Perilesional Skin Of Patients Research Articles

An Atlas of the Hidradenitis Suppurativa Transcriptome.

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin. Both genetic and environmental factors contribute to the risk of developing HS, but the pathogenesis of this disease is currently not fully understood. The aim of this study was to further current understanding of the molecular background of HS with the use of global transcriptome analyses. Transcriptome profiling of perilesional and lesional skin of five patients with HS and six healthy control patients was performed by next-generation sequencing. Groups of differentially expressed genes characteristic of the skin of patients with HS were shortlisted by bioinformatic analysis. RNA sequencing followed by bioinformatic profiling revealed profound enrichment of inflammatory-related processes in both lesional and perilesional skin of patients with HS. There were, however, distinct differences in the gene expression profiles between the lesional and perilesional skin, with 1488 genes differentially expressed. Genes encoding typical proinflammatory cytokines were profoundly enriched within HS lesions. In contrast, those encoding mediators of extracellular matrix organization were highly expressed mostly in the perilesional area. Our study provides novel insights into the mechanisms underlying the pathogenesis of HS, and the results also have potential clinical implications in both diagnosis and therapeutics.

The lupus band test: A review of the sensitivity and specificity in the diagnosis of lupus erythematosus.

The lupus band test (LBT) is a direct immunofluorescence (DIF) technique which shows a band of localised immunoglobulins at the dermo-epidermal junction in lesional, non-sun-exposed skin of patients with both systemic and cutaneous lupus erythematosus (LE), and in perilesional skin of patients with systemic LE. However, low sensitivity and poor concordance between histological and clinical diagnoses warrant a review of the application of the LBT in the diagnosis of LE. To assess the sensitivity and specificity of the LBT in diagnosing LE following clinico-pathological correlation (CPC). All cases sent to our pathology department between 2011 and 2018 for DIF with a clinical query of LE were reviewed. Data collection included demographic details, pathology requests, histology and DIF reports, clinical reports and diagnoses, and serology. Of 256 histology requests, 9% (n=23) had a positive LBT. This was discordant with the prevalence of LE diagnosis, as 46.3% were diagnosed with LE following CPC. The sensitivity and specificity of the LBT for LE was 17.6% and 98.8% respectively, with a positive predictive value of 92.9% and negative predictive value of 58.2%. The LBT is not a sensitive diagnostic test for LE, but is highly specific, and should be considered as a supportive diagnostic tool for LE. This is the largest reported case series evaluating the efficacy of the LBT in the diagnosis of LE.

DP09 The lupus band test: a review of the sensitivity and specificity in the diagnosis of lupus erythematosus

Abstract The lupus band test (LBT) is a direct immunofluorescence (DIF) technique which shows a band of localized immunoglobulins at the dermoepidermal junction in lesional, non-sun-exposed skin of patients with both systemic (SLE) and cutaneous lupus erythematosus and in the perilesional skin of patients with SLE. However, low sensitivity and poor concordance between histological and clinical diagnoses warrant a review of the application of the LBT in the diagnosis of lupus erythematosus (LE). The aim of this study was to assess the sensitivity and specificity of the LBT in diagnosing LE following clinicopathological correlation (CPC). All cases sent to our pathology department between 2011 and 2018 for DIF with a clinical query of LE were reviewed. Data collection included demographic details, pathology requests, histology and DIF reports, clinical reports and diagnoses and serology. Of 256 histology requests, 9.0% (n = 23) had a positive LBT. This was discordant with the prevalence of LE diagnosis, as 46.3% were diagnosed with LE following CPC. The sensitivity and specificity of the LBT for LE were 17.6% and 98.8%, respectively, with a positive predictive value of 92.9% and negative predictive value of 58.2%. The LBT is not a sensitive diagnostic test for LE, but is highly specific and should be considered as a supportive diagnostic tool for LE. This is the largest reported case series to evaluate the efficacy of the LBT in the diagnosis of LE.

