INTRODUCTION

Psoriasis is a genetically determined immune-mediated, inflammatory skin disease.[1] Both T helper type 1 “Th1” and T helper type 17 “Th17” cytokines play a role in its pathogenesis. This cytokines mixture act on dermal and epidermal cells, altering the gene expression and maturation of keratinocytes and other cells.[2] Vitamin D is produced by keratinocytes following exposure to sunlight; it regulates multiple immunological functions, in addition to skeletal ones.[3] Vitamin D receptor (VDR) is a nuclear receptor that mediates most of the known functions of 1,25-dihydroxyvitamin D (1,25(OH)₂D₃), the active metabolite of vitamin D[4], that acts mainly on the VDR to regulate the epidermal keratinocyte growth and differentiation.[5] It also inhibits the production or the expression of the Th1 and Th17 cytokines.[6] Resting T-cells express mostly undetectable VDR levels, which increase as T-cells proliferate in response to antigenic activation.[7] In absence of the VDR, Th17 and Th1 cells are highly pathogenic.[8]

Vitamin D deficiency is associated with psoriasis and could play a significant role in its pathogenesis.[9] The clinical significance of hypovitaminosis D in psoriasis as well as the role and mode of its administration are topics currently under study.[3] Phototherapy increases the levels of serum 25(OH)D in patients with psoriasis,[10] and it has been proposed that narrowband ultraviolet (UV) B radiation may mediate its beneficial effect on psoriasis also by increasing endogenous vitamin D levels.[111213]

The observation that keratinocytes and T cells express VDR and that 1,25(OH)2D is a potent stimulator of keratinocyte differentiation provides a potential basis for the clinical use of VDR ligands for the treatment of psoriasis.[1415]

SUBJECTS AND METHODS

METHODS

RESULTS

Immunohistochemical results of VDR expression

VDR expression was evaluated according to Viscont et al.[16] in the studied patients as follows:

For non-lesional skin

VDR was expressed in the nuclei of the epidermal cell layers of all specimens. 18 (45%) with a moderate degree of positivity (+2), and 22 (55%) with a marked degree of positivity (+3) [Figure 1A and Table 2].

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Figure 1

(A) Non lesional skin of chronic plaque psoriasis showed marked (+3) expression of VDR in both basal cell layer and prickle cell layer (streptavidin–biotin ×200). Chronic plaque psoriasis (lesional skin) (B) before treatment with NB-UVB showed mild (+1) expression of VDR in basal cell layer (streptavidin–biotin ×40), (C) after treatment with NB-UVB showed marked (+3) expression of VDR all layers of epidermis (streptavidin–biotin ×100)

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Table 2 Comparison between VDR expression in lesional skin before and after treatment with NB-UVB and non lesional skin of the studied patients

	VDR
	Non lesional skin (n = 40)		Lesional skin before NB-UVB (n =40)		Lesional skin after NB-UVB (n = 40)
	No.	%	No.	%	No.	%
Negative	0	0.0	6	15.0	0	0.0
Mild	0	0.0	8	20.0	6	15.0
Moderate	18	45.0	16	40.0	16	40.0
Marked	22	55.0	10	25.0	18	45.0
Non lesional versus lesional skin before NB-UVB			MHχ2		3.411*
			P		0.001*
Lesional skin before versus after NB-UVB			t		4.819
			P		0.000*

^MHχ²: Chi square for marginal homogeneity test

* Statistically significant at P ≤ 0.05

For lesional skin of psoriatic patients before NB-UVB

VDR was expressed in the nuclei of epidermal cell layers in 34 patients (85%) with different degrees of positivity. Eight of them (20%) with a mild degree of positivity (+1) [Figure 1B], 16 (40%) had a moderate degree of positivity (+2), and ten (25%) with a marked degree of positivity (+3) [Table 2].

VDR expression was statistically decreased in lesional skin before NB-UVB compared to non-lesional skin of the studied psoriatic patients (P value = 0.001*) [Table 2].

For lesional skin of psoriatic patients after NB-UVB

VDR was expressed in the nuclei of epidermal cell layers in all the patients (100%) with different degrees of positivity. Six of them (15%) with a mild degree of positivity (+1), 16 (40%) had a moderate degree of positivity (+2), and 18 (45%) with a marked degree of positivity (+3) [Figure 1C and Table 2].

Relation between VDR expression in lesional skin before treatment and clinical parameters of the patients

The VDR expression did not show any statistically significant difference regarding gender or age of the patients or age of onset of the disease.

The strength of VDR expression was negatively correlated with the following: duration of the disease (P value = 0.036*), the family history of the disease (P value = 0.032*), and PASI score (P value = 0.001*).

Relation between VDR expression in lesional skin after treatment with NB-UVB and before treatment.

VDR expression was statistically increased in lesional skin post-treatment with NB-UVB compared to lesional skin before treatment (P value = 0.000*) [Table 2] [Graph 1].

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Graph 1

Correlation between VDR expression in lesional skin before and after treatment with NB-UVB

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DISCUSSION

The current study was conducted on forty patients with different severities of chronic plaque psoriasis, immunohistochemistry staining of VDR was performed for perilesional and lesional skin before NB-UVB therapy, then for lesional skin after completing sessions of NB-UVB therapy.

