Basic science is often considered an oppressive and complicating component of residency training as well as a necessary but unappreciated part of the assemblage of details needed for the boards and recertification. For modern dermatologists, a grasp of the basic science underpinnings of the profession is essential. It has become the norm to not only have to recognize complex clinical presentations and histopathologic entities, but also to have a deep understanding of the biological and molecular mechanisms through which disease states progress. This understanding and visualization of disease from the cell to the skin fuels the development of novel therapies targeting molecular defects or dysregulation, for example, the “biologics.” Even more importantly, knowing how these therapies work strengthens both our approach to treating our patients, as well as our ability to tackle the dermatology boards and recertification examination successfully. Therefore, the purpose of this column is two-fold: 1) to succinctly review board and recertification relevant basic science topics (highly pertinent information will be bolded); 2) to summarize the most current discoveries and investigations with respect to updates in each of these subjects. For the purposes of the first few installments, a broad overview of skin biology will be provided, with subsequent columns delving deeper into each major component or mechanism followed by a correlating literature review.
Basic Science and Structure of the Skin
A discussion regarding the anatomy of the skin begins with the epidermis. The composition and thickness of the epidermis varies depending on anatomical site. For example, the thickness of the epidermis varies from 0.04 mm on the eyelids to 1.6 mm on the palms and soles of the feet. The key cell of the epidermis is the keratinocyte, which comprises approximately 80% of the epidermis. Keratinocytes are of ectodermal derivation and can express the 30 different keratins — 20 epithelial, 10 nail —both as a skeletal structure adhering to desmosomes and hemi-desmosomes and as secrete cytokines and chemokines, such as TNF-alpha and nitric oxide, in order to regulate wound healing and combat infection. Keratins (K), or rather defects in keratins result in a broad array of genodermatoses ranging from the benign white sponge nevus (defects in K4 and K13) to devastating epidermolytic hyperkeratosis (with associated defects in K1 and K10). Different keratins are expressed throughout the epidermis, and therefore a review of the epidermal subdivisions is warranted. At the ground level is the stratum basale or <>basal layer. Basal cells are the source of epidermal regeneration, and rely on ornithine decarboxylase (ODC) as part of this process. (ODC is a great marker for proliferative activity!) Basal cells are stimulated by trauma, UV, growth factors, estrogens and tumor promoters, yet can be inhibited by protein deprivation, as is seen with the use of retinoids and steroids in psoriatic lesions. K5 and K14 are expressed in this layer; K5 and K14 filaments are altered in the pathogenesis of epidermolysis bullosa simplex. Microfilaments (actin, myosin, and alpha-actinin) assist in upward movement of cells as they differentiate, while integrins regulate adhesion and initiation of differentiation. Not all basal cells have potential to divide, and it is the basal stem cells that give rise to transient amplifying cells. Normal transit time for keratinocytes from the basal layer to the stratum corneum is at least 14 days (shortened in hyperproliferative states such as psoriasis), and transit through stratum corneum to desquamation requires an additional 14 days. Moving up into the stratum spinosum, keratinocytes begin to change in their morphology, with rounder nuclei as well as a more flattened appearance histologically. K5 and K14 are still present, but are not made de novo in this layer. Rather, K1 and K10, markers of terminal differentation (and the defect in epidermolytic hyperkeratosis), are now synthesized. Of note, in psoriasis, actinic keratoses and wound healing, suprabasal keratinocytes downregulate K1/K10 and instead make K6/K16 - mRNA for K6/K16 is always present, but only translated during proliferative states. The spinous layer has a heavy content of adhesion proteins and communicating gap junctions. Desmosomal proteins form plaques with calcium-dependent “spines” to promote adhesion, further supported by transmembrane cadherins (ie, desmoglein I and III) through intracellular linking to the intermediate filament cytoskeleton. Both plaque and transmembrane proteins play a role in both immune mediated (eg, pemphigus vulgaris: desmolgein 1&3) and inherited (eg, plakoglobin: Naxos disease) diseases, all of which will be discussed in greater detail in future columns. Furthermore, there are extra gap junctions mediating intercellular communication in the spinous layer. (Note the rule of connexins: The more differentiated the keratinocyte, the greater the number of gap junctions.) Similar to the desmosomal proteins, there are numerous diseases resulting from defects in gap junctions, such as Vohwinkel’s syndrome (connexin 26) and hidrotic ectodermal dysplasia (connexin 30), just to name two. (See Table 1: Epidermal Elements and Associated Diseases.) Of equal importance, keratinocytes of the spinous layer begin to generate lamellar granules, a membrane-bound intracellular structure with secretory functions. Although they first appear in stratum spinosum, their primary activity is in stratum corneum. Their purpose is to discharge lipid precursor contents into the extracellular space at the junction of the stratum granulosum and corneum, establishing a barrier to water loss. They also work with filaggrin to mediate stratum corneum adhesion. Defective lamellar granule production is seen in Flegel’s disease, X-linked icthyosis and Harlequin fetus. Keratinocytes continue to mature as they travel superficially forming the granular layer, and contain both keratin filaments and keratohyaline granules. These components are of great importance and are ultimately responsible for formation of the cornified cell envelope (CE) — the source of epidermal barrier strength and function. The CE is a composite of several covalently cross-linked proteins, such as involucrin, loricrin (#1), envoplakin, periplakin and filaggrin, most of which are encoded by genes located on chromosome 1. Cross linking of these proteins is dependent on the transglutaminases. Loss-of-function mutations in the gene that encodes transgluatminase 1 lead to lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. An autoimmune response directed against transglutaminase 3 results in dermatitis herpetiformis. There are also mutations in some of the genes that encode these proteins that lead to skin disorders, for example: Loricrin– Vohwinkel’s palmoplantar keratoderma (yes, there are two forms; the other is caused by a defect in connexin 26); and filaggrin-ichthyosis vulgaris, and even more recently discovered, atopic dermatitis. As mentioned above, the lamellar granules also contain phospholipids, cholesterol, and glucosylceremides. These elements are synthesized as precursor lipids and stored in the lamellar granules of the stratum granulosum keratinocytes, along with their required enzymes and proteases. At the transition layer of the granulosum to the stratum corneum, the lamellar granule contents are extruded from the cells and chemically processed to form the intercellular structure. The final lipids in the stratum corneum intercellular complex are equimolar amounts of cholesterol and cholesterol esters, ceramides, and long-chain fatty acids. The internal processing of keratohyalin filaments and specifically the proteins involucrin and filaggrin leads to development of the mature corneocytes, which can simultaneously bond to this intercellular lipid complex. The stratum corneum is ultimately responsible for the skin barrier protection, preventing water loss, maintaining hydration of the skin while also preventing overhydration in addition to many other protective functions. Any disruption of the skin barrier/stratum corneum will initiate reparative mechanisms through an inflammatory response, signaling for increased mitotic activity in the basal layer, secretion of lamellar granules into the intercellular space (forming more stratum corneum), and initiation of a cytokine response to upregulate immune defense responses to any potential invading pathogens. Therefore, although each strata of the epidermis varies significantly, there is a cohesiveness and impressive communication allowing for physiologic harmony. Dr. Friedman is Chief Resident in the Department of Medicine, Division of Dermatology at Albert Einstein College of Medicine in New York. Disclosure: Dr. Friedman has no conflicts of interest with any material in this column.