Dermoscopic Features of Perilesional Skin of Unstable Vitiligo: A Cross-Sectional Study

Objectives: Dermoscopy is a very useful tool in determining stability in vitiligo. Dermoscopic features of unstable vitiligo are trichrome appearance, comet tail appearance, star burst appearance, amoeboid pattern, nebular pattern, tapioca sago pattern and perifollicular hypopigmentation. Most studies are done on determining features of vitiligo lesions; however, there is lack of studies on dermoscopy in normal appearing perilesional skin. This would give an insight into the extent of the disease process, beyond the borders of skin lesions. We conducted a study on 100 unstable lesions of vitiligo and studied dermoscopic features in its perilesional skin. The objective of this study was to observe dermoscopic features of apparently normal perilesional skin in patients of unstable vitiligo. Materials and Methods: A cross-sectional study was conducted in a tertiary care centre in New Delhi. We evaluated perilesional skin of 100 unstable vitiligo lesions over a span of 1 year. The perilesional skin has been defined as area within 5 cm of the lesion. Dermoscopy was performed using DERMLITE 4 Dermoscope at 10X magnification with inbuilt white light and polarised light. Polarised light was used to study changes in the pigmentary network and other patterns. We looked for features such as pigment network, perifollicular pigmentation, presence of leukotrichia, microkoebner phenomenon and satellite lesions in the perilesional skin. Results: The study included a total of 100 unstable lesions. Majority of patients belonged to the age group of 18−30 years. Females outnumbered males (1.8:1). All cases had progressive disease and mean duration of disease was 12.07 ± 10. 85 years. Dermoscopic features of vitiligo were observed in 56% of patients even in normal appearing perilesional skin. The most common dermoscopic finding observed was reduced pigment network which was seen in 33% of cases. Perifollicular hypopigmentation and depigmentation were observed in 23 and two sites, respectively, while leukotrichia was seen at ten sites. Eight sites showed microkoebners phenomenon. Conclusion: The perilesional apparently normal skin also shows signs of disease activity in cases of unstable vitiligo. Hence, perilesional skin should also be examined carefully with the dermoscope and topical treatment and targeted phototherapy should aim at covering the normal looking perilesional skin as well, at least within 5 cm of the borders of the skin lesions. Importantly, the perilesional skin should also be examined before surgery.

Immunohistochemical expression of Axin-2, as an implication of the role of stem cell in scar pathogenesis and prognosis.

Wound healing is a multi-phased process. A disruption in these phases could result in a persistent wound or an atypical scar. Wounding activates wingless proteins (Wnt) signaling, which aids in the healing process. Axis inhibition protein-2 regulates a variety of cellular activities through the Wnt and other pathways. To assess the role of Axin-2 in patients with abnormal scars, using immunohistochemical study. This case-control study enrolled a total of 60 participants: 30 patients with abnormal scars (12 hypertrophic scars, 13 atrophic scars, and 5 keloid scars) and 30 age, sex, and site matched, apparently healthy controls. For immunohistochemistry examination of Axin-2 expression, skin samples were obtained from (i) lesional and (ii) perilesional skin of patients with aberrant scars, as well as (iii) normal control's skin. Epidermal Axin-2 expression positivity, cellular topography, intensity, and H score showed significant differences between the groups (p < 0.05). In the dermis (fibroblast/myofibroblast), there were significant differences in Axin-2 expression positivity, location, intensity, and H score (p < 0.001 for all). The epidermal Axin-2 H score and the Manchester scale had a significant positive correlation (r=0.832, p=0.001). The epidermal Axin-2 H score and age (r=-0.576, p=0.001), and the Stony Brook scale (r=-0.419, p=0.021), had significant negative correlations. Axin-2 overexpression might be accused in pathogenesis of abnormal scar and clinical worse scar outcome. In order to deprive scars of their regenerative cell pools, future scar therapies may target Axin-2 as a stem cell marker.

Evidence for cutaneous dysbiosis in dystrophic epidermolysis bullosa.

