RESUMO
Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.
Assuntos
Autoanticorpos , Autoantígenos , Melanoma , Penfigoide Bolhoso , Humanos , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/etiologia , Melanoma/imunologia , Melanoma/etiologia , Autoanticorpos/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/etiologia , Colágeno Tipo XVII , Colágenos não Fibrilares/imunologia , Melanócitos/imunologia , Melanócitos/patologia , Animais , Relevância ClínicaRESUMO
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.
Assuntos
Células Dendríticas , Melanócitos , Nevo com Halo , Humanos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Melanócitos/metabolismo , Melanócitos/imunologia , Nevo com Halo/metabolismo , Nevo com Halo/imunologia , Uridina Difosfato Glucose/metabolismo , Vitiligo/imunologia , Vitiligo/metabolismo , Masculino , Feminino , Adulto , Apoptose , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem , AdolescenteRESUMO
Vitiligo is an autoimmune disease characterized by epidermal melanocyte destruction, with abnormal autoimmune responses and excessive oxidative stress as two cardinal mechanisms. Human umbilical mesenchymal stem cells-derived exosomes (hUMSCs-Exos) are regarded as promising therapeutic choice for autoimmune diseases due to potent immunosuppressive and anti-oxidative properties, which can be potentiated under 3D cell culture condition. Nevertheless, whether exosomes derived from 3D spheroids of hUMSCs (3D-Exos) exhibit considerable therapeutic effect on vitiligo and the underlying mechanism remain elusive. In this study, systemic administration of 3D-Exos showed a remarkable effect in treating mice with vitiligo, as revealed by ameliorated skin depigmentation, less CD8+T cells infiltration, and expanded Treg cells in skin, and 3D-Exos exerted a better effect than 2D-Exos. Mechanistically, 3D-Exos can prominently facilitate the expansion of Treg cells in vitiligo lesion and suppress H2O2-induced melanocytes apoptosis. Forward miRNA profile analysis and molecular experiments have demonstrated that miR-132-3p and miR-125b-5p enriched in 3D-Exos greatly contributed to these biological effects by targeting Sirt1 and Bak1 respectively. In aggregate, 3D-Exos can efficiently ameliorate vitiligo by simultaneously potentiating Treg cells-mediated immunosuppression and suppressing oxidative stress-induced melanocyte damage via the delivery of miR-132-3p and miR-125b-5p. The employment of 3D-Exos will be a promising treament for vitiligo.
Assuntos
Modelos Animais de Doenças , Exossomos , Melanócitos , Células-Tronco Mesenquimais , Estresse Oxidativo , Linfócitos T Reguladores , Vitiligo , Vitiligo/terapia , Vitiligo/imunologia , Animais , Exossomos/metabolismo , Exossomos/imunologia , Camundongos , Linfócitos T Reguladores/imunologia , Melanócitos/imunologia , Humanos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Terapia de Imunossupressão/métodos , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Introduction: Vitiligo is an acquired de-pigmentation disorder characterized by the post-natal loss of epidermal melanocytes (pigment-producing cells) resulting in the appearance of white patches in the skin. The Smyth chicken is the only model for vitiligo that shares all the characteristics of the human condition including: spontaneous post-natal loss of epidermal melanocytes, interactions between genetic, environmental and immunological factors, and associations with other autoimmune diseases. In addition, an avian model for vitiligo has the added benefit of an easily accessible target tissue (a growing feather) that allows for the repeated sampling of an individual and thus the continuous monitoring of local immune responses over time. Methods: Using a combination of flow cytometry and gene expression analyses, we sought to gain a comprehensive understanding of the initiating events leading to expression of vitiligo in growing feathers by monitoring the infiltration of leukocytes and concurrent immunological activities in the target tissue beginning prior to visual onset and continuing throughout disease development. Results: Here, we document a sequence of immunologically significant events, including characteristic rises in infiltrating B and αß T cells as well as evidence of active leukocyte recruitment and cell-mediated immune activities (CCL19, IFNG, GZMA) leading up to visual vitiligo onset. Examination of growing feathers from vitiligo-susceptible Brown line chickens revealed anti-inflammatory immune activities which may be responsible for preventing vitiligo (IL10, CTLA4, FOXP3). Furthermore, we detected positive correlations between infiltrating T cells and changes in their T cell receptor diversity supporting a T cell-specific immune response. Conclusion: Collectively, these results further support the notion of cell-mediated immune destruction of epidermal melanocytes in the pulp of growing feathers and open new avenues of study in the vitiligo-prone Smyth and vitiligo-susceptible Brown line chickens.
