Atopic Dermatitis (AD) is characterized clinically by chronic skin inflammation and intense pruritus, and pathologically by a defective skin barrier. We reviewed the main defects in AD epidermal barrier and the positive effects of short-term suberythemal dose of Ultraviolet B (UVB) on disrupted epidermal barrier. Although AD has a correlation with Filaggrin (FLG) loss-of-function mutations, a study showed that the defective skin barrier is not inherent. Recent knowledge on the role of inflammation in inducing the disruption of skin barrier function has helped to understand AD pathogenic mechanisms. It has been observed by many that AD becomes more prevalent in winter, when people lack sufficient UVB for vitamin D synthesis. A study has demonstrated that a suberythemal dose of UVB exposure should suffice to generate synthesis of sufficient vitamin D3 to impact downstream events in the epidermis. In conclusion, repeated short-term low doses of UVB irradiation on hairless mice significantly accelerate the kinetics of barrier recovery without clinically evident inflammation, one of the factors that disrupt the barrier function in AD. This might be a useful therapeutic strategy for the use of UVB irradiation for treating AD.
AD: Atopic Dermatitis
UVB: Ultraviolet B
SC: Stratum Corneum
LB: Lamellar Bodies
AMP: Antimicrobial Peptides
SPT: Serine Palmitoyltransferase
SCCE: Stratum Corneum Chymotryptic Enzyme
TEWL: Transepidermal Water Loss
NMF: Natural Moisturizing Factors
FAS: Fatty Acid Synthase
Atopic Dermatitis (AD) is characterized clinically by chronic skin inflammation and intense pruritus, and pathologically by a defective skin barrier. It has been observed by many that AD becomes more prevalent in winter, when people lack sufficient Ultraviolet B (UVB) for vitamin D synthesis . Thus, UVB radiation has been applied for the treatment of AD [2-4]. However, UVB irradiation on the skin is known to induce disruption of the epidermal barrier [5,6], and AD is characterized by a defective skin barrier . Moreover, long-term and/or high dose of UVB irradiation can damage the barrier function .
We reviewed the negative changes of epidermal barrier in AD and the positive changes caused by short-term low doses of UVB irradiation in the epidermal barrier, with the aim of understanding the possible therapeutic strategy on using UVB irradiation for treating AD.
Although AD has a correlation with Filaggrin (FLG) loss-of-function mutations, a study showed that the defective skin barrier is not inherent . Another study showed that there is a reduced skin barrier in AD patients, irrespective of FLG genotype, implying that other factors besides FLG loss-of-function mutations modulate skin barrier integrity . Various causes for the impaired barrier in AD have been suggested, mainly are the changes in the epidermal barrier, the disrupted Stratum Corneum (SC) .
Several studies have reported that patients with AD have a defective skin barrier that even exists in nonlesional skin as characterized by increased TEWL [7,45]. However, a study has demonstrated that the difference in the increased TEWL and reduced SC water content in patients with completely healed AD compared to normal control is not significant . Thus, the barrier function recovers to normal levels when the AD has completely healed [46,47], suggesting that the disrupted barrier function in AD can be treated and maintained at normal condition.
In intertropical zones (between latitudes 23.5°N and 23.5°S), UVB rays are more intense and vitamin D synthesis is possible throughout the year . In temperate zones (23.5°-66.5°), people lack sufficient UVB for vitamin D synthesis for 1 month during the year, while those closer to the poles do not get enough UVB radiation for most of the year [1,48-50]. It is also influenced by the season of the year, with a seasonal decline occurring in winter [1,51], the same season of the year when Atopic Dermatitis (AD) becomes worse or more prevalent.
A study by Vahavihu et al. demonstrated that 17 patients (94%) with AD had vitamin D insufficiency (calcidiol<50 nmol/L), and 7 patients among them had vitamin D deficiency (calcidiol<25 nmol/L) . A study by Peroni et al.  has demonstrated that the serum levels of 25(OH)D were higher in children with mild AD compared to those with moderate or severe cases (p<0.05) . These results suggest that vitamin D deficiency may be related to the severity of AD.
Byremo et al.  conducted a study in which 30 randomly selected children from 4-13 years of age with severe AD in Norway (subarctic/temperate climate) moved into a tropical zone for 4 weeks and the other 26 children remained in Norway, then were followed up for 3 months. A significant reduction in clinical signs and symptoms, an improvement in the quality of life index, and reduced use of topical corticosteroids was observed in the children that moved into a tropical zone after 4 weeks and 3 months (p<0.0005) . The study results suggest that enough doses of UVB radiation to generate sufficient vitamin D synthesis have the potential to treat AD.
Both natural and artificial UVB irradiations are commonly used in the treatment of AD [3,4]. The same dose of UVB exposure gives different effects on different skin types. The Minimal Erythema Dose (MED) of a fair-skinned (Fitzpatrick type I) person is approximately 10 to 25 mJ/cm2 [55,56]. Those with darker skin needs higher level of MED to produce the same effect . Therefore, in the UVB treatment, the skin type of the patients also determines the treatment dose. Exposure dose is an important factor in determining the effects of UVB exposure since UV-induced DNA damage and barrier disruption increase linearly with increasing dose [6,58].