The human microbiome project addresses the relationship between bacterial flora and the human host, in both healthy and diseased conditions. The skin is an ecosystem with multiple niches, each featuring unique physiological conditions and thus hosting different bacterial populations. The skin microbiome has been implicated in the pathogenesis of many dermatoses. Given the role of dysbiosis in the pathogenesis of inflammation, which is prominent in dystrophic epidermolysis bullosa (DEB), we undertook a study on the skin microbiome. To characterize the skin microbiome in a series of patients with DEB. This was a case-control study of eight patients with DEB and nine control cases enrolled between June 2017 and November 2018. The skin of patients with DEB was sampled at three different sites: untreated wound, perilesional skin and normal-appearing (uninvolved) skin. Normal skin on the forearm was sampled from age-matched healthy controls (HCs). We used a dedicated DNA extraction protocol to isolate microbial DNA, which was then analysed using next-generation microbial 16S rRNA sequencing. Data were analysed using a series of advanced bioinformatics tools. The wounds, perilesional and uninvolved skin of patients with DEB demonstrated reduced bacterial diversity compared with HCs, with the flora in DEB wounds being the least diverse. We found an increased prevalence of staphylococci species in the lesional and perilesional skin of patients with DEB, compared with their uninvolved, intact skin. Similarly, the uninvolved skin of patients with DEB displayed increased staphylococcal content and significantly different microbiome diversities (other than staphylococci) compared with HC skin. These findings suggest the existence of a unique DEB-associated skin microbiome signature, which could be targeted by specific pathogen-directed therapies. Moreover, altering the skin microbiome with increasing colonization of bacteria associated with nonchronic wounds may potentially facilitate wound healing in patients with DEB.

Beclin1 in psoriasis: an immunohistochemical study.

Abnormal autophagy is known to be associated with the pathogenesis of some skin disorders. The protein Beclin1 plays a central role in the machinery of autophagy. To assess the expression of Beclin1 in psoriasis, using immunohistochemical study in lesional and perilesional skin in patients with psoriasis, and to compare the results with those of an apparently healthy control (HC) group. This case-control study enrolled a total of 40 participants: 20 patients with chronic plaque psoriasis and 20 age- and sex-matched, apparently HCs. Skin biopsies were taken from (i) lesional and (ii) perilesional skin of patients with psoriasis and from (iii) normal skin of HCs for immunohistochemical evaluation of Beclin1 expression. Epidermal Beclin1 expression was positive in all three studied groups. There was a significant difference between the three studied groups regarding Beclin1 epidermal topographic distribution, epidermal staining intensity, H score and H-score category (P<0.01 for all). Significant differences were found between the three studied groups regarding Beclin1 H score and H-score category for skin adnexal structures (P<0.01 for both). For dermal inflammatory infiltrate, significant differences were found between lesional and perilesional skin regarding Beclin1 expression status, staining intensity, H score and H-score category (P<0.01, P=0.01, P<0.01 and P<0.03, respectively). The increased expression of Beclin1 in psoriatic skin, both lesional and perilesional, reflects increased autophagy, which could be a consequence of the rapid keratinocyte proliferation in psoriasis, which would also ramp up all the cellular processes including autophagy. The cellular localization of Beclin1 was nucleocytoplasmic in psoriasis skin but cytoplasmic only in normal HC skin, which needs further study to allow its interpretation.

Expression of liver X receptor-α in lesional and perilesional skin in patients with psoriasis vulgaris

