Alice Verdelli

The Treg/Th17 cell ratio is reduced in the skin lesions of patients with pyoderma gangrenosum

DEAR EDITOR, Pyoderma gangrenosum (PG) is a rare, inflammatory skin disease that, together with other conditions such as Sweet syndrome (SS), is included within the group of neutrophilic dermatoses. Although its pathogenesis remains poorly understood, the treatments with the best clinical evidence are tumour necrosis factor inhibitors, high-dose systemic corticosteroids and ciclosporin, suggesting the pivotal role of inflammatory pathways in the development of PG. Interestingly, recent studies have highlighted the role of T helper (Th)17 cells in neutrophilic dermatoses, and an increase of interleukin (IL)-17 and IL-23 expression was found in PG lesions. Together with Th17 cells, regulatory T cells (Tregs) play a major role in human disease. Accordingly, recent reports suggest that controlling the balance between Tregs and Th17 cells may be a promising therapeutic strategy for inflammatory diseases. However, no data are present in the literature about Tregs in PG. In this study, we investigated the proportions of Tregs and Th17 cells in the skin of 15 patients with PG (seven male, eight female; age range 27–69 years), on neither immunosuppressive treatment nor topical steroids for at least 4 weeks prior to entering the study. Their clinical findings are presented in Table S1 (see Supporting Information). As a control, skin samples from five patients with SS (two male, three female; age range 31–64 years) and six healthy subjects (HS) (three male, three female; age range 28–59 years) were collected. The trial was approved by the local ethics committee and conducted according to the Declaration of Helsinki. All of the patients and controls provided written informed consent. Treg and Th17 markers were analysed by immunohistochemistry using the monoclonal antibodies anti-CD4 (1 : 20; Dako, Copenhagen, Denmark), anti-CD25 (1 : 25; Histo-Line Laboratories, Milan, Italy), anti-CD161 (1 : 80; AbD Serotec, Oxford, U.K.), antiforkhead box protein P3 (anti-FOXP3) (1 : 80; Abcam, Cambridge, U.K.), anti-IL-10 (1 : 300; Dako), anti-IL-17 (1 : 1000; Abcam), anti-RORct (1 : 2000; R&D Systems, Minneapolis, MN, U.S.A.) and antitransforming growth factor (anti-TGF)-b1 (1 : 2000; Abcam), as described previously. The results of quantitative analysis of these markers are described in Table S2 (see Supporting Information). The stained cells were counted in three consecutive microscopic fields (4009). Furthermore, FOXP3/CD4, TGF-b/CD4, IL-10/CD4 and RORct/CD4 cell ratios were calculated. The results were analysed with the Mann– Whitney U-test and were considered significant with a P-value < 0 05. In PG and SS, CD4 and CD25 cells were located in the whole dermis, with some cells scattered in the epidermis (Fig. 1a,b,d,e). The number of CD4 cells in PG was significantly higher than in SS (P < 0 001), while no differences were found for CD25 cells. By contrast, CD4 and CD25 cells were significantly less represented in HS than in the other two groups (P < 0 001) (Fig. 2a). Some FOXP3 cells were detected within the superficial dermis of patients with PG (Fig. 1g); their number was higher than in HS (P = 0 004) but lower than in SS (P < 0 001) (Fig. 2a). Interestingly, the FOXP3/CD4 cell ratio was significantly lower in PG than in SS (P < 0 001) and HS (P < 0 001) (Fig. 2a). Some IL-10 cells were found in the superficial dermis of patients with PG (Fig. 1j); their number was significantly lower than in SS (P < 0 001) and higher than in HS (P < 0 001). Moreover, the IL-10/CD4 cell ratio was reduced in PG vs. SS and HS (P < 0 001 and P = 0 03, respectively) (Fig. 2a). TGF-b staining was diffusely distributed within the superficial and medium dermis in PG and SS. Moreover, some TGF-b cells could be detected in the same areas (Fig. 1m,n). Their number was similar in both PG and SS. By contrast, the TGF-b/CD4 cell ratio was significantly reduced in PG (P = 0 01). Moreover, although HS showed a lower number of TGF-b cells than PG (P < 0 001) and SS (P < 0 001), their TGF-b/CD4 cell ratio was significantly higher (HS vs. PG, P = 0 001; HS vs. SS, P < 0 001) (Fig. 2a). Regarding Th17 markers, RORct cells were distributed in the upper dermis in PG (Fig. 1p); their number was similar to that found in SS. By contrast, the RORct/CD4 ratio was significantly lower in PG than in SS (P = 0 008) (Fig. 2a). As expected, no RORct expression was found in HS. The numbers of both CD161 and IL-17 cells, which were distributed predominantly in the superficial and medium dermis (Fig. 1s, t,v,w), were similar in PG and SS, while no CD161 nor IL-17 expression was detected in HS (Fig. 2a). Finally, in order to quantify the balance between Tregs and Th17 cells, we calculated the ratio between FOXP3 and RORct, which was significantly lower in PG than in SS (P < 0 001) (Fig. 2b).

Estrogens, estrogen receptors and melanoma

The skin is the largest nonreproductive target tissue on which estrogen plays many beneficial and protective roles. Although neither exogenous hormones nor pregnancy represent significant risk factors for melanoma, epidemiological data suggest a higher survival rate in women with metastatic disease versus men and in premenopausal versus postmenopausal patients. Despite the fact that hyperestrogenic signaling has long been implicated in the initiation and progression of several tumors, the role of estrogens in malignant melanoma is still unclear. The cellular effects of estrogens are mediated by two subtypes of estrogen receptors (ERs). Estrogen receptor β (ERβ), the predominant ER in the skin, antagonizes the proliferative action mediated by estrogen receptor α. According to recent immunohistochemical studies, ERβ protein expression decreases progressively with increased Breslow thickness and results in more invasive melanomas; thus, ERβ immunophenotype may distinguish melanomas linked to poor prognosis from those with a favorable course and lead to melanoma unresponsiveness to both estrogen and anti-estrogen treatment. Therefore, if future large-scale immunohistochemical and molecular studies point towards ERβ as an important factor in malignant melanoma progression, they will open up novel and targeted prognostic and therapeutic perspectives.

