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A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.

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BACKGROUND: Vitiligo and halo nevus are two common T-cell-mediated skin disorders. Although autoimmunity has been suggested to be involved in both diseases, the relationship between vitiligo and halo nevus is not fully understood. OBJECTIVE: The aim of the current study was to investigate whether vitiligo and halo nevus share the same immunological and oxidative stress response. METHODS: Infiltrations of T cells, and expressions of chemokine receptors (CXCR3, CCR4, CCR5) and cytotoxic markers (Granzyme B, Perforin) in the lesions of vitiligo and halo nevus were examined by immunohistochemistry. Enzyme-linked immunosorbent assay was performed to analyze the expressions of chemokines in the serum samples and cytotoxic markers secreted by CD8+ T cells which were sorted from the peripheral blood mononuclear cells in healthy donors, vitiligo and halo nevus patients. Tissue levels of chemokine receptors and CXCR3 ligands in healthy controls, vitiligo patients and halo nevus patients were determined by qRT-PCR analysis. The percentages of CXCR3+ CD4+ T and CXCR3+ CD8+ T cells from the peripheral blood samples were examined by flow cytometry. Tissue and serum hydrogen peroxide (H2O2) concentrations were measured using H2O2 assay kit. RESULTS: Immunohistochemistry revealed a significant T-cell response, with pronounced dermal infiltrates of CD8+ T cells in vitiligo and halo nevus. The inflammatory cytotoxic markers such as Granzyme B and Perforin were also elevated in vitiligo and halo nevus, suggesting inflammatory responses in situ. By qRT-PCR and ELISA assay, we found significantly increased expressions of the chemokine receptor CXCR3 and its ligands, especially the accumulated CXCL10 in the skin lesions of vitiligo and halo nevus. Moreover, the level of H2O2, a key player involved in regulation of the immune response was significantly upregulated in the skin lesions of vitiligo and halo nevus. In addition, the increased H2O2 concentration correlated positively with CXCL10 level in skin lesions of vitiligo and halo nevus. CONCLUSIONS: These results demonstrate a H2O2-involved autoimmune phenotype in vitiligo and halo nevus, characterized by increased level of IFN-γ-inducible chemokine pair CXCL10-CXCR3, as well as a dense CD8+ T infiltration in the skin lesions, thus suggesting a similar pathogenesis of the two diseases.

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A case of halo naevi and café au lait macule regression in a renal transplant patient receiving long-term immunosuppressive therapy is described. We propose the direct transfer of an auto-reactive antibody, CD8 T-cells or tumour necrosis factor α from the transplant donor to the recipient as a possible cause. We have also considered insufficient immunosuppressive therapy as a possible mechanism.

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The pathogenesis and prognostic implications of regression in melanoma are not well understood. It has traditionally been considered an immunologically mediated phenomenon. Improvement in the knowledge of the mechanisms that lead to regression may prove to be of great value in an era in which treatments oriented to the augmentation of the host's immunity against melanoma have demonstrated excellent clinical results. This study was designed to improve the understanding of the mechanisms underlying melanoma regression and the differences between similar situations in benign melanocytic nevus. The study sample consisted of 77 lesions: 62 melanomas and 15 halo nevi. The following markers were included in the study: CD4, CD8, FoxP3, PD1, CD123, granzyme, and TIA-1. Staining was evaluated in 5 categories, according to the percentage of labeled cells. Granzyme, PD1, and TIA-1 stained significantly more cells in halo nevi than in melanomas with regression (P < 0.01). The ratio CD123/TIA-1 was higher in melanomas than in halo nevi (1 vs. 0.67, P < 0.05). Regression in the 62 melanomas was categorized as early in 14 cases and late in 48 cases. Early regression was associated with a higher percentage of CD123, CD4, and TIA-1 staining than late regression. The inflammatory infiltrate found in halo nevi is characterized by a higher number of active cytotoxic T cells and regulatory PD1-positive T cells than the infiltrate found in melanoma with regression. CD123 staining was higher in early regression than in late regression, suggesting the presence of a tolerogenic mechanism in this phenomenon's initiation phase.

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A 25-year-old Caucasian female with multiple genital warts involving the vulvar area was treated with imiquimod 5% cream. During follow-up the patient developed areas of hypopigmentation at the site of application of imiquimod cream and areas of hypomelanosis around multiple preexisting nevi of the trunk. At 18 months follow-up genital depigmentation persisted and halo nevi of the trunk were still present. Different mechanisms of imiquimod-induced depigmentation have been reported. Halo nevi are considered expression of an autoimmune response. In the case presented here, it might be conceivable that both vitiligo-like depigmentation at the site of application and halo of hypomelanosis around melanocytic nevi have been induced by the same immunologic mechanism elicited by topical application of imiquimod.

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A 25-year-old Caucasian female with multiple genital warts involving the vulvar area was treated with imiquimod 5% cream. During follow-up the patient developed areas of hypopigmentation at the site of application of imiquimod cream and areas of hypomelanosis around multiple preexisting nevi of the trunk. At 18 months follow-up genital depigmentation persisted and halo nevi of the trunk were still present. Different mechanisms of imiquimod-induced depigmentation have been reported. Halo nevi are considered expression of an autoimmune response. In the case presented here, it might be conceivable that both vitiligo-like depigmentation at the site of application and halo of hypomelanosis around melanocytic nevi have been induced by the same immunologic mechanism elicited by topical application of imiquimod.

