«Медицинская вселенная». Cпецвыпуск по проблемам ВИЧ / СПИДа. Том 3. (2003)
Epidermis: a front line of the immune system
Cellular and humoral mechanisms of protection
The main task of the immune system is to defend its host by eliminating or neutralizing foreign molecules and, at the same time, recognizing and preserving host-owned molecules. Epidermis is an integral part of the immune system and the first barrier set against microbes, irradiations, or mechanical injuries. It is the first echelon where antigens are met and destroyed; its cells initiate and stabilize immunological status of the whole organism.
Keeping the corneal layer (CL) safe and integral is the necessary condition for preventing microbes penetrate through the skin . CL consists of cellular and molecular components. The permanent desquamation of the CL corneocites contributes to pathogens’ elimination. Other factors provide mechanical strength of the CL, the acidity, or hydrogen index, of the skin surface (it varies typically between 4 and 6.5 ), and tolerance to resident non-pathogenic flora (Propionibacterium acne, Staphylococcus epidermidis, Pityrosporum ovale). When a trauma or other factors break the skin continuity and integrity, these microorganisms may become pathogenic
Lipids – the molecular components – are permanently present at the skin surface where they form a supracutaneous barrier. Appearing as secretions of oil glands and epidermis cells, lipids play an important role in anti-microbe defense. Free fatty acids originate from bacterial hydrolytic ferments acting upon triglycerides of the skin fat. Experimental data confirm that endogenous lipids of the skin may also contribute in the anti-microbe resistance of the skin. In addition to the free fatty acids, epidermis produces also polar lipids and glycosphingolipids; the latter show surface activity and, like the lung surfactants, provide antibacterial action "in vitro" as well as "in vivo" .
Any disintegration of the epidermal structure opens a portal for infections, which give rise to many skin diseases such as syphilis, herpes, contagious mollusc (Fig. 1), pyogenic granulomas (Fig. 2), warts (Fig. 3 and 4), etc.
Giant pyogenic granuloma on the scalp. The growth of the tumor was triggered by microtrauma.
Multiple viral warts of the hands.
Multiple flat warts in the knee zone.
Mechanical damage protection
While the CL is as thin as 15 to 20 microns, its mechanical strength is sufficiently high. It depends on high-tensile external keratinous coat, structural proteins (keratin fibers, filaggrin), corneocites, and desmosomes, which join adjacent cells. The CL water-holding (hydrophilic capacity), an important factor of the skin elasticity , depends on proteins and phospholipids content. Free amino acids resulting from the filaggrin hydrolysis  also contribute to the skin water retention. Phospholipids are especially important for the water retention because they possess hydrophilic groups and are situated in the CL intracellular spaces. Ceramids having relatively short nonbranched and saturated alkyl chains are primarily tied with the hydrophilic function. Acylceramids with linoleic acid and ceramids with long alkyl chains are responsible for the protective function. Thus, the hydrophilic and the protective properties of the CL may be independent .
This is the reason why botryomycomas (Fig. 5), contagious mollusks (Fig. 6) and warts (Fig. 7) are predominantly located at the frequently traumatized areas. Another protective mechanism against repetitive mechanical skin irritations is provided by the high-intensive mitotic activity of the basal layer and by the epidermis thickening . For example, because of frequent squeezing and friction, the palmer and plantar CL is much thicker (up to 500 microns) than elsewhere.
|Rapidly growing pyogenic granuloma of the periorbital zone.||Multiple elements of molluscum contagiosum in the armpit.||Multiple flat warts, located horseshoe-like in the calcaneal zone. Appear after injuring uncomfortable shoes.|
Protection against ultra-violet radiation
Protection against actinic damage is one of the most important and evolution-conditioned functions of the skin. Solar radiation that reaches our body surface every day consists of infrared, visible, and ultra-violet (UV) spectra. The UV radiation of spectral zone B (290–320 nm) may damage DNA molecules  while the A-zone (320–400 nm) provide sunburn, erythematous effect, and ageing of the skin. The main part of the short-wave radiation (below 320 nm) is absorbed in epidermis, thus stimulating proliferation of melanocytes, and does not reach the basal layer. The long-wave radiation (above 320 nm) penetrates into reticular layer of the dermis and into subcutaneous fatty tissue.
