanical injury is also provided by the tightly bundled keratin filaments of the corneocyte, the resilience of the cornified envelope, the adhesion of the cornified envelope and intercellular lipids, and the corneodesmosomes. In addition, the keratinocytes contain keratin filaments and form desmosomal junctions with adjacent cells (see Fig. 17-4). The keratin filaments perform a structural role (i.e., cytoskeletal) in the cells, and the desmosomes promote adhesion of epidermal cells and resistance to mechanical stresses. The basement membrane anchors the epidermis to the dermis via hemidesmosomes providing structural integrity against trauma. Dermal collagen and elastic tissue provide resilience and strength to the skin and support for the vessels, nerves, and adnexa. The panniculus protects against surface trauma by providing some shock absorption (e.g., pawpads), by facilitating movement, and by anchoring the dermis to fascia. Thus the various components of the epidermis, dermis, adnexa, and panniculus provide a flexible interconnecting framework to protect the host against mechanical injury.

Innate Immunity

Innate immunity is a primitive, highly conserved response that quickly detects and impairs pathogens and harmful environmental stimuli encountered daily in life and does not require antigen-specific receptors. Innate immunity protects the host during the first 7 days of exposure to a pathogen before development of an adaptive immune response, and also initiates and assists the adaptive immune response (see Web Table 17-1). The diversity of microorganisms requires equal diversity in host defense responses. The first phase of innate host defense consists of the barrier of the stratum corneum, which prevents pathogen adherence and provides an antimicrobial surface consisting of antimicrobial peptides and fatty acids. The antimicrobial peptides (e.g., β-defensins and cathelicidins) are effective against many organisms, including viruses, bacteria, protozoa, and insects, and probably kill some of these pathogens by damaging their lipid membranes. The surface barrier also includes normal flora of nonpathogenic bacteria that competes with pathogenic microorganisms for nutrients and for attachment sites on cells. The normal flora also produces antimicrobial substances that prevent pathogen colonization. Because the dry cornified surface is such an effective barrier to pathogens, a wound or abrasion is usually necessary for a pathogen to gain entrance. Web Fig. 17-1 provides an illustration of how the innate and adaptive (acquired) immune systems participate in host defense against bacterial pathogens that have gained entrance into the skin through a wound in the epidermis. When injured, keratinocytes release a variety of antimicrobial peptides, chemokines, and cytokines, which activate endothelial cells and attract macrophages, neutrophils, and lymphocytes to the site of injury. Early key cells that play a role in innate immunity are the tissue macrophages that contact, bind, phagocytose, and thereby eliminate many types of pathogens. Pathogen recognition is mediated by pattern-recognition receptors (PRRs), including Toll-like receptors and others, that recognize repeating patterns of molecular structures common to broad classes of pathogens and efficiently differentiate pathogen antigens from self-antigens. The repeating patterns of molecular structures on pathogens are called pathogen-associated molecular patterns (PAMPs).

A few examples of PAMPs include lipopolysaccharide (most Gram-negative bacteria), peptidoglycan (Gram-positive bacteria), CpG motifs (mostly bacterial pathogens), lipoarabinomannan (mycobacteria), mannans and zymosan (yeast), double and single stranded RNA (viruses), and heat shock proteins (bacteria, fungi, algae, protozoa). These PAMPs have been conserved during evolution and allow the innate immune system to broadly distinguish between self-antigens and pathogen antigens. The important outcomes of pathogen-receptor binding include the activation of phagocytic and other immune effector cells and release of cytokines, chemokines, adhesion molecules, and other inflammatory mediators initiating an acute-phase response. The acute-phase response proteins can opsonize a broad range of pathogens and can also activate the complement cascade, making pathogens more susceptible to phagocytosis and killing by macrophages and neutrophils. Once initiated, the innate immune response helps to start the antigen-specific immune response (i.e., adaptive immunity). Innate immunity is crucial to protecting the host in the early days of infection; however, pathogens can evade innate immunity and innate immunity does not lead to immunologic memory characteristic of adaptive immunity.

Acquired (Adaptive) Immunity

Whereas innate immunity works immediately to detect and destroy microorganisms, acquired or adaptive immunity develops later because the lymphocytes that contribute to adaptive immunity specific for the invading pathogen must increase in number by clonal expansion (see Web Table 17-2). The major components of the cutaneous adaptive immune system include keratinocytes, dendritic antigen-presenting cells (Langerhans’ cells and dermal dendritic cells), lymphocytes, and endothelial cells (see Web Fig. 17-1).

The adaptive-immune response is initiated by a stimulus (in this example, the epidermal injury, microbial invasion, and signals provided from the innate immune system), at which time the bone marrow–derived antigen processing and antigen-presenting cells (Langerhans’ cells in the epidermis and dendritic cells in the perivascular dermis) ingest and process the antigen. Pathogen recognition is mediated through PAMPs as described previously. The major function of Langerhans’ cells and dermal dendritic cells is antigen processing and presentation; thus these cells are referred to as “professional antigen processing and presenting cells.” Langerhans’ and dermal dendritic cells reexpress the ingested and processed antigen on their cell surfaces and migrate via afferent lymphatic vessels to the paracortical areas of skin-associated lymph nodes, where they arrive as mature and powerful antigen-presenting cells. These skin-derived dendritic cells then initiate a pathogen-specific protective immune response by presenting antigen to the naïve T lymphocytes. Langerhans’ cells also produce cytokines (e.g., IL-1 and TNF-α), thus participating in upregulation of inflammatory and immune responses in the skin.

