Expression of hornerin in skin lesions of atopic dermatitis and skin diseases.

We have previously identified the filaggrin (FLG)-like protein, hornerin (HRNR). Recently, there have been several reports regarding the relationship between HRNR and atopic dermatitis (AD). In the present study, we examined HRNR expression in the skin lesions of seven unrelated patients with AD to clarify the role of HRNR in the pathogenesis of AD. HRNR was detected in chronic AD lesions (n = 4), whereas no HRNR signals were observed in acute AD lesions (n = 3). HRNR was detected in the cytokeratin 6-expressing epidermis, and Ki67-positive keratinocytes were more abundant in the HRNR-positive epidermis. These findings suggest that HRNR may be associated with epidermal hyperproliferation in AD lesions. Next, we examined HRNR expression in skin diseases associated with hyperkeratosis. HRNR signals were irregularly observed in different cells from those expressing FLG in epidermolytic ichthyosis and actinic keratosis. Therefore, HRNR may play a unique role in the molecular process of cornification.

Ganciclovir-induced drug reaction with eosinophilia and systemic symptoms.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction involving multiorgan failure, with a complex interaction of various drugs, human herpesvirus reactivation and immune abnormalities suggested as the aetiology. We herein present the case of a 70-year-old man with a one-week history of fever, facial oedema, erythematous macules and purpura on his trunk and extremities. He had anti-TIF1γ antibody-positive dermatomyositis and was treated with prednisolone sodium succinate (20 mg/day). Three weeks earlier, he was treated with ganciclovir (250 mg/day) for 7 days to treat asymptomatic cytomegalovirus viraemia. Laboratory investigations revealed eosinophilia with atypical lymphocytes and elevated liver enzyme levels. A histological examination showed interface dermatitis with necrotic keratinocytes, perivascular infiltration of lymphocytes and eosinophils in the upper dermis and erythrocyte extravasation without vasculitis. A lymphocyte transformation test (LTT) was positive for ganciclovir (stimulation index: 260%; normal: <180%). We diagnosed DRESS caused by ganciclovir on the basis of clinical findings and course (Definite; RegiSCAR score: 7). He was treated with prednisolone sodium succinate (40 mg/day) and topical clobetasol propionate (0.05%) ointment twice daily. After the initiation of treatment, the skin lesions and laboratory abnormalities gradually improved. To our knowledge, this is the first case of DRESS caused by ganciclovir. The patients in whom ganciclovir is used are often immunosuppressed and may be overlooked as the causative drug for DRESS by conventional skin tests. We considered that LTT is useful for identifying causative drugs of DRESS, especially in immunosuppressed patients, such as the present case.

Usefulness of immunofluorescence overlay antigen mapping in the identification of autoantigen in anti-p200 pemphigoid.

Anti-p200 pemphigoid is a rare subepidermal blistering disease showing immunoglobulin G (IgG) autoantibodies reactive with a 200-kDa protein. In most patients, serum IgG antibodies react with laminin γ1. The diagnosis of anti-p200 pemphigoid is occasionally difficult, mainly due to the lack of standardized tests. We performed fluorescence overlay antigen mapping by laser scanning confocal microscopy (FOAM-LSCM) to identify autoantigens in an anti-p200 pemphigoid patient and assessed its usefulness for the diagnosis. A 71-year-old man presented with blisters and erosions on the bilateral forearms. No mucosal lesions were observed. Laboratory examinations revealed mild leukocytosis and antinuclear antibody negativity. A histopathological examination showed subepidermal blisters with neutrophil infiltration. Direct immunofluorescence showed linear IgG staining along the basement membrane zone. Indirect immunofluorescence using 1 M NaCl-split skin sections revealed IgG reactivity on the dermal side. Immunoblotting detected circulating IgG autoantibodies that reacted with a 200-kDa protein. Accordingly, anti-p200 pemphigoid was diagnosed. FOAM-LSCM revealed that the patient's IgG signals were co-localized with laminin γ1 but were observed above type VII collagens. A direct immunofluorescent analysis for IgG deposition patterns showed an n-serrated pattern. Thus, FOAM-LSCM may be useful for diagnosing anti-p200 pemphigoid.

Altered expression of S100 fused-type proteins in an atopic dermatitis skin model.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with elevated interleukin (IL)-4 and IL-13 signatures and extensive barrier dysfunction, which is correlated with the downregulation of filaggrin (FLG). FLG is a member of the S100 fused-type protein family and this family also includes cornulin (CRNN), filaggrin-2 (FLG2), hornerin (HRNR) repetin (RPTN), trichohyalin (TCHH) and trichohyalin-like 1 (TCHHL1). The present study aimed to examine the effects of IL-4 and IL-13 and the downregulation of FLG on the expression of S100 fused-type proteins using a three-dimensional (3D) AD skin model by immunohistochemical study and quantitative polymerase chain reaction. In the 3D AD skin model, which was generated by a stimulation of recombinant IL-4 and IL-13, the expression of FLG, FLG2, HRNR and TCHH was decreased, while that of RPTN was increased in comparison to the 3D control skin. In the FLG knockdown (KD) 3D skin model, which was generated using FLG siRNA, the expression of HRNR was increased. The expression of the other proteins did not differ to a statistically significant extent. The expression of fused-S100 type protein family members may differ in AD skin. This suggests that these proteins play different roles in the pathogenesis of AD.

