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Effect of narrow-band ultraviolet B on the expression of human β-defensin 2 in psoriatic patients, using immunohistochemistry

Aly, Adel A.S.a; AbdElMaksoud, Rania A.S.a; El Gendi, Saba M.b; Amin, Olaa

Egyptian Journal of Pathology: July 2013 - Volume 33 - Issue 1 - p 42–49
doi: 10.1097/01.XEJ.0000429925.93864.f7
ORIGINAL ARTICLES
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Background Administration of narrow-band ultraviolet B (NB-UVB) is a routine treatment modality for psoriasis, but its effect on human β-defensin 2 (HBD2) level has not been well studied.

Aim of the study The aim of the study was to assess immunohistochemically the expression of HBD2 in patients before treatment and compare the results with controls and also assess immunohistochemically the expression of HBD2 in psoriatic lesions before and after NB-UVB phototherapy treatment, thereby assessing the effect of NB-UVB phototherapy treatment on HBD2 expression.

Patients and methods This study included 30 patients with psoriasis and 30 age-matched and sex-matched controls.

HBD2 expression was detected by immunohistochemical analysis in patients before and after NB-UVB treatment. It was also detected in control specimens, which were obtained from excess skin that was removed as a routine during procedures such as abdominoplasty and partial thickness skin grafting in the plastic surgery department.

Results HBD2 was found to be highly expressed in normal individuals.

HBD2 was also found to be highly expressed in patients before NB-UVB treatment but showed a significant decrease in expression after treatment (P<0.001).

Conclusion The study found that there was a noticeable increase in the expression of HBD2 in normal individuals.

The present study shows that, in addition to a significant improvement in psoriasis, NB-UVB decreased HBD2 levels in healing psoriatic lesions.

Departments of aDermatology, Venereology and Andrology

bPathology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Correspondence to Rania A.S. AbdElMaksoud, MD, Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Alexandria University, Alexandria, Egypt Tel: +00201229992543; e-mail: drranyah2002@ymail.com

Received January 5, 2013

Accepted March 12, 2013

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Introduction

Psoriasis is a common chronic skin disease, affecting ∼2% of the world’s population (Nestle et al., 2009).

Psoriasis is considered an organ-specific autoimmune disease that is triggered by an activated cellular immune system involving innate and adaptive mechanisms. Clinically and histologically, psoriasis has a well-characterized appearance (Lowes et al., 2007).

The exact etiology of psoriasis has not been completely understood yet, and it is suggested that the psoriatic epidermis and dermis are genetically programmed with capacity to express the disease. The evolving evidence suggests that psoriasis is a complex disorder caused by the interaction between multiple genes, the immune system, and environmental factors (Krueger, 2002).

Studies have shown the presence of immune cells in patients with psoriasis, suggesting a possible pathogenic role. Scientific evidence accumulated since then provides support for a functional role of a dysregulated immune system in psoriasis (Galadari et al., 2005).

Thus, psoriatic lesions probably evolve as an interplay between cells and mediators of the immune system – specifically, between its innate and adaptive function, skin epithelium, and connective tissue (Krueger and Ellis, 2005).

Initially, antimicrobial peptides (AMPs) were characterized as effector molecules of innate immunity as they provide a first barrier of defense against microbial pathogens (Lai and Gallo, 2009). In the meantime, an array of additional functions of AMPs have been identified, and because of their multiple functions as activators of adaptive immune responses and inflammation the term ‘alarmins’ has been introduced (Büchau and Gallo, 2007).

Two families of AMPs are among the best characterized for their ‘alarmin’ function: the defensins and the cathelicidins.

Defensins are a family of evolutionarily related vertebrate AMPs with a characteristic β-sheet-rich fold and a framework of six disulfide-linked cysteines (Ganz, 2003).

The two main defensin subfamilies, α-defensins and β-defensins, differ in terms of the length of peptide segments between the six cysteines and the pairing of the cysteines, which are connected by disulfide bonds (Lai and Gallo, 2009).

β-Defensins are secreted peptides of low molecular weight ranging from 3 to 5 kDa. These peptides, which are expressed by epithelia, possess a broad spectrum of antimicrobial activity against both Gram-positive and Gram-negative bacteria, fungi, and viruses (Ganz, 2003).