Background Psoriasis is a common chronic recurrent immune-mediated disease of the skin. Liver X receptor-alpha (LXR-α) is a member of the nuclear receptor family of transcription factors. LXR-α was found to be expressed in the skin. Objective To assess immunohistochemical expression of LXR-α in psoriatic (perilesional and perilesional) skin compared with control and to correlate its expression with the clinical and histopathological parameters of that disease in the studied patients. Patients and methods This case–control study was carried out on 76 participants, including 38 patients having chronic plaque psoriasis, besides 38 age-matched and sex-matched apparently normal volunteers (control group). The severity of psoriasis was assessed by Psoriasis Area and Severity Index score. The skin biopsies were subjected to hematoxylin and eosin and immunohistochemical staining of LXR-α. Results There was a significant stepladder downregulation of LXR-α from control to perilesional psoriatic skin, ending with lesional psoriatic skin, regarding its expression and H score in epidermis and dermal elements (P<0.001 for all). In the dermis, LXR-α topography was cytoplasmic in all psoriatic (perilesional and lesional) skin sections (100%) versus 22.2% in controls, where it was nucleocytoplasmic in 28 (77.8%) sections. Moreover, epidermal keratinocytes LXR-α demonstrated cytoplasmic localization in nearly all psoriatic sections (100% lesional and 90.9% perilesional) versus 18.9% controls (P<0.001). Conclusion Decreased LXR-α in psoriatic tissue may participate actively in psoriasis. LXR-α agonist may be of value in psoriasis management program.

2125. Staphylococcus Species Identification by Fourier Transform Infrared (FTIR) Spectroscopic Techniques: A Cross-Lab Study

Background Staphylococcus aureus is well known to be associated with atopic dermatitis. Recent studies also report S. aureus presence in lesional skin of squamous cell carcinoma (SCC) and its precursor lesion, actinic keratosis (AK). Therefore, it is of potential clinical interest to monitor skin S. aureus colonization on AK lesions. Fourier transform infrared (FTIR) spectroscopy is a cost-effective, nondestructive, and reagent-free technique for rapid microbial identification. It is based on the use of spectral databases developed with well-characterized strains in conjunction with the application of multivariate statistical analysis to elaborate classification models. In the present cross-lab study, spectral databases containing FTIR spectra of over 1000 staphylococcal isolates obtained from reference and clinical microbiology laboratories across Canada were employed in the FTIR spectroscopic identification of Staphylococcus spp. isolated from AK, SCC and perilesional skin of patients at the Princess Alexandra Hospital Dermatology Clinic in Brisbane, Australia.MethodsFTIR spectra of 51 staphylococcal isolates from AK, SCC and perilesional skin were acquired by both attenuated total reflectance (ATR)-FTIR and transflection-FTIR spectroscopy. All isolates had been previously characterized by 16S rRNA sequencing. ATR- and transflection-FTIR spectra were recorded in triplicate from isolated colonies taken from the same agar plate. Identification of the bacteria was based on the similarities of their spectra with those in ATR- and transflection-FTIR spectral databases originating from the Canadian lab.ResultsAmong the 51 staphylococcal isolates included in this study, identification of S. aureus (n = 24) with 100% specificity and 100% sensitivity was achieved by both ATR- and transflection-FTIR spectroscopy. Overall, FTIR-based species identification was in 90.2% concordance with 16S rRNA sequencing.ConclusionThis cross-lab study demonstrates the applicability of Canadian isolate-based ATR- and transflection-FTIR spectral databases for the identification of clinical staphylococcal isolates obtained in Australia. The results support the potential utility of FTIR spectroscopic techniques to monitor skin S. aureus colonization on AK lesions.Disclosures All authors: No reported disclosures.

Assessment of macrophage migration inhibitory factor in patients with verruca vulgaris.

BackgroundCommon warts are caused by human papillomaviruses (HPVs), they are among the most common cutaneous viral infections. Macrophage migration inhibitory factor (MIF) is an essential contributor in many inflammatory and immune skin diseases. Yet, its role in the pathology of common warts is unclear.ObjectiveTo assess MIF levels in lesional and perilesional skin in patients with common warts in comparison to apparently healthy control group with matching age and sex.Subjects and methodsA case-control study performed on 60 patients with common warts (group A) and 30 age and sex matching healthy controls (group B). Two biopsies were taken from each patient in group A; one from the lesion (lesional) and the other one from the skin around the wart (perilesional), while biopsies of controls were taken from matched sites to patients. Measurement of MIF in all groups was done by quantitative ELISA kits.ResultsSignificant high MIF levels were detected in lesional and perilesional skin biopsies compared to controls (P<0.001). Yet, the difference in MIF levels between lesional and perilesional skin biopsy was non-significant. No significant relations were found between lesional and perilesional MIF levels and clinical characteristics of the studied patients while both lesional and perilesional MIF levels were significantly correlated (rh=0.269, P=0.021).ConclusionThe significantly elevated MIF levels in lesional and perilesional skin biopsies compared to controls point to its role in wart progression from HPV infected cells.