The skin has two main barriers against UV radiation: keratin, which is diffused mainly inside the CL, and melanin, concentrated in melanocytes. Physiological response of the skin to solar radiation manifests itself by the CL thickening and by increasing melanin level in epidermis . Under vitiligo or albinisme, when the melanin content in epidermis in insufficient, the protective reaction against UV radiation is weakened and depends more on the CL thickness. Also, R*** acid produced by keratinocytes, as well as nucleinic acids, lipids, lipoproteins, and carotenoids, possess photoprotective capacities . These substances absorb, diffuse or reflect irradiations, protect DNA, cellular proteins and membrane lipids from UV damaging. Complex damaging action of the UV radiation on the cells’ DNA and suppression of immune reactions may provoke a group of diseases, such as actinic (solar) keratoses, solar elastosis, basal or squamous cell carcinoma of skin (Fig. 8), and melanoma (Fig. 9).
|Surface-spreading basal cell carcinoma of the skin of the back of the nose, provoked by permanent sunburn.||Piogenic granuloma of pregnant women, appeared on the third month of pregnancy in the left lumbar zone.||Primary focus of melanoma of the skin of the anterior surface of the tibia with a site of ulceration in the center. Multiple satellites and foci of perifocal inflammation.|
Skin barrier in pathological processes
Skin diseases decrease protective capacities of the skin barrier: they may change the level of hydration, protein content, lipid composition of the CL, as well as cause a damage of the CL by deranging keratinocytes proliferation .
At patients affected by atopic dermatitis, there is a primary defect in epidermal barrier caused by stunting the lipid synthesis, ceramids in particular [9, 10]. This gives rise to defects in plasmatic cell membranes [11, 12]. As a result, a tenfold falling of the protective function may occur, thus giving easy way to pathogenic organisms and their toxins . An allergic contact dermatitis also lowers the CL barrier capacities and increases its susceptibility to physical stimuli and sensitizing agents .
An opinion exists that a moderate irritation of the CL enhances epidermal proliferation. Besides, the epidermal DNA synthesis increases when organic solvents derange the CL protective capacity. Such could be a manifestation of a homeostatic reaction [14, 15]. The protective function of the skin also falls at ichthyosis and psoriasis. In such cases, hyperproliferation of keratinocytes, epidermal hyperplasia, and further inflammatory reactions occur [14, 16]. Transepidermal water loss (TEWL) augments at various forms of ichthyosis, a group of diseases characterized by keratosis which may be caused either by epidermal hyperproliferation or by a slowed loss of corneocytes [14, 17, 18]. The hypothesis that CL alteration may regulate the epidermal proliferation is evident at harlequin ichthyosis when lamellar bodies are absent. Dry environment intensifies TEWL. The proliferation of keratinocites is also increasing at psoriasis ; this is confirmed by the defective differentiation of cells and by the skin permeability change [20, 21].
Active psoriasis is characterized by crucial increase of TEWL (by up to 20 times) and by multiplication of epidermal lamellar bodies. Thus, clinical signs of psoriasis may relate to changes in the skin protective function as one of mechanisms of homeostatic equilibrium. The mitotic cycle in psoriatic epidermis was experimentally proved to shorten down to 3 or 4 days. As a result, parakeratosis arises and leads to lesser permeability, because the water content in living parakerotitic cells is increased, and the skin barrier is less compact in comparison with dead corneocytes forming the CL.
In some cases, individual particularities of the patient (age, anatomical position, CL hydratation, CL damage) may favor penetration of foreign agents through the skin. During period of gestation, the skin protective capacity decreases, and this allows new skin diseases to appear or some old to progress – for example, pyogenic granulomas at pregnant women (Fig. 10).
The epidermis is the main front line of the immune system. Langerhans' cells, keratinocytes, and T-lymphocytes are responsible for initiating and providing the immune reactions in the skin.