Besides antimicrobial activity, they also exhibit proinflammatory properties such as acting as chemoattractants for memory T cells, immature dendritic cells, mast cells, and neutrophils (Niyonsaba et al., 2004).

It has also been shown that AMPs in general, and above all human β-defensin 2 (HBD2), are induced in lesional epidermal cells of patients with psoriasis, compared with lesional epidermal cells of patients with atopic dermatitis and normal skin (De Jongh et al., 2005). These findings have been interpreted to explain the relatively low prevalence of bacterial and viral infections among psoriasis patients (Wahba-Yahav et al., 1996).

HBD2 and HBD3 were isolated from psoriatic scales by Harder et al. (2001).

Known studies suggest a role for defensins and cathelicidins in the pathogenesis of skin inflammation in psoriasis (Lande et al., 2007). In particular, increased gene copy numbers of HBDs correlate with the risk of developing this disease (Hollox et al., 2003), and cathelicidin peptide, which is increased in psoriatic skin, induces an autoinflammatory cascade leading to skin inflammation (Ong et al., 2002).

The mechanism of induction of HBD expression has been studied by many groups but the role of these peptides in the pathogenesis of psoriasis has not been fully understood, although the abundance of AMPs in psoriatic skin offers an explanation that patients with psoriasis suffer from fewer cutaneous bacterial and viral infections than expected (Ong et al., 2002).

The aim of the present study was to assess immunohistochemically the expression of HBD2 in patients before treatment and compare the results with controls, and detect the effect of narrow-band ultraviolet B (NB-UVB) on HBD2 expression level in psoriatic lesions before and after treatment.

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Patients and methods

The present study was conducted on 30 patients who were classified as follows: group A1 – this group included 30 psoriatic patients before NB-UVB treatment; group A2 – this group included 30 psoriatic patients after NB-UVB treatment; group B – this group included 30 age-matched and sex-matched control individuals (their specimens were taken from excess skin removed from the thigh and abdomen as a routine during operations in the plastic surgery department of Alexandria University Hospital). Informed written consent was taken from the patients before beginning the study. To be included in the study patients had to be suffering from psoriasis affecting 20% or more of their body surface area (Prignano et al., 2009). Psoriasis Area and Severity Index (PASI) score was estimated for all patients to record their baseline scores. Topical treatments apart from emollients and salicylic acid were stopped at least 2 weeks before the study. Patients exposed to phototherapy or solarium during the preceding 2 months were excluded from the study.

Thirty patients were subjected to NB-UVB radiation (311 nm) for a total of 15–21 times 3 times a week (Kleinpenning et al., 2009).

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Light source

A Waldmann UV 7001K Light Cabin (Waldmann Medizinische Technik, Villingen-Schwenningen, Germany) with Philips TL-01 Lamps (Philips, Eindhoven, the Netherlands) (311 nm) was used (Kleinpenning et al., 2009).

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Dosing schedule

The approach used involved a standard starting dose of 0.3 mJ/cm2, with stepwise increase (usually 20%) depending upon the patient’s erythema response (Dogra and Kanwar, 2004; Amer et al., 2007).

The dosage of UVB may also be administered according to the Fitzpatrick skin type with subsequent dosages adjusted accordingly (Menter et al., 2010).

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Regimen

The standard starting dose was 0.3 mJ/cm2, with stepwise increase (usually 20%) depending on the patient’s erythema response (Dogra and Kanwar, 2004; Amer et al., 2007). Treatment schedule was 3 times/week. The increase in the irradiation dose depended on erythema response 48 h after the last treatment. Increments given at each visit were based on a percentage of the previous dose and erythema response. Depending on the grade of erythema the irradiation dose was adjusted.

Patients were assessed after treatment using the PASI score and classified as follows: those with mild psoriasis (PASI<10); those with moderate psoriasis (PASI≥10); and those with severe psoriasis (PASI≥20) (EMEA, 2003).

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Skin biopsies and immunohistochemistry

HBD2 immunohistochemical expression was estimated for all collected skin biopsies from psoriatic patients before and after NB-UVB treatment as well as from healthy controls using the avidin–biotin method (Hsu et al., 1981).

Punch biopsies of 6 mm thickness were taken from the psoriatic skin before treatment. Control skin biopsies were obtained from excess skin removed as a routine during operations performed in the plastic surgery department.

