Multiple environmental antigens may trigger autoimmunity in psoriasis through T-cell receptor polyspecificity.

Introduction: Psoriasis is a T-cell mediated autoimmune skin disease. HLA-C*06:02 is the main psoriasis-specific risk gene. Using a Vα3S1/Vß13S1 T-cell receptor (TCR) from a lesional psoriatic CD8+ T-cell clone we had discovered that, as an underlying pathomechanism, HLA-C*06:02 mediates an autoimmune response against melanocytes in psoriasis, and we had identified an epitope from ADAMTS-like protein 5 (ADAMTSL5) as a melanocyte autoantigen. The conditions activating the psoriatic autoimmune response in genetically predisposed individuals throughout life remain incompletely understood. Here, we aimed to identify environmental antigens that might trigger autoimmunity in psoriasis because of TCR polyspecificity. Methods: We screened databases with the peptide recognition motif of the Vα3S1/Vß13S1 TCR for environmental proteins containing peptides activating this TCR. We investigated the immunogenicity of these peptides for psoriasis patients and healthy controls by lymphocyte stimulation experiments and peptide-loaded HLA-C*06:02 tetramers. Results: We identified peptides from wheat, Saccharomyces cerevisiae, microbiota, tobacco, and pathogens that activated both the Vα3S1/Vß13S1 TCR and CD8+ T cells from psoriasis patients. Using fluorescent HLA-C*06:02 tetramers loaded with ADAMTSL5 or wheat peptides, we find that the same CD8+ T cells may recognize both autoantigen and environmental antigens. A wheat-free diet could alleviate psoriasis in several patients. Discussion: Our results show that due to TCR polyspecificity, several environmental antigens corresponding to previously suspected psoriasis risk conditions converge in the reactivity of a pathogenic psoriatic TCR and might thus be able to stimulate the psoriatic autoimmune response against melanocytes. Avoiding the corresponding environmental risk factors could contribute to the management of psoriasis.

Lichen Planopilaris Arising between Two Linear Surgical Scars.

Lichen planopilaris (LPP) is a type of lymphocytic cicatricial alopecia, which can occur at unusual sites. It can be difficult to diagnose at an early stage and may be misdiagnosed as seborrheic dermatitis or psoriasis in early stages before alopecia occurs. We report a rare case in which alopecia occurred between two long surgical scars on the scalp several years after surgery. Dermoscopy and biopsy led to a diagnosis of LPP. The localization of the lesions in our case suggests that oxidative stress from the failure of lymph flow might have induced LPP. Oral roxithromycin, a macrolide antibiotic, with anti-oxidative and anti-inflammatory was effective at stopping its progression.

Increased plasma miR-24 and miR-191 levels in patients with severe atopic dermatitis: Possible involvement of platelet activation.

BACKGROUND: Platelets are involved in the pathomechanisms of atopic dermatitis (AD). This study aimed to elucidate the levels of platelet-related miRNAs, (miR-24 and miR-191) in the plasma of AD patients and their relationships with the disease severity and laboratory data. METHODS: miRNAs were detected in the subjects plasma using specifically primed quantitative reverse transcription polymerase chain reaction. RESULTS: The patients with severe AD had significantly higher plasma miR-24 or miR-191 levels than the patients with mild AD, the urticaria patients, and the healthy volunteers. The plasma miR-24 and miR-191 levels of the AD patients were correlated with their serum thymus and activation-regulated chemokine levels. In addition, plasma miR-24 and miR-191 levels were correlated with their plasma levels of platelet factor 4 and ß-thromboglobulin. CONCLUSION: Our findings imply that miR-24 and miR-191 may be involved in the pathomechanisms responsible for the worsening of AD, possibly through their effects on platelet activation.

ERAP1 Controls the Autoimmune Response against Melanocytes in Psoriasis by Generating the Melanocyte Autoantigen and Regulating Its Amount for HLA-C*06:02 Presentation.

Autoimmune diseases develop when autoantigens activate previously quiescent self-reactive lymphocytes. Gene-gene interaction between certain HLA class I risk alleles and variants of the endoplasmic reticulum aminopeptidase ERAP1 controls the risk for common immune-mediated diseases, including psoriasis, ankylosing spondylitis, and Behçet disease. The functional mechanisms underlying this statistical association are unknown. In psoriasis, HLA-C*06:02 mediates an autoimmune response against melanocytes by autoantigen presentation. Using various genetically modified cell lines together with an autoreactive psoriatic TCR in a TCR activation assay, we demonstrate in this study that in psoriasis, ERAP1 generates the causative melanocyte autoantigen through trimming N-terminal elongated peptide precursors to the appropriate length for presentation by HLA-C*06:02. An ERAP1 risk haplotype for psoriasis produced the autoantigen much more efficiently and increased HLA-C expression and stimulation of the psoriatic TCR by melanocytes significantly more than a protective haplotype. Compared with the overall HLA class I molecules, cell surface expression of HLA-C decreased significantly more upon ERAP1 knockout. The combined upregulation of ERAP1 and HLA-C on melanocytes in psoriasis lesions emphasizes the pathogenic relevance of their interaction in patients. We conclude that in psoriasis pathogenesis, the increased generation of an ERAP1-dependent autoantigen by an ERAP1 risk haplotype enhances the likelihood that autoantigen presentation by HLA-C*06:02 will exceed the threshold for activation of potentially autoreactive T cells, thereby triggering CD8+ T cell-mediated autoimmune disease. These data identify ERAP1 function as a central checkpoint and promising therapeutic target in psoriasis and possibly other HLA class I-associated diseases with a similar genetic predisposition.