Detection of FIP1L1-PDGFRA fusion gene-positive cells in the skin lesion of a patient with hypereosinophilic syndrome.

Hypereosinophilic syndrome (HES) is a heterogeneous group of diseases, characterized by persistent hypereosinophilia and end-organ damage. The FIP1L1-PDGFRA (F/P) fusion gene is found in 3-25% of patients with HES and is an oncogenic driver of myeloid neoplasms with clonal eosinophilia. Although cutaneous symptoms are the most common type of symptom in patients who have F/P fusion gene-positive HES (F/P HES), histological reports are limited. We herein present the case of a 78-year-old man with erythematous macules and severe pruritus on his trunk and extremities. Laboratory investigations revealed marked eosinophilia and elevated serum vitamin B12. A histological examination showed massive infiltration of eosinophils and mast cells around the vessels in the upper dermis. Fluorescence in situ hybridization revealed F/P fusion genes in nuclei in the peripheral blood and the skin lesion. The patient was diagnosed with F/P HES, and showed an excellent clinical and haematological response to imatinib.

Identification of a de novo mutation of the elastin gene by targeted exome sequencing in autosomal dominant cutis laxa.

Cutis laxa (CL) comprises a heterogeneous group of entities mainly classified as X-linked, autosomal dominant and recessive forms, which differ in severity. We encountered a CL baby with no familial history. We performed targeted exome sequencing, and detected a de novo heterozygous frameshift mutation in the elastin gene of the baby.

Two cases of Hailey-Hailey disease effectively treated with apremilast and a review of reported cases.

Hailey-Hailey disease (HHD) is an autosomal dominant genetic disease caused by a mutation of the ATP2C1 gene. Corticosteroids, antibiotics or cyclosporine have been administered to reduce inflammation and prevent flare-ups, but the efficacy is not always sufficient. We herein report two cases of HHD effectively treated with apremilast and review the previous literature. Patient 1 was a 28-year-old male and patient 2 was a 35-year-old female. Both patients were diagnosed with HHD based on histological and genetic analyses. Both patients were treated with oral antibiotics or topical corticosteroids, but their symptoms were refractory, therefore apremilast was administered to both patients. Two weeks later, the skin lesion of both patients was improved. No adverse reaction was observed except for mild headache in patient 2. There have been 13 reported cases of HHD treated with apremilast, including our cases. Eight cases showed a good response to apremilast, whereas five cases showed no response. There seems to be no association between the disease severity and efficacy of apremilast, although the reason remains unknown. Interestingly, an early improvement of the HHD lesion was observed in all good response cases. Although digestive symptoms, headache, and myalgia were observed as adverse events, the treatment was well-tolerated. The accumulation of a greater number of similar cases and further research will be required. We hypothesize that apremilast may be a useful therapeutic option for skin lesions of HHD.

Trichohyalin-like 1 protein plays a crucial role in proliferation and anti-apoptosis of normal human keratinocytes and squamous cell carcinoma cells.

Epidermal differentiation is a complex process that requires the regulated and sequential expression of various genes. Most fused-type S100 proteins are expressed in the granular layer and it is hypothesized that these proteins may be associated with cornification and barrier formation. We previously identified a member of the fused-type S100 proteins, Trichohyalin-like 1 (TCHHL1) protein. TCHHL1 is distributed in the basal layer of the normal epidermis. Furthermore, the expression is markedly increased in cancerous/non-cancerous skin samples with the hyperproliferation of keratinocytes. We herein examined the role of TCHHL1 in normal human keratinocytes (NHKs) and squamous cell carcinoma (SCC). The knockdown of TCHHL1 by transfection with TCHHL1 siRNA significantly inhibited proliferation and induced the early apoptosis of NHKs. In TCHHL1-knockdown NHKs, the level of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was markedly decreased. In addition, the slight inhibition of v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation and upregulation of forkhead box-containing protein O1(FOXO1), B-cell lymphoma2 (BCL2) and Bcl2-like protein 11 (BCL2L11) was observed. Skin-equivalent models built by TCHHL1-knockdown NHKs showed a markedly hypoplastic epidermis. These findings highlight that TCHHL1 plays an important role in homeostasis of the normal epidermis. TCHHL1 was expressed in the growing cells of cutaneous SCC; therefore, we next examined an association with the cell growth in HSC-1 cells (a human SCC line). In HSC-1 cells, the knockdown of TCHHL1 also suppressed cell proliferation and induced apoptosis. These cells showed an inhibition of phosphorylation of ERK1/2, AKT and signal transducers and activator of transcription 3, and the significant upregulation of FOXO1, BCL2, and BCL2L11. Accordingly, TCHHL1 is associated with survival of cutaneous SCC. In addition, we hypothesize that TCHHL1 may be a novel therapeutic target in cutaneous SCC.