Receptor for advanced glycation end products is overexpressed in psoriatic plaques independent of disease severity.

Enhanced expression and excitation of the receptor for advanced glycation end products is considered to play a role in the regulation of many pro-inflammatory genes involved in the pathogenesis of psoriasis. We investigated the expression of receptor for advanced glycation end product in various cell types, in lesional and peri-lesional skin of patients with psoriasis, and its correlation with disease severity. Paraffin-embedded punch biopsy tissue taken from psoriatic plaques and peri-lesional normal appearing skin tissue of twenty patients with psoriasis, and normal skin samples of eleven healthy participants, were enrolled in the study. The sections were stained immunohistochemically with anti-receptor for advanced glycation end product antibody. The intensity of receptor for advanced glycation end product expression was assessed semi-quantitatively on epidermal cells, microvascular endothelium, dermal fibroblasts and inflammatory cells. They were graded as follows: 0 (no staining), 1 (weak), 2 (moderate) and 3 (strong) intensity. Receptor for advanced glycation end product expression on epidermis, microvascular endothelium, inflammatory cells and fibroblasts in the psoriatic plaques was more intense than perilesional and normal tissue (all P < 0.05). It did not correlate with disease severity. The main limitation of our study is that this was a semi-quantitative assessment, detected immunohistochemically in skin biopsies. Receptor for advanced glycation end product expression may have an important role in psoriasis pathogenesis, independent of disease severity.

IFN-γ Promotes Apoptosis of Melanocytes in Vitiligo

Vitiligo is an immune-mediated inflammatory condition characterized by selective destruction of epidermal and or follicular melanocytes. It is well established that cell-mediated immunity has been implicated in the pathogenesis of this common skin disorder. Although abnormalities in different subpopulations of T cells may play a role in induction and development of vitiligo, great attention has been paid to CD4+ Th1 cells and cytotoxic CD8+ T lymphocytes (CTLs) (1, 2). The significance of both subgroups in vitiligo development is supported by different observations. For instance, CD8+ T cell-mediated melanocyte destruction has been demonstrated in vitiligo. In addition, an increased accumulation of CD8+ T cells in peripheral blood mononuclear cells (PBMCs) and perilesional skin of patients with progressive vitiligo has been reported (1, 3). On the other hand, elevated expression of Th1 cell specific transcription factor (T-bet) and cytokine (IFNγ) was indicated in PBMCs of patients with vitiligo (2). The exact mechanism by which these cells exert their cytotoxic effects on melanocytes is not well understood. Nonetheless, the results of different laboratory and histological examinations support the hypothesis that apoptosis is an important mechanism for melanocyte disappearance. Apoptosis is a complex process and can be initiated through intrinsic and extrinsic pathways. These pathways are activated by a variety of factors such as cytokines, certain chemicals and other molecular mechanisms. Amongst these factors, cytokines appear to play a pivotal role in promoting apoptotic melanocyte cell death. Cytokines are small secreted proteins that participate in cellular communication and many immunologic functions. Abundant evidence indicated cytokine imbalance (such as IFN-γ, IL-10, IL-17) in the skin and circulation of patients with vitiligo. Therefore, disturbed expression of these molecules may be involved in disease pathogenesis. IFN-γ is a proinflammatory cytokine mainly produced by Th1 lymphocytes, NK cells and CD8+ cytotoxic T cells. This cytokine plays a major role in both innate and adaptive immune response. It can also affect the action of other cytokines in a synergistic or antagonistic manner. The exact function(s) of IFN-γ in the pathology of vitiligo is not known and it may act via different mechanisms. For instance, IFN-γ may participate in the homing of CD8+ T cells to the skin through local induction of chemokines and expression of adhesion molecules on endothelial cells (4). Cytotoxicity via induction of apoptosis has been considered as a major effector mechanism of autoreactive CTLs. Therefore, recruited CD8+ T cells may specifically induce autologous melanocyte apoptosis resulting in disappearance of melanocytes (3). On the other hand, CD4+ Th1 cells (one of the main sources of IFN-γ production) are required for optimal induction of antigen-specific CD8+ T cell effector responses. CD8+ T cells can be considered as a main effector cell of Th1 immunity (5). Therefore, cooperation between CD4+ and CD8+ T cells plays an important role in complete melanocyte clearance. In addition, IFN-γ may influence melanin production. For instance, treatment of melanocytes with IFNγ resulted in significant suppression of melanin production and reduction of mRNA expression levels of tyrosinase and microphthalmia-associated transcription factor (MITF), which regulates differentiation and development of melanocytes and retinal pigment epithelium (6). Moreover, Natarajan et al. indicated a regulatory role of IFN-γ in skin pigmentation. They showed that IFN-γ signaling impedes maturation of the melanosome, which is a major site for synthesis and storage of melanine (7). Altogether, the actual mechanism of melanocytes killing in the skin of patients with vitiligo has not been definitively determined. Current studies indicate a potential role of Th1 and CTL subpopulations in vitiligo pathology as well as a link between IFN-γ and melanocyte abnormalities in this disease. However, further studies are needed to unravel the exact mode of IFN-γ action. A deeper understanding of these mecha-