Metal patch testing in patients with oral symptoms.

The number of patients with metal allergies has increased recently, and patch testing is useful for investigating such patients. However, the efficacy of restoration removal in patients with oral metal allergies is disputed. This study aimed to investigate the relationships between oral symptoms and metal allergies. We conducted a retrospective analysis of 60 patients with oral symptoms. The most common oral symptom was an abnormal oral sensation. Thirty-eight percent of the patients exhibited positive allergic reactions to one or more metal. Nickel was the metal allergen that produced positive reactions most frequently. Of the seven patients whose restorations were removed, complete and partial remission were achieved in one and two patients, respectively. Interestingly, metal alloy removal was effective in 33% (n = 1) of the positive patch test group and 50% (n = 2) of the non-positive patch test group. Our results demonstrated the difficulty of predicting the efficacy of restoration removal at ameliorating oral metal allergies based on patch testing alone.

Novel ex vivo disease model for extramammary Paget's disease using the cancer tissue-originated spheroid method.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare skin cancer that frequently occurs in the anogenital region in the elderly. Prognosis in patients with metastatic EMPD is poor as EMPD treatment has advanced little in recent years, primarily because no EMPD cell line has been established. OBJECTIVE: We aimed to establish an ex vivo EMPD disease model using the cancer tissue-originated spheroid (CTOS) method, which is used to prepare and culture primary cancer cells while maintaining cell-cell contact. METHODS: Thirteen samples from 12 EMPD patients were obtained. CTOSs were prepared and cultured using CTOS method. Histopathological examination of the CTOSs was performed. We investigated optimum medium conditions and effects of growth factors for CTOS growth. Chemo-sensitivity assays were conducted. RESULTS: CTOSs were successfully prepared from 3 primary lesions and 2 metastatic lymph nodes. Of these, 2 CTOSs (EMPD-3 and EMPD-4) could be maintained and passaged long term ex vivo. Following transplantation of CTOSs to NOD/Scid mice, CTOS-derived xenotumors exhibited ductal formation, indicating that CTOSs retained the original tumor characteristics. Chemo-sensitivity assays revealed that docetaxel significantly inhibited EMPD-3 growth in a dose-dependent manner, whereas EMPD-4 was not clearly inhibited. These findings indicate the heterogeneity of EMPD and potential use of chemosensitivity assays with patient-derived CTOS to select the most effective drugs for each patient. CONCLUSION: To our knowledge, this study represents the first establishment of an ex vivo-EMPD disease model involving conventional cell lines. EMPD CTOSs might be useful for developing new therapeutic strategies.

CD163-positive macrophage infiltration predicts systemic involvement in sarcoidosis.

BACKGROUND: Sarcoidosis is a chronic and systemic inflammatory disease, in which patients present with noncaseating epithelioid granulomas. Cutaneous lesions of sarcoidosis develop in 9% to 35% of all sarcoidosis patients and comprise various clinical subtypes. It usually affects multiple organs and has a variable clinical course; this is called systemic sarcoidosis (SS). However, occasionally, it only affects the skin and is then called cutaneous sarcoidosis (CS). Recent observations suggest that serum levels of soluble CD163 correlate with immune cell activity in sarcoidosis patients; however, the contribution of M1 and M2 macrophages toward disease progression remains unclear. METHODS: We evaluated macrophage phenotypes histopathologically using skin biopsy samples obtained from patients with CS (n = 8) and SS (n = 31) and performed immunostaining with CD68, iNOS (M1 macrophages), PD-L1, and CD163 (M2 macrophages). RESULTS: The density of CD163-positive cells in the SS group was significantly higher than that in the CS group. There was no significant correlation between the CD163 (+) cell density and serum angiotensin-converting enzyme level, serum calcium, or tuberculin reaction. CONCLUSIONS: Immunostaining for CD163 may be a novel and useful marker to predict systemic involvement in patients with cutaneous lesions of epithelioid granulomas.

Three hundred and eight nanometer excimer light therapy for alopecia universalis that is resistant to other treatments: A clinical study of 11 patients.

Three hundred and eight nanometer excimer light therapy has recently been reported to be effective against patchy alopecia areata (AA) in several clinical studies. However, these studies only included a few patients with severe forms of AA, and all of them exhibited poor outcomes. We further investigated the use of excimer light as a therapeutic option for cases of alopecia universalis (AU) that are resistant to other treatments. Eleven treatment-resistant AU patients were treated with a 308-nm excimer light at 2-week intervals for more than 16 sessions. Four patients achieved good responses and two patients exhibited poor responses. Three patients had Japanese skin type 1 and all of them achieved good responses. The radiation dose was increased until the patients exhibited marked erythema. The patients with Japanese skin type 3 who achieved good responses exhibited strong pigmentation at the irradiated sites. In conclusion, 308-nm excimer light therapy has significant effects on some AU patients who are resistant to other treatments and may be an alternative therapeutic option for AU. During the treatment of AU, high doses of radiation should be administrated until a strong inflammatory skin reaction is seen.