The T lymphocytes activated by antigen presentation in the skin-associated lymph nodes are also known as sensitized or memory T lymphocytes. These memory T lymphocytes are subdivided into two types, central memory and effector memory T lymphocytes. The central memory cells generally circulate between the blood and lymph nodes, serve mostly as long-term reservoirs of immunologic memory, and when stimulated by antigen give rise to both central memory and effector memory T lymphocytes. The effector memory T lymphocytes express skin-associated homing receptors (e.g., cutaneous lymphocyte antigen [CLA]) that interact with adhesion molecules (E-selectin, P-selectin, vascular cell adhesion molecule 1 [VCAM-1], and intercellular adhesion molecule 1 [ICAM-1]) on cytokine-activated endothelial cells in the dermal vessels at the site of initial injury, thus providing a way for the effector memory T lymphocytes to find their way back to the site of the injury and pathogen entrance. Once in the skin and after receipt of a renewed antigenic stimulus by the professional antigen-presenting cells, the effector memory T lymphocytes undergo clonal expansion, resulting in the generation of protective effector mechanisms. Most of the lymphocytes in the skin are T-helper lymphocytes, but various types of T and B lymphocytes contribute to adaptive immunity.

Lymphocytes recognize pathogens (i.e., antigens) via cell surface receptors. The B lymphocytes have immunoglobulin molecules as the receptors for antigen, and on activation, B lymphocytes secrete immunoglobulin, which provides defense against pathogens (often bacteria) in the extracellular spaces. Antibody facilitates pathogen neutralization, complement activation, and enhanced endocytosis by phagocytes. In contrast, T lymphocytes have receptors that recognize foreign antigens expressed as peptide fragments bound to major histocompatibility complex (MHC) proteins (see Chapter 5 for a review). One class of T lymphocyte expresses the CD8 molecule on the surface (i.e., CD8⁺ T lymphocytes). These CD8⁺ T lymphocytes recognize peptide fragments bound to MHC I, then kill the cell, and thus are also called cytotoxic T lymphocytes.

Another class of T lymphocytes expresses the CD4 molecule on their surface. This class of T lymphocyte is divided into subclasses. One subclass, the CD4⁺ T lymphocyte subset (T_H1 [helper]), recognizes peptide fragments (e.g., microbial antigen) bound to MHC II and releases cytokines, including interferon-γ (IFN-γ), resulting in an inflammatory response via macrophage activation. A second subclass, CD4⁺ T lymphocyte subset (T_H2 [helper]), recognizes peptides (including allergens) bound to MHC II and releases cytokines, including IL-4, IL-5, and IL-13, resulting in inflammatory responses in which eosinophils predominate and stimulates B lymphocytes to secrete immunoglobulin. Another subclass, the T regulatory lymphocyte (Treg), acts to suppress responses of other T lymphocytes. Most antigens require an accompanying signal from helper T lymphocytes before they can stimulate B lymphocytes to proliferate and differentiate into antibody-secreting plasma cells. Thus T lymphocytes are crucial to adaptive immunity by destroying pathogen-infected cells, by activating macrophages, and by activating B lymphocytes.

Thus complex interactions between host cells, pathogens or other antigens, and inflammatory mediators of the innate and adaptive immune system typically result in appropriate host defenses, the removal of the inciting pathogen, and the generation of differentiated memory lymphocytes through clonal expansion, allowing faster specific immune responses in future encounters with the offending antigen. Impaired host defense mechanisms can lead to increased susceptibility to infection, to development of neoplasia, or to chronic inflammatory or autoreactive disorders such as atopic dermatitis, contact hypersensitivity, or lupus erythematosus.

Disease Example of Barrier Dysfunction

Atopic dermatitis (atopy) serves as an example of a common disease associated with impaired function of the epidermal barrier and immunity. It is a multifactorial, chronic and relapsing, often severely pruritic skin disease that affects humans, horses, dogs, and cats. It can cause severe discomfort including sleeplessness from pruritus, and is associated with secondary skin infections. Although the etiopathogenesis of atopic dermatitis has been studied most extensively in humans, many similarities with the human disease have been identified in atopic dogs. Advances in the knowledge of canine atopic dermatitis have occurred through the recent development and validation of animal models of the disease; these models have allowed more in-depth investigative studies in dogs and more precise comparisons of the disease between humans and dogs. Atopic dermatitis is a common problem in dogs; it is estimated to affect 10% to 15% of the population (Web Fig. 17-2). It is also a common human disease estimated to affect 5% to 20% of children. Similarities in the disease in humans and dogs include young age of onset; genetic inheritance; similar clinical lesion distribution; similar histopathologic lesions, including infiltration of immunoglobulin E (IgE⁺) CD1c⁺ dendritic cells; dry skin with increased transepidermal water loss; decreased stratum corneum ceramides (lipids); decreased epidermal filaggrin; increased colonization of surface staphylococci; positive atopy patch test; increased IgE-specific responses; and T_H2-dominated immune responses. A major difference in the disease is that children with atopic dermatitis often develop asthma and allergic rhinitis, whereas dogs do not; the reason for this difference is currently unknown.

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