The skin specimens were fixed in 10% neutral buffered formalin and processed to formalin-fixed paraffin-embedded blocks.

All blocks were cut into 3-μm-thick sections, mounted on glass slides, and subjected to conventional H&E staining to assess histopathologic changes (Drury and Wallington, 1980). The rest of the specimen was prepared for immunohistochemical staining.

Tissue sections were analyzed to determine the histopathological features of psoriasis.

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Grading of immunohistochemical staining (De Jongh et al., 2005)

Expression of HBD2 was assessed in two ways:

First, distribution of HBD2 (HBD2 intensity score), which is the measurement of HBD2 distribution in the epidermis, was scored on a three-point scale: 0, absent; 1, patchy; 2, continuous.

Second, the HBD2 mean score was calculated, which is the mean of three measurements. Each measurement is the positively stained area of the epidermis, which was expressed as the mean ratio of positive cell layers divided by the total number of epidermal cell layers in a rete ridge.

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Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percentage. Quantitative data were described using median, minimum and maximum values, and mean and SD. The study protocol was approved by the Ethics Committee of the Faculty of Medicine, University of Alexandria.

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Results

Analysis of HBD2 expression in the epidermis of both psoriatic patients before treatment and controls revealed high expression in both groups: 86.7% of specimens in each group had an HBD2 intensity score of 2. Hence, there was no significant difference between the two groups regarding the HBD2 intensity score (Table 1).

Table 1

Table 1

Analysis of HBD2 expression levels before and after NB-UVB treatment revealed significantly decreased levels of HBD2 after treatment (Fig. 1 and Table 2).

Fig. 1

Fig. 1

Table 2

Table 2

Table 2 shows the HBD2 intensity score before and after treatment. It was seen that the majority of patients after treatment had an intensity score of 1 (n=28, 93.3%), whereas only two (6.7%) patients had an intensity score of 2 after treatment. The intensity score of most of the patients decreased from 2 to 1 (n=24, 80.0%). This decrease was statistically significant (Z=4.90, P<0.001). Four patients remained at score 1 (not changed before and after treatment) (n=4, 13.3%). Two patients remained at score 2 (not changed before and after treatment) (n=2, 6.7%).

We also proved that NB-UVB significantly improves psoriasis as it improved PASI from a mean of 16.93 (SD=4.35) to a mean of 3.64 (SD=1.73) (Tables 2 and 3 and Figs. 2–6).

Table 3

Table 3

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Fig. 4

Fig. 4

Fig. 5

Fig. 5

Fig. 6

Fig. 6

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Discussion

In this study we confirmed strong epidermal expression of HBD2 in the psoriatic plaque at the protein level, which was in agreement with the results of other studies of De Jongh et al. (2005), Guttman-Yassky et al. (2008), Jansen et al. (2009), and Gläser et al. (2010). Other studies proved the expression of HBD2 at the mRNA level (De Jongh et al., 2005; Gambichler et al., 2008; Guttman-Yassky et al., 2008; Jansen et al., 2009; Peric et al., 2009). Two studies reported HBD2 expression in the serum of psoriatic patients (Jansen et al., 2009; Gambichler et al., 2012).

Our study showed that HBD2 expression was strongly expressed in controls and in patients before NB-UVB treatment, which might be explained by several factors such as racial variation, skin flora, and ultraviolet (UV) radiation.

The controls in our study were from the Middle East, whereas in other studies the controls were from the UK and Europe.

This racial variation in AMP expression is supported by four factors that are universally agreed upon (Lewontin, 2005).

First, there exists immense genetic variation among individuals belonging to the human species. Any two unrelated human beings differ by about three million distinct DNA variants.

Second, the genetic variation in each population depends on the extent of immigration into it from other populations and also depends on its size.

Third, a small number of genetic traits, such as skin color, hair type, nose shape (traits for which the genes have not actually been identified), and a few proteins such as the Rh blood type vary together so that many populations with very dark skin color also have dark tightly curled hair, a broad nose, and a high frequency of the Rh blood type R0.

Fourth, these differences between groups are in the process of disintegrating because of the extent of migration and intergroup mating that was always prevalent but is now more widespread than ever.