Histopathological study of perilesional skin in patients diagnosed with nonmelanoma skin cancer.

Epidemiological and clinical data suggest that actinic damage to the skin is an important predictor of skin carcinogenesis. To investigate the association of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with sun-damage alterations seen by histopathology. In the current prospective study, perilesional skin of SCC or BCC lesions was evaluated for presence of alterations associated with chronic photodamage. Presence of scarring, perineural/perivascular invasion, haemorrhage/haemorrhagic crust, ulceration/erosion and margin involvement were also assessed. Of 6038 included lesions, 4523 (74.9%) were BCCs and 1515 (25.1%) were SCCs. Presence of actinic damage was five times more frequent in SCC than in BCC (OR=5.29, 95% CI 4.44-6.00, P<0.001), and diagnosis of SCC was twice as common in photo-exposed than nonphoto-exposed body sites (OR=2.34, 95% CI 2.03-2.70, P<0.001). There were twofold higher odds for actinic damage in SCC compared with Bowen disease (OR=2.015, 95% CI 1.55-2.61, P<0.001). Assessing the different BCC histological subtypes, we found that nodular BCC had at least twofold higher odds (OR=2.63, 95% CI 2.09-3.32), infiltrative BCC had 48% higher odds (OR=1.487, 95% CI 1.18-1.87) and basosquamous BCC had fourfold higher odds (OR=4.10, 95% CI 3.01-5.57) of having actinic damage compared with superficial BCC. Histological verification of ultraviolet-associated alterations in the perilesional skin in patients with NMSC in our study confirms the aetiopathogenic link between sun exposure and epithelial carcinogenesis on a histopathological basis. This correlation was stronger for SCCs than for BCCs.

Tissue Factor in Dermatitis Herpetiformis and Bullous Pemphigoid: Link between Immune and Coagulation System in Subepidermal Autoimmune Bullous Diseases.

Dermatitis herpetiformis (DH) and bullous pemphigoid (BP) are skin diseases associated with eosinophilic and neutrophilic infiltrations. Although chemokines are critical for the selective accumulation and activation of various leukocyte subsets in the inflammatory process, there are few findings concerning inflammatory cells and production of coagulation factors in blistering diseases. Skin biopsies were taken from 14 patients with DH, 27 with BP, and 20 control subjects. The localization and expression of tissue factor (TF) in skin lesions and perilesional skin were studied by immunohistochemistry and confirmed by Western Blot. Moreover the plasma concentrations of TF were measured by immunoassays. D dimers, fibrinogen, and selected coagulation parameters were measured by routine methods. Expression of TF in the epidermis and in inflammatory influxed cells in dermis was detected in skin biopsies from BP patients. Examined TF expression was detected in perilesional skin of all BP patients too. The expression of TF was not observed in biopsies from healthy people and DH patients. The findings of the study show an increased expression of tissue factor in the lesional and perilesional skin of patients with bullous pemphigoid. The difference in chemokine pattern expression and variations in the cellular infiltration in BP and DH cause variable expression of TF.