VDR expression was significantly increased in lesional skin after NB-UVB sessions compared to pretreatment level, P = 0.000*. Up to the best of our knowledge, there is no available literature about the immunohistochemical expression of VDR in psoriasis patients after exposure to NB-UVB compared to pretreatment level. These results may suggest an additional mechanism for the therapeutic effect of NB-UVB on psoriasis. El-Hanbuli et al.[17] detected improved VDR expression in the skin and serum 25-hydroxyvitamin D [25(OH)D] in vitiligo patients after NB-UVB therapy.

Studies done by Ryan et al.,[11] Wheinhold et al.[18] and Gupta et al.[19] found that NB-UVB (310–315 nm) treatment of psoriasis increased serum 25(OH)D levels together with PASI score improvement.

Chen et al.[20] detected increased VDR mRNA in psoriasis lesions treated with 1,25(OH)₂D₃ compared to lesions treated with Vaseline, While Ala-houhala et al.[21] demonstrated that serum 25-OH vitamin D levels increased by 58% from baseline when patients received oral vitamin D concurrently.

Vitamin D via VDR exerts an immunosuppressive, anti-proliferative, and pro-differentiation effect on the skin. Thus, VDR may play a role in controlling immune-mediated diseases, including psoriasis through its effect on regulating the functions of the epidermal barrier and/or local immune response.[22] It is known that vitamin D3 inhibits the production of IL-2 and IL-6, blocks transcription of IFN-γ and granulocyte-macrophage colony-stimulating factor mRNA, and inhibits cytotoxic T cells and natural killer cell activity.[4]

In the present study, VDR expression was detected in the nuclei of epidermal cell layers in psoriasis lesions and non-lesional skin except in the stratum corneum. These results agreed with the results of Milde et al.[23] and Solvsten et al.[24]

The present study detected a statistically significant decrease of VDR expression in lesional skin compared to non-lesional skin of psoriatic patients (P value = 0.001*). These results agreed with the studies done by Kim et al.[25] and Khalil et al.[26]

Visconti et al.[16] found a reduction of VDR expression in psoriasis skin compared to normal skin. This could be explained by the anti-proliferative effect of the VDR on keratinocytes. Also, they suggested a new role of VDR in the maintenance of the homeostasis of the skin barrier through its ability to modulate junctional protein expression.[16] This could be supported by the in vitro culture systems done by Kong et al.[27] treated with 1,25 (OH)₂D₃ for 24h, which showed increased levels of tight junction proteins ZO-1 and claudin-1.

Contrary to our results, Milde et al.[23] showed a significant increase in VDR expression in basal and suprabasal epidermal keratinocytes and the skin immune system cells in lesional psoriatic skin compared to non-lesional skin. The keratinocytes, activated macrophages, and melanoma cells have the ability to convert 25-hydroxyvitamin D₃ into the active metabolite 1,25(OH)₂D₃in vitro. This might explain the role of 1,25(OH)₂D₃ in normal differentiation and immune response in the skin.[23]

The results of the current study disagreed with the results of Jensen et al.[28] and Solvsten et al.[24] They did not detect any significant difference in VDR levels between uninvolved and involved psoriatic skin.

The discrepancy of the results of the studies done on VDR (onset or therapy of disease) could be explained on the basis of genetic variation of the studied groups, different sampling strategies, more specifically, different constituent ratios of patients in terms of clinical types of psoriasis, age of onset of the disease, family history, size of the population samples, and therapeutic response to different treatment modalities with different concentrations.[29]

The present study detected a significant negative correlation between VDR expression and PASI score, this could support the possible role of this receptor in the severity of psoriasis. This agreed with the results of Chandra et al.[30] While Morimoto et al.[31] found a significant negative correlation between serum concentration of 1,25-(OH)₂D and the severity of psoriatic skin lesions. El-Farargy et al.[32] showed a significant negative correlation between serum 25-hydroxyvitamin D and PASI score, duration of disease. However, Nayak et al.[33] did not find a correlation between serum 25(OH) and PASI score

It has been found that, topical calcipotriol treatment increased the expression of VDR on keratinocytes, therefore its effect on the proliferation and differentiation of keratinocytes was more than on dermal inflammation.[2021,34]

On the other hand, Zuel-Fakkar et al.[35] and Okita et al.[36] did not reveal any correlation between VDR gene polymorphisms and psoriasis development.

There were statistically significant correlations between degree of VDR expression and both of family history of the disease (P value =0.032*) and duration of the disease (P value =0.036*). Dayangac-Erden et al.[37] Kaya et al.[38] Park et al.[39] concluded that VDR gene was associated with familial psoriasis

It was postulated that VDR gene polymorphism influences serum level of vitamin D and consequently has an impact on the genetic susceptibility to psoriasis[2240] Liu et al.[41] stated that there is a relation between VDR gene polymorphisms and susceptibility to psoriasis and response to topical vitamin D (calcipotriol). On the other hand, Li et al.[42] failed to find a relation between VDR gene polymorphisms and susceptibility to psoriasis

The current study did not detect any significant correlation between VDR expression and gender, age of patients or age of onset of psoriasis. This agrees with Morimoto et al.,[31] Okita et al.[36] Zuel-Fakkar et al.[35] and Weinhold et al.[18] but, Park et al.[39] reported a significant association between VDR genotype and mean age of psoriasis onset.

Based on the current study, it could be concluded that VDR may play a key role in the pathogenesis as well as the severity of psoriasis. Our results showed increased expression of VDR in psoriasis skin lesions after NB-UVB compared to pretreatment levels, which was correlated with clinical improvement of the lesions.

The limitation of the present work was the inability to evaluate VDR in non-lesional skin after treatment because a fourth biopsy couldn’t be taken from the studied patients due to ethical considerations.