Natural Skin Structure & Function and What goes Wrong in the Ichthyoses
In order to understand what causes ichthyoses, it is necessary to understand how normal skin functions and how it is renewed. The skin's primary function is to protect the body – to keep the outside out and the inside in. This barrier function itself has many components, which include a barrier to excessive loss of body fluids or uptake of noxious chemicals in contact with the skin (the permeability barrier), as well as to provide a chemical and mechanical shield against invasion by microorganisms (viruses, bacteria, fungi, etc.), and protection against mechanical injury and injury from ultraviolet light, oxidative injury and many other stressors. While the skin is made up of several layers, it is the outermost layer, the stratum corneum, that is largely responsible for these protective functions. Because the diverse members of the FIRST family of disorders have in common problems with the function of the stratum corneum, problems that result in visible roughness and scaling, a more detailed look at the stratum corneum is required for understanding these conditions.
The stratum corneum is made up of many thin layers of flattened, dead cells called squames (or corneocytes) that contain keratin fibers, a tough, threadlike protein. The corneocytes are surround-ed by a resilient shell of proteins knitted together, called the cornified cell envelope. Together, these protein structures give the stratum corneum its mechanical strength and flexibility. Outside the corneocytes are sheets (lamellar membranes) composed of fatty substances (lipids) that wrap around the corneocytes in multiple layers and fill the spaces between the cells. These membranes are composed of specific types of lipids, cholesterol, free fatty acids and ceramides, that repel water (i.e., are very hydrophobic); thus these membranes are responsible for waterproofing the skin (i.e., for permeability barrier function). Because our body is mostly composed of water, yet we live surrounded by a dry atmosphere, formation of a competent barrier to prevent water loss, and, conversely, to prevent a flood of water coming inside when we bathe or swim, is perhaps the most critical function of the stratum corneum. This function is impaired to some degree in virtually all of the ichthyoses.
The corneocytes are connected by protein bridges (corneodesmosomes) that hold the corneocytes together. These bridges are gradually dissolved through the action of enzymes that digest proteins (proteases) as corneocytes are pushed outward toward the skin surface. By the time the squames reach the skin surface, these connectors are weakened sufficiently to allow them to separate from one another and be swept away by frictional forces, individually and invisibly. This process of normal shedding (desquamation) is also abnormal in all of the FIRST family of diseases.
Within the corneocytes are also found small molecules derived from the breakdown of cellular proteins, especially filaggrin, as the cells die. These small molecules help to attract water into the corneocytes, thereby hydrating the skin. Also in the corneocytes are signaling molecules, that, in case of injury or loss of permeability barrier function, can initiate repair (homeostatic) responses in the underlying living cell layers. Also present in the spaces between the corneocytes (intercellular domains) are proteins and lipids that have anti-microbial activity; i.e., they protect against invasion by bacteria and other microbes.
Genetic defects in many of these stratum corneum components have been found among the causes of the FIRST family of diseases. For example, defects in keratins cause EI, and defects in corneocyte envelope formation are the cause of LI/CIE in some patients, while deficiency of filaggrin is the cause of IV. Defects resulting in the wrong lipids forming the lamellar membranes, or deficiency of lamellar membranes underlie a number of disorders, including XLI, Neutral lipid storage disease, and Harlequin ichthyosis.
The underlying layers of the skin can be thought of as providing the supporting structures and materials, including new cells and chemical and protein building blocks needed to generate a normal stratum corneum. The direct suppliers of the stratum corneum are cells (keratinocytes) of the underlying, living epidermis. Keratinocytes have nuclei and are active synthetic factories, making keratin, filaggrin and other corneocyte proteins, including enzymes, as well as the lipids that will form the lamellar membranes. The dividing or renewing cells (basal cells) reside in the inner or bottom layer of the epidermis. As the skin constantly renews itself, new cells formed by cell division move upward through the epidermis, synthesizing proteins and lipids, and eventually “dying”, i.e., turning into corneocytes. Within the cytoplasm of the keratinocytes, the newly synthesized lipids, along with antimicrobial proteins and certain enzymes, including proteases and the protease inhibitors that keep their activities in check, are packaged into membrane-bound organelles (lamellar bodies). These organelles are expelled or secreted into the spaces between the cells (intercellular domain) of the stratum corneum, where their contents are in a position to form the lamellar membranes and to perform their other functions. Failure to form lamellar bodies underlies Harlequin ichthyosis; while in other disorders (e.g., EI), there is failure of secretion.
The entire process from formation of a new cell to migration to the inner surface of stratum corneum normally takes about 2 weeks; to migrate through the stratum corneum and desquamate at the skin surface takes another 2 weeks. As long as the corneocytes are shed from the surface at the same rate that new cells are created in the basal layer of the epidermis, the skin is in a normal state of equilibrium, or "steady state." In some of the ichthyoses the entire process is accelerated, with more basal cells dividing and new cells reaching the stratum corneum within only 4 to 5 days (e.g., EHK, CIE); while in others, rates of cell regeneration and maturation are essentially normal, but desquamation is delayed (e.g., IV, XLI). Ichthyosis can be visualized as a traffic jam of corneocytes, similar to the traffic jam that results if an inordinate number of cars enter the highway - rush hour, for instance - or if the normal number of cars cannot exit —because of an accident or other obstruction in the road. In the ichthyoses, a "traffic jam" of corneocytes can occur for either of these reasons: because the production of cells is too rapid or because the natural shedding process is slowed or inhibited, or both.
For squames to be shed invisibly, they must be released from the connections that hold them to one another. This process of release is gradually accomplished as the corneocytes move outward through the stratum corneum through the action of proteases. The proteases in turn are switched on and off by activators and inhibitors. In some ichthyoses (e.g., EHK and Harlequin ichthyosis), this protease activity is deficient because of a failure to deliver them to the right location while in others, their activity is switched off because of too much inhibitor (e.g., XLI). What we see as thickened, rough, scaly skin in the ichthyoses is the consequence of a thickened stratum corneum.  Moreover, these ichthyotic cells are often shed in large clumps. The shedding of these easily visible scales is often a source of considerable annoyance and embarrassment to the person with ichthyosis.
The thick stratum corneum in most of the ichthyoses can be viewed as a quantitative response to a qualitative defect. To varying degrees, its permeability barrier function is impaired, resulting in increased rates of loss of water from the skin. This results in repair signals (“Make and deliver more lipid!” “Make more cells!”) that result in increased metabolic activity (hypermetabolism) in the epidermis and increased rates of new cell production (hyperplasia). In normal skin, once repair is completed, these signals are switched off and the normal steady-state resumes. In the ichthyoses, because the underlying cause (genetic defect) persists, the repair signals are not terminated and hypermetabolism and hyperplasia persist. Perhaps it is helpful to add to the visual analogy of a traffic jam what would happen in one composed of broken, barely operative vehicles, fenders missing, running on only a few cylinders; because in the hyperproliferative ichthyoses in the rush to provide corneocytes to the stratum corneum, maturation may be incomplete and all the components of a well-functioning stratum corneum not completely assembled. Thus in the ichthyoses there is “too much of a bad thing”: the stratum corneum is thicker than normal, but it is not capable of performing its duties normally.]
 Below the epidermis is another, larger layer called the dermis, which contains supporting structures, including collagen and elastic fibers, blood vessels and nerves. And below the dermis is the subcutaneous fat layer.
 In contrast, in Netherton syndrome, there is deficiency of a protease inhibitor, with the result that proteases are too active, digesting the corneodesmosomes too soon and resulting in a thin, incompetent stratum corneum.
 As noted above, with the exception of Netherton syndrome.
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