Intense pulsed light enhances transforming growth factor beta1/Smad3 signaling in acne-prone skin

Recently, much interest has been generated in the use of intense pulsed light (IPL) sources in the treatment of various skin conditions. However, the underlying mechanism for its therapeutic action has not been elucidated. To investigate the effect of IPL on the in vivo expression of transforming growth factor beta1 (TGF-β1) and on the immunolocalization of Smad3 in biopsies obtained from perilesional skin in patients with mild-to-moderate inflammatory acne vulgaris. Biopsies obtained from 20 patients with inflammatory acne vulgaris at baseline (B1) and post-IPL treatment (B2=48h after first treatment and B3=1week after final treatment) were immunohistochemically analyzed to determine the expression of TGF-β1 and the immunolocalization of Smad3. Digital images were semiquantitatively assessed using image analysis software. Intense pulsed light elicited a consistent increase in epidermal TGF-β1 expression (B2 vs. B1: P=0.004 and B3 vs. B1: P=0.007). Furthermore, it resulted in enhanced nuclear immunolocalization of Smad3 (B2 vs. B1: epidermis, P=0.000055 and dermis, P=0.014; B3 vs. B1: epidermis, P=0.00024 and dermis, P=0.008). Intense pulsed light upregulates TGF-β1/Smad3 signaling in perilesional skin obtained from patients with mild-to-moderate inflammatory acne vulgaris. Further experiments on lesional skin and downstream effects are warranted to determine whether it may play a role in IPL-induced resolution of acne vulgaris.

Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin

We have hypothesised that melanocytes disappear in vitiligo because they are weakly attached to the epidermal basal membrane (melanocytorrhagy). In the epidermis, attachment of melanocytes to collagen IV is mediated through DDR1, which is under the control of CCN3. DDR1 genetic variants have been associated with vitiligo in patients of different ethnic origin. In vitro studies have shown that inhibition of CCN3 induces the detachment of melanocytes. We have studied in parallel the expression of CCN3 and DDR1 in lesional and perilesional skin of patients with vitiligo and the impact of the silencing of CCN3 and DDR1 in normal human melanocytes on their behaviour in epidermal reconstructs. Our in vivo study provides evidence of a dysregulation of the DDR1-CCN3 interaction in vitiligo skin as melanocytes remaining in perilesional skin did not express CCN3. Expression of DDR1 was decreased in lesional versus perilesional vitiligo skin in the majority of patients, and the expression of collagen IV was found decreased in all patients. Silencing of CCN3 in melanocytes induced a significant inhibition of cell adhesion to collagen IV whereas melanocytes transduced with shDDR1 still adhered well on collagen IV and did not increase melanocyte loss in epidermal reconstructs as compared with normal melanocytes. Melanocyte detachment was observed but not in all reconstructs using CCN3 silenced melanocytes. Overall, our study confirms that a downregulation of CCN3 is implicated in melanocyte adhesion in part through DDR1. In vitiligo skin, the interaction of CCN3 with other molecules, such as TGFβ and CCN2, needs to be addressed.