Multiple primary melanoma: the impact of atypical naevi and follow up

Background  Patients with melanoma are especially encouraged to have regular follow‐up visits with their dermatologist and to perform total‐body skin examination on a routine basis to identify new pigmented lesions or detect significant changes in existing naevi.

Dermatitis Herpetiformis: From the Genetics to the Development of Skin Lesions

Dermatitis herpetiformis (DH) is a rare autoimmune disease linked to gluten sensitivity with a chronic-relapsing course. It is currently considered to be the specific cutaneous manifestation of celiac disease (CD). Both conditions are mediated by the IgA class of autoantibodies, and the diagnosis of DH is dependent on the detection of granular deposits of IgA in the skin. There is an underlying genetic predisposition to the development of DH, but environmental factors are also important. This paper describes these different factors and discusses the known mechanism that lead to the development of skin lesions.

Dermoscopy pattern of cutaneous angiosarcoma

Auteur(s) : Vincenzo DE GIORGI vincenzo.degiorgi@unifi.it, Marta GRAZZINI, Susanna ROSSARI, Alessia GORI, Alice VERDELLI, Elisa CERVADORO, Torello LOTTI Department of Dermatology, University of Florence, Via della Pergola 60, 50121 Firenze, Italy Cutaneous angiosarcoma (AS) is an aggressive malignant tumor that is generally divided into three clinical subtypes: classical AS (head and neck type), AS arising in the context of Stewart-Treves syndrome, and AS arising in irradiated skin areas [1]. Lymphedema, [...]

Hailey-Hailey disease treated with methotrexate.

BACKGROUND Hailey-Hailey disease (HHD) is a chronic, recurrent blistering disorder characterized clinically by erosions occurring primarily in intertriginous regions and histologically by suprabasal acantholysis. MAIN OBSERVATIONS We report a long standing case of HHD initially unresponsive to cyclosporin, multiple topical and systemic steroids. Good response was achieved with methotrexate 7,5 mg weekly for 16 week, intramuscularly, and topical steroids as needed. CONCLUSION In conclusion, we suggest that methotrexate could be considered a therapeutic option for the treatment of HHD and in particular as a maintaining therapy to control the disease flares.

Newly Described Clinical and Immunopathological Feature of Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is an inflammatory cutaneous disease with typical histopathological and immunopathological findings clinically characterized by intensely pruritic polymorphic lesions with a chronic-relapsing course. In addition to classic clinical manifestations of DH, atypical variants are more and more frequently reported and histological and immunological are added to them, whereas the impact on quality of life of patients with DH is increasingly important to a certain diagnosis. The aim of this paper is to describe all the possible clinical, histological, and immunological variants of DH in order to facilitate the diagnosis of a rare disease and, therefore, little known.

Cutaneous Manifestations of Non-Celiac Gluten Sensitivity: Clinical Histological and Immunopathological Features

Background: The dermatological manifestations associated with intestinal diseases are becoming more frequent, especially now when new clinical entities, such as Non-Celiac Gluten Sensitivity (NCGS), are identified. The existence of this new entity is still debated. However, many patients with diagnosed NCGS that present intestinal manifestations have skin lesions that need appropriate characterization. Methods: We involved 17 patients affected by NCGS with non-specific cutaneous manifestations who got much better after a gluten free diet. For a histopathological and immunopathological evaluation, two skin samples from each patient and their clinical data were collected. Results: The median age of the 17 enrolled patients affected by NCGS was 36 years and 76% of them were females. On the extensor surfaces of upper and lower limbs in particular, they all presented very itchy dermatological manifestations morphologically similar to eczema, psoriasis or dermatitis herpetiformis. This similarity was also confirmed histologically, but the immunopathological analysis showed the prevalence of deposits of C3 along the dermo-epidermal junction with a microgranular/granular pattern (82%). Conclusions: The exact characterization of new clinical entities such as Cutaneous Gluten Sensitivity and NCGS is an important objective both for diagnostic and therapeutic purposes, since these are patients who actually benefit from a GFD (Gluten Free Diet) and who do not adopt it only for fashion.

Specific challenges in the management of subungual melanoma

Subungual melanoma (SUM) is infrequent in the general population, accounting for 0.7–3.5% of all cutaneous melanomas. SUM absolute incidence is similar among different racial groups; however, the relative proportion among overall cutaneous melanoma cases within each population varies in relation to the frequency of sun-induced melanoma. Subungual melanoma most commonly presents as a discoloration of the nail, followed by a recalcitrant wound, a tumor, nail splitting and nail bed bleeding. In most cases, the clinical presentation will already exhibit features typical of late-stage lesions because many patients wait for several months or even years before consulting a physician for evaluation of nail changes. Misdiagnosis of SUM as subungual hematoma, chronic trauma or onychomycosis is still a frequent occurrence, significantly reducing the chances for early treatment. An appropriate diagnostic approach is crucial to allow early-stage diagnosis. The correct management of SUM hinges on early diagnosis and selection of the most appropriate surgical technique. Curative treatment of SUM currently entails surgical excision when the extent of invasion is limited.

Skin self‐examination and the ABCDE rule in the early diagnosis of melanoma: is the game over?

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