Our control results were also affected by skin flora.

Human skin flora refers to the entire collection of microbes, which include bacteria, archaebacteria, fungi, virus, and mites. The type and number of skin microbiomes vary from one individual to another and from one region of the body to another.

There is both an intrapersonal and an interpersonal variation in skin microflora. Bacterial colonization depends on the physiology of the region sampled with humidity and sebaceous environment influencing the type of bacteria. Interpersonal variation depends on intrinsic factors such as the individual’s state of health, age, and sex and on extrinsic factors such as clothing, hygiene, humidity, and occupation (Kiprono et al., 2012).

Larson et al. (2000) reported a significantly larger number of colony-forming units among African Americans. The variation may be because of external factors such as humidity, weather conditions, type of clothing, and the level of hygiene, which have been reported to influence bacterial skin colonization.

Our result agreed with those of Ali et al. (2001), in whose study HBD2 was detected in 18 of 25 (72%) normal skin samples analyzed. HBD2 expression was found in 100% of the facial and foreskin samples analyzed but only in 50% of skin samples from the breast and abdomen (four of nine patients), suggesting regional variation in levels of HBD2 expression between facial skin/foreskin and breast/abdominal skin. Regional variations in expression may reflect variations in skin flora, cell turnover, or other factors, such as UV radiation exposure, which can activate nuclear factor-κB, which regulates HBD2 transcription. In addition, there were interindividual differences but no significant age or sex variation.

To show how UV exposure affects HBD2 expression, Gläser et al. (2009) showed that in skin explants (which were taken from the plastic surgery department) UV radiation induces different classes of keratinocyte-derived AMPs both in vitro and in vivo and both at the mRNA and at the protein level in human beings. Among other AMPs, HBD2 mRNA was clearly induced by UV radiation. This induction by UV radiation appears to be one of the first indications that UV radiation may foster the innate immune response. Because UV exposure can result in a disruption of the epidermal barrier and thus may increase the risk for bacterial infections, induction of AMPs as a counter-regulatory phenomenon may be beneficial.

In contrast to our results, De Jongh et al. (2005) showed that HBD2 is absent in normal epidermis, although it can be found in some regions (e.g. the face). The authors did not find epidermal HBD2 expression at the protein level in normal skin biopsies (from the trunk) in nine different individuals. Also, by qPCR it is barely detectable.

Our finding that HBD2 level was elevated in psoriatic skin and also highly expressed in normal healthy controls was in contrast to the results of other studies, such as the one by Jansen et al. (2009), who reported low levels of HBD2 mRNA in normal tissues and hence low levels of HBD2 protein in circulation, and those by Peric et al. (2009), Kim et al. (2010), and Vähävihu et al. (2010), who proved that it was elevated in psoriatic skin compared with healthy skin.

Despite the fact that HBD2 was highly expressed in controls as well, apart from psoriatic patients before treatment, in our study, HBD2 was thought to play a role in psoriasis pathogenesis. Psoriasis is a multifactorial disease that plays an important role in the expression of HBD2. Mature dendritic cells produce multiple cytokines that promote differentiation and expansion of Th1 [i.e. interleukin (IL)-12], and Th1 cytokines [i.e. IL-21, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α)] induce keratinocytes to produce CCL20, a chemoattractant for CCR6-expressing dendritic cells and T cells, thus promoting the accumulation of these cells in psoriatic skin (Monteleone et al., 2011).

It was reported by Joly et al. (2005) that the induction of Th1 response – that is, TNF-α and IFN-γ – might directly induce or enhance the expression of HBDs. IL-1β, TNF-α, and IFN-γ were determined to be the most frequent inducers of the three β-defensins. Further, it was found that the expression of HBD2 was evidently higher when IL-1β and TNF-α were combined (average of four-fold increase compared with IL-1β induction alone).

We reported that the mean of PASI before treatment was 16.93 and it decreased to 3.64 after treatment; we also reported that the HBD2 intensity score of most of the patients (n=24.80%) decreased from 2 to 1, which was statistically significant (Z=4.68, P<0.001). However, the correlation between PASI and HBD2 intensity score could not be proved statistically, which might have been because of the small sample size.