The role of natural killer cells in autoimmune blistering diseases

The major focus of this paper is to describe and evaluate current information on the role of natural killer cells (NK cells) in the pathogenesis of blistering diseases. Until now, only pemphigus vulgaris (PV) has been studied. One co-culture study demonstrated that CD4+ T cells from the peripheral blood or perilesional skin of patients with active disease proliferate and secrete cytokines in the presence of major histocompatibility class II-expressing NK cells loaded with antigenic desmoglein self-peptides. Another study showed that NK cells can contribute to a T helper type 2-biased immune response through impaired interleukins (IL)-12 signaling and upregulation of IL, IL-10 and IL-5. Although significant data on other blistering diseases are unavailable at present, some studies implicate NK cells in disease progression. For instance, information on the role of NK cells in psoriasis and their production of tumor necrosis factor-α (TNF-α) will be provided since several TNF-α-inhibitors are used in its treatment. Studies on alopecia areata are also included in this paper because NK cells seem to play a key role in its pathogenesis. This review highlights the potential importance of NK cells and NKT cells as members of the large repertoire of cells and soluble mediators that play a critical role in pathogenesis of blistering diseases and other autoimmune diseases involving the skin. Therefore, the authors advocate a greater focus and interest on the study of the interaction of NK cells and the skin.

Comprehensive understanding of idiopathic guttate hypomelanosis: clinical and histopathological correlation

The histological findings associated with idiopathic guttate hypomelanosis (IGH) are hyperkeratosis, an atrophic epidermis, and flattened rete ridges. In addition, a decreased melanin content and reduced numbers of melanocytes are reported features. However, there are few recent studies that have been published on the histopathology of IGH and no comparative studies are available on the skin lesions and perilesional skin of patients with IGH. The goals of this study were to identify the clinical and histopathological features of IGH and determine their correlation. We evaluated the clinical features and the histopathological differences between the skin lesions and the perilesional skin in patients with IGH. A clinical survey was carried out on 47 patients with IGH. Specimens from skin lesions and perilesional skin were stained with hematoxylin-eosin, Fontana-Masson, MART-1, and NKI/beteb. We also studied the ultrastructure of four cases. About 30% of the patients had their initial lesions prior to 20 years of age. The arm was the most commonly affected site (53%). Histologically, we found hyperkeratosis in 18 cases (38.3%), but epidermal atrophy was present in only five cases (10.6%), and flattened rete ridges in seven cases (14.9%) compared to the normal skin. Epidermal atrophy was more frequently found at nonsun-exposed areas. The IGH lesions demonstrated decreased melanin pigment and reduced numbers of melanocytes by NKI/beteb and MART-1. The ultrastructural evaluation showed degenerative melanocytes and decreased melanosomes. One specimen had normal melanocytes with decreased melanosomes. Idiopathic guttate hypomelanosis is a disorder with multifactorial etiology; its pathogenesis may depend on various factors such as patient age and sun-exposure. Histopathologically, hyperkeratosis was frequently found; however, the other characteristic findings such as epidermal atrophy and flattened rete ridges were relatively rare.

Videodermoscopy of the hyponychium in nail bed psoriasis

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Immunomorphologic and Biochemical Identification of the Pemphigus Foliaceous Autoantigen Within Desmosomes

Desmosomes are specialized domains of the plasma membrane that play a fundamental role in intercellular adhesion. This adhesive function is mediated at least in part by the cadherin homologous cell adhesion molecule (CAM) desmoglein (dg). Autoantibodies (aab) from patients with pemphigus foliaceous (pf), a blistering disease of the epidermis, have been shown by immunochemical methods to bind to desmoglein. However, the molecular localization of the binding sites of these antibodies, especially as it relates to the ultrastructure of the desmosomes, has not been definitively characterized. We therefore performed pre-embedding direct immunoelectron microscopy (IEM) on perilesional skin of patients with pf and post-embedding indirect IEM using sera from five patients with pf. We first confirmed by immunoprecipitation and immunoblotting that these sera bound dg. Both IEM methods showed that pf-aab exclusively bind to desmosomes. Double-labeling IEM of several other constitutive desmosomal proteins further suggests that most likely pf-aab bind to an extracellular domain of the transmembrane CAM dg. Our studies suggest one possible pathophysiologic mechanism for the clinical manifestations of pf: namely, that the binding of aab to an extracellular epitope of desmoglein might impair the adhesive properties of desmosomes mediated by dg and result in the loss of cell adhesion leading to acantholysis and blister formation.