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BACKGROUND: Regulatory T cells (Tregs) play an important role in autoimmune diseases. In skin, the presence of Tregs is thought to be mandatory for suppression of autoreactive T cells. Here, we assess the number of Tregs in skin of healthy subjects and patients with an autoimmune dermatosis. METHODS: Immunohistochemical stainings for CD3 and FOXP3 on skin biopsies of healthy subjects and subjects with psoriasis, vitiligo, pemphigus vulgaris, bullous pemphigoid, and halo nevus to assess the number of T and regulatory T cells, respectively. RESULTS: Low numbers of CD3+ and FOXP3+ cells were seen in the skin of healthy controls (median = 0.5%). A significantly higher frequency of Tregs was seen in lesional skin of patients with psoriasis (median = 12.4%) and patients with bullous pemphigoid (median = 10.1%) as compared to controls. In vitiligo (median = 0.0%), pemphigus vulgaris (median = 5.2%), and halo nevi (median = 5.4%), no significant difference in number of FOXP3+ cells was observed when compared to controls. CONCLUSIONS: As confirmed in the literature, few Tregs were seen in healthy skin. A high number of Tregs were present in lesional skin from patients with psoriasis and bullous pemphigoid. These results support the hypothesis that not a decrease in number but rather a decrease in function of Tregs would be at the basis of autoimmune skin diseases, which could result in unrestrained activation autoreactive T cells in skin of patients with autoimmune dermatoses.

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BACKGROUND: There have been few clinical studies of the role of regulatory T cells (Tregs) in halo formation of halo nevus. OBJECTIVE: To evaluate the clinicopathologic features and the presence of Tregs in halo nevi. METHODS: We analyzed 30 halo nevi and performed immunohistochemical analysis using antibodies against CD4, CD8, CD25 and Foxp3. We also performed double immunohistochemical staining for Foxp3 and CD25. RESULTS: We found significant increases in Foxp3(+) Tregs, and the shorter the halo nevus duration, the more Foxp3(+) Tregs were detected. Also, the ratio of Foxp3 to CD8 T cells was increased in early stages of halo nevi. Double immunohistochemical staining suggested that the Tregs in the halo nevi were CD25(+)Foxp3(+) T cells. CONCLUSIONS: Foxp3(+) Tregs were greatly increased in the halo nevi. The shorter the halo nevi duration, the more Foxp3(+) Tregs were involved in the earlier developmental stages of halo nevi.

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BACKGROUND: Vitiligo is the most common pigmentation-related disorder worldwide. An autoimmune etiology is widely considered, and genetic factors may play an important role in its pathogenesis. The purpose of this study was to assess the incidence of thyroid dysfunctions and autoimmune thyroiditis in children with vitiligo and to identify related factors. METHODS: Fifty children with vitiligo and 50 control children were enrolled. Data on age, onset, duration, disease activity, presence of thyroid disorder, other autoimmune diseases, halo nevi, poliosis, and mucosal vitiligo were determined. Serum free triiodothyronine, free thyroxine, total T3, total T4, thyroid-stimulating hormone, and antibodies to thyroperoxidase and thyroglobulin were measured. Thyroid gland efficiency was evaluated. RESULTS: The mean age at onset of vitiligo was 7.26 ± 4.43 years. The duration of vitiligo was 2.26 ± 2.95 years. Vulgaris-type vitiligo was the most common form in our patients (56%), and 42% reported at least one family member with thyroid disorder, autoimmune disease, or both. Overt hypothyroidism or hyperthyroidism were not detected. We found a significant association between autoimmune thyroiditis and both sex and disease duration (P = 0.046 and P = 0.07, respectively), but no association between autoimmune thyroiditis and age, age at onset of vitiligo, halo nevi, poliosis, mucosal involvement, disease activity, or family history of vitiligo, autoimmunity, or thyroid disorders. CONCLUSIONS: Children with vitiligo show an increased incidence of autoimmune thyroiditis. Children with vitiligo, especially girls and subjects with generalized/vulgaris-type vitiligo, should be screened annually for thyroid function and antithyroid antibodies to assist in the early diagnosis and therapy of autoimmune thyroiditis.

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Segmental vitiligo is often ascribed to the neurogenic theory of melanocyte destruction, although data about the initial etiopathological events are scarce. Clinical, histopathological and T-cell phenotypic analyses were performed during the early onset of a segmental vitiligo lesion in a patient with associated halo nevi. Histopathological analysis revealed a lymphocytic infiltrate, mainly composed of CD8+ T-cells and some CD4(+) T-cells around the dermo-epidermal junction. Flow cytometry analysis of resident T-cells revealed a clear enrichment of pro-inflammatory IFN-gamma producing CD8+ T-cells in lesional skin compared to the non-lesional skin. Using human leukocyte antigen-peptide tetramers (MART-1, tyrosinase, gp100), increased numbers of T cells, recognizing melanocyte antigens were found in segmental vitiligo lesional skin, as compared with the non-lesional skin and the blood. Our findings indicate that a CD8+ melanocyte specific T cell-mediated immune response, as observed in generalized vitiligo, also plays a role in segmental vitiligo with associated halo nevi.

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Halo nevi, also termed Sutton nevi, are defined as benign melanocytic nevi that are surrounded by an area of depigmentation resembling a halo. Halo nevi are common in children and young adults, with a mean age at onset of 15 years. The incidence in the population is estimated to be approximately 1%. Affected individuals frequently have multiple lesions which are usually localized on the back. A familial tendency for halo nevi has been reported. The etiology of halo nevi is unknown. It is an autoimmune response and T lymphocytes are considered to play a key role in the progressive destruction of nevus cells. Halo nevi may be associated with autoimmune disorders such as vitiligo, Hashimoto thyroiditis, alopecia areata, celiac disease, atopic dermatitis and others. It has been proved that halo nevi are detected after an intense sun exposure especially after sunburns. The etiology of halo nevi, association with malignant melanoma and the role of sun exposure in the development of halo nevi are discussed.

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