Through powerful anti-body-producing cells, Langerhans' cells, cytokine-secreting keranocytes, and transferring lymphocytes, the epidermis ensures the afferent phase of the immune reaction and initiates its further stages. Depending on predominance of T-active cells, a group of cytokines is infused into intracellular space; the cytokines will determine whether the immune reaction is originally humoral or cellular (direct result of T-cells activity). An important function of the skin is to provide a protective barrier between the individual and his environment. The skin barrier confines the water losses, minimizes toxic substances inflow, and resists mechanical injuries. The skin capability to buildup barrier preserving the body against aggressive microorganisms and toxins depends on age, immunological state, and health level of the individual. Healthy skin is a guaranty of sound health.
O. V. Bogomolets, M.D., Coordinator of European Laser Dermatology Association in Eastern Europe
1. Blank I. Cutaneous barriers. J Invest Dermatol 1965; 45: 249-56
2. Dikstein S., Zlotogorski A. Measurement of skin pH. Acta Derm Venereol 1994; 185 (Suppl.): 18-20
3. Miller S., Aly R., Shinefeld H., Elias P. In vitro and in vivo antistaphylococcal activity of human stratum corneum lipids. Arch Dermatol 1988; 124:209-15
4. Imokawa G., Kuno H., Kawai M. Stratum corneum lipids serve as a bound-water modulator. J Invest Dermatol 1991; 96:845-51
5. Williams M., Elias P. From basket weave to barrier: unifying concepts for the pathogenesis of disorders of cornification. Arch Dermatol 1993; 129:626-8
6. MacKenzie I. The effects of frictional stimulation on mouse ear epidermis. I: cell proliferation. J Invest Dermatol 1974; 62:80-5
7. Stierner U. Melanocytes, moles and melanoma. A study on UV effects. Acta Derm Venereol 1991; 168(Suppl.):l-31
8. Baden H., Pathak M. The metabolism and function of urocanic acid in skin. J Invest Dermatol 1967; 48:11-17
9. Werner Y., Lindberg M. Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta Derm Venereol 1985; 65:102-5
10. Imokawa G., Abe A., Jin K., Higaki Y., Kawashima M., Hidano A. Decreased levels of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 1991; 96:523-6
11. Schafer L., Kragballe K. Abnormalities in epidermal lipid metabolism in patients with atopic dermatitis. J Invest Dermatol 1991; 96:10-15
12. Ogawa H., Yoshiike T. Atopic dermatitis: studies of skin permeability and effectiveness of topical PUVA treatment. Pediatr Dermatol 1992; 9:383-5
13. Brasch J, Burgard J, Sterry W. Common pathogenic pathways in allergic and irritant contact dermatitis. J Invest Dermatol 1992; 98:166-70
14. Williams M. Ichthyosis: mechanisms of disease. Pediatr Dermatol 1992; 9:365-8
15. Proksch E., Feingold K., Mao-Quiang M., Elias P. Barrier function regulates epidermal DNA-synthesis. J Clin Invest 1991; 87:1668-73
16. Ghadially R., Reed J., Elias P. Stratum corneum structure and function correlates with phenotype in psoriasis. J Invest Dermatol 1996; 107:558-64
17. Frost P., Weinstein G., Bothwell J., Wildnauner R. Ichthyosiform dermatoses. III. Studies of transepidermal water loss. Arch Dermatol 1968; 98:230-3
18. Lavrijsen A., Oestmann E., Hermans E., Bodde H., Vermeer B., Ponec M. Barrier function parameters in various keratinization disorders: transepidermal water loss and vascular response to hexyl nicotinate. Br J Dermatol 1993; 129:547-54
19. Dover R., Watt F. Measurements of the rate of epidermal terminal differentiation: expression of involucrin by S-phase keratinocytes in culture and in psoriatic plaques. J Invest Dermatol 1987; 89:349-352
20. Blichmann C., Serup J. Reproducibility and variability of transdermal water loss measurements. Acta Derm Venereol 1989; 67:206-10
21. Bernard F., Magnaldo T., Darmon M. Delayed onset of epidermal differentiation in psoriasis. J Invest Dermatol 1992; 98:902-10.