Nevertheless, it can be reported that there was an increase in PASI score and also an increase in HBD2 expression level before treatment, which was in agreement with the results of Jansen et al. (2009). Although the results of Vähävihu et al. (2010) with respect to the decrease in HBD2 after NB-UVB were also similar to our results they did not correlate this decline with disease severity. In contrast, Gambichler et al. (2012) showed that serum HBD2 did not correlate with disease severity.

In our study we proved that HBD2 level decreased after treatment with NB-UVB; this finding was in agreement with that of Vähävihu et al. (2010), who concluded that repeated NB-UVB treatment significantly reduced HBD2 expression in psoriatic lesions by reduction of IL-1β and IL-17A, which were found in significantly higher amounts in psoriatic skin lesions.

From the study by Gläser et al. (2009) it is obvious that UV radiation at low (suberythemogenic) doses suppresses the adaptive immune response through the suppression of T-cell-mediated immune response and thus suppresses the cytokines that induce HBD2. Most of the inflammatory dermatoses are T-cell driven. Thus, one may speculate that a certain degree of immunosuppression by daily solar exposure may prevent the induction of these unwanted immune responses.

From the previous results, and from those of Wainwright et al. (1998), Tanew et al. (1999), Dawe (2003), and Berneburg et al. (2005), we can conclude that NB-UVB is an effective treatment modality in psoriasis patients.

We did not use the minimal erythema dose method inNB-UVB treatment. Instead, the dosage regimen was as per Dogra and Kanwar (2004) and Amer et al. (2007): a standard starting dose of 0.3 mJ/cm2, with a stepwise increase (usually 20%) depending upon the patient’s erythema response was followed. Another study reported that the dosage of UVB may be administered according to the Fitzpatrick skin type with subsequent dosages adjusted accordingly (Menter et al., 2010).

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Summary

High concentrations of AMPs have been observed in specimens of psoriatic skin from patients, which supports the hypothesis that patients with psoriasis possess an unusually high ‘chemical skin barrier,’ which may account for their low rate of susceptibility to infections (Wahba-Yahav et al., 1996).

HBD2 is a secreted peptide of low molecular weight ranging from 3 to 5 kDa. These peptides, which are expressed by epithelia, possess a broad spectrum of antimicrobial activity against both Gram-positive and Gram-negative bacteria, fungi, and viruses (De Jongh et al., 2005).

The present study included 60 individuals divided into three groups: group A1 included patients before treatment and group A2 included patients after treatment with NB-UVB. Group B included 30 age and sex-matched controls.

The patients were subjected to history taking and clinical examination to determine the clinical type of psoriasis. PASI score was estimated before and after treatment. Skin biopsy was taken before the start of NB-UVB treatment and then another biopsy was taken from healed psoriatic lesions and to detect HBD2 expression in both groups. Moreover, control specimens were subjected to estimation of HBD2 immunohistochemically.

The study found that there was significant increase in the expression of HBD2 in psoriatic patients and in normal individuals. The study also found that there was significant decrease in the expression of HBD2 in psoriatic lesions after treatment with NB-UVB.

We reported that there was a decrease in PASI score after treatment (statistically significant) as well as a decrease in HBD2 expression level after treatment (statistically significant). However, the correlation between PASI and HBD2 expression level could not be proved statistically because of the small sample size.

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Conclusion

  • HBD2 is a skin AMP that has been suggested to have an important role in the pathogenesis of skin inflammation in psoriasis.
  • HBD2 is highly induced in psoriatic patients, which supports the finding that these patients have a low rate of susceptibility to infection.
  • Psoriasis is a chronic T-cell-mediated disease that can be significantly improved with NB-UVB treatment.
  • Repeated treatment with NB-UVB reduces the increased expression of the AMP HBD2 in healing psoriasis.
  • HBD2 is highly induced in healthy controls, which might be due to several factors such as race, skin flora, and UV radiation exposure.
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Recommendations

  • Further studies are required with larger sample sizes of patients and controls.
  • More studies are needed to study the expression of HBD2 in normal skin from different regions of the human body, as well as in the Caucasian race and in sunny countries.
  • Further studies are required on a larger scale to highlight the correlation between the level of HBD2 and psoriasis area and severity index (PASI score).
  • Further studies are required to compare the therapeutic effect of NB-UVB on HBD2 level in psoriasis.
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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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