A study on hairless mice exposed to 0.5 MED of UVB irradiation (40 mJ/cm2) daily for 3 days demonstrated positive effects of UVB on epidermis, which, at least in part, is mediated by cutaneous vitamin D3 activation . There was an upregulation of cutaneous vitamin D3 system and an increase in the mRNA levels for the epidermal lipid synthetic enzymes, HMG-CoA, Fatty Acid Synthase (FAS), and SPT . There was also an upregulation of AMP in the outer epidermis, which is thought to be mediated through cutaneous production of 1,25(OH)2D3, the most active form of vitamin D3. There was also an increase in the expression of involucrin and FLG, without the concurrent development of epidermal hyperplasia, implying that UVB can also regulate the epidermal differentiation . Moreover, there was no clinically evident inflammation or barrier disruption . Another study using 0.5 MED of UVB irradiation for 3 days prior to tape-stripping showed significantly accelerated barrier recovery rates [6,59].
According to a study by Janssens et al., decreased CER [EOH] level and increased CER [AS] level in AD patients are most significantly associated with TEWL . Therefore, to increase the level of CER [EOH] and to decrease the level of CER [AS] might be a novel therapeutic entry to repair skin barrier defects in AD patients. A study by Jakob Mutanu Jungersted et al. demonstrated that after 18 treatments of UV light therapy (UVB, UVA, and psoralen+UVA), CER [EOH] was increased and CER [AS+AH] were decreased. The dosage and period of UV light therapy were not mentioned . A study by Yutaka Takagi et al. demonstrated that a single UVB irradiation at a dose of 75 mJ/cm2 impaired the skin barrier. The results showed increased level of CER [EOH] and CER [AS] simultaneously. However, a closer look at the result showed that the ratio of CER [EOH] to CER [AS] was slightly increased after UVB irradiation. This shows an interesting potential of UVB irradiation on improving the average Cer chain length, even at a dose known to disrupt the skin barrier . Further studies to investigate the effectiveness of short-term suberythemal UVB on average CER chain length in AD patients are required.
1,25(OH)D has been demonstrated to increase expression of major epidermal differentiation proteins, such as involucrin, loricrin, FLG, and transglutaminase, as well as to stimulate cornified envelope formation . In vitro studies show that 1,25(OH)D induces the expression of cathelicidin-a broad spectrum AMP-in keratinocytes . Exposure to UVB radiation in sunlight is the most efficient way to boost vitamin D supply but it is still unclear how much sunlight is required to produce a given level of 25(OH)D. Environmental and personal factors greatly affect vitamin D production in the skin, making it impossible to recommend a one-size-fits-all level of exposure for the general population. It has been consistently shown that vitamin D can be efficiently and sufficiently produced at doses of UVB below those which cause reddening of the skin or sunburn [62,63]. A suberythemal dose of UVB exposure should suffice to generate synthesis of sufficient vitamin D3 to impact downstream events in the epidermis leading to barrier recovery [6,59].
Amestejani et al.  conducted a study in which 30 AD patients received vitamin D 1,600 IU/day and the other 30 AD patients received placebo. After 60 days, the group treated with vitamin D improved significantly, regardless of the initial severity of AD (p<0.05), whilst the improvement in the placebo group was not significant (p>0.05) . A study by Byremo et al.  demonstrated that 30 randomly selected children from 4-13 years of age with severe AD in Norway (subarctic/temperate climate) were significantly improved after they were moved into a tropical zone for 28 days. The study results show that the effect of vitamin D supplementation will be significant after 60 days of daily vitamin D intake, whilst the effect of natural exposures (no known average doses of UVB exposure) of AD patients to sunlight (UVB radiation) will be significant after 28 days.
The present literature evidences show that a short-term suberythemal UVB therapy may benefit AD patients by yielding several advantages: a relatively quick treatment outcome, a direct effect on the epidermal barrier since UVB exposures can be directed only onto the lesional AD skin, the treatments are done with controlled unharmful UVB doses by experts in this field, and less responsibility especially for children to take daily vitamin D3 supplementation. A study comparing the effects and costs of vitamin D supplementation with a short-time suberythemal UVB course in the treatment of AD would be of importance.
The defective skin barrier in AD is not inherent. Inflammation-induced downregulation of caspase 14 and decreased average CER chain length with subsequent loss of NMF may be responsible for disrupting the barrier function of AD skin, regardless of FLG mutations. Therefore, AD can be healed and maintained at normal condition. Repeated, short-term exposures to low-dose UVB on hairless mice significantly accelerate the kinetics of barrier recovery without clinically evident inflammation. Since inflammation is one of the factors that may disrupt the barrier function in AD, using UVB irradiation while attempting to avoid further barrier disruption and/or inflammation might be a useful therapeutic strategy for the use of UVB irradiation for treating AD. Further studies are needed to determine the efficacy of the repeated short-term exposures to low dose UVB irradiation on the skin of patients with AD.
This work was supported by Grants from the China National Natural Science Foundation (81000700, 81171518, and 81301384), science project from Traditional Chinese Medicine Bureau of Jiangsu Province (LZ11084), Jiangsu National Natural Science Foundation (BK2012877), and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.
Citation: Permatasari F, Zhou BR, Luo D (2014) Epidermal Barrier: Negative Changes in Atopic Dermatitis and Positive Changes Induced by Short-term Suberythemal Ultraviolet B Irradiation. J Clin Dermatol Ther, 1: 001.
Copyright: © 2014 Felicia Permatasari, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.