Assuntos
Galinhas , Modelos Animais de Doenças , Plumas , Melanócitos , Vitiligo , Animais , Vitiligo/imunologia , Galinhas/imunologia , Plumas/imunologia , Melanócitos/imunologia , Melanócitos/metabolismo , Linfócitos T/imunologiaRESUMO
Vitiligo belongs to a frequent chronic autoimmune skin disease with the features of pigmented plaques on the diseased skin along with potential damage of melanocytes. There are many factors underlying the pathogenesis of vitiligo, among which oxidative stress is extensively regarded to be the critical factor leading to the loss of melanocytes. The changed redox state resulting from oxidative stress, containing ROS overproduction along with the reduced activity of the skin's antioxidant system, makes melanocytes less resistant to exogenous or endogenous stimuli, and ultimately pushes normal defense mechanisms, resulting in the loss of melanocytes. Given the crucial potential of innate together with adaptive immunity in vitiligo, there is growing evidence of a relation between oxidative stress and autoimmunity. Our review offers estimable insights into the possible properties of oxidative stress and autoimmunity in pathogenesis of vitiligo, as well as the potential role of antioxidant-based supportive therapy in vitiligo repigmentation, providing a hopeful value for further research and development of effective treatments.
Assuntos
Autoimunidade , Melanócitos , Estresse Oxidativo , Vitiligo , Vitiligo/imunologia , Vitiligo/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/imunologia , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Pigmentação da Pele , AnimaisRESUMO
Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from the endoplasmic reticulum to the membrane in melanocytes under oxidative stress. To investigate the potential role of CRT in the pathogenesis of vitiligo, we analyzed the correlation between CRT and ROS in serum and lesions of vitiligo, detected CRT and protein kinase RNA-like endoplasmic reticulum kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway and then tested the chemotactic migration of CD8+ T cells or CD11c+ CD86+ cells. Initially, we verified the overexpression of CRT in perilesional epidermis that was positively correlated with the disease severity of vitiligo. Furthermore, the PERK branch of UPR was confirmed to be responsible for the overexpression and membranal translocation of CRT in melanocytes under oxidative stress. We also found that oxidative stress-induced membranal translocation of CRT promoted the activation and migration of CD8+ T cells in vitiligo. In addition, dendritic cells from patients with vitiligo were also prone to maturation with the coincubation of melanocytes harboring membranal CRT. CRT could be induced on the membrane of melanocytes through UPR and might play a role in oxidative stress-triggered CD8+ T-cell response in vitiligo.
Assuntos
Autoimunidade , Linfócitos T CD8-Positivos , Calreticulina , Melanócitos , Estresse Oxidativo , Resposta a Proteínas não Dobradas , Vitiligo , Vitiligo/imunologia , Vitiligo/metabolismo , Vitiligo/patologia , Humanos , Melanócitos/metabolismo , Melanócitos/imunologia , Estresse Oxidativo/imunologia , Calreticulina/metabolismo , Resposta a Proteínas não Dobradas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Masculino , Adulto , eIF-2 Quinase/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem , Membrana Celular/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologiaRESUMO
BACKGROUND: Distinguishing melanocytic pseudonests encountered in lichenoid dermatoses or lichenoid keratoses from melanoma in situ (MIS) with brisk lichenoid inflammation can prove challenging. METHODS: We designed a case-control study to evaluate the accuracy metrics of PRAME immunohistochemistry to distinguish melanocytic pseudonests in lichenoid dermatoses or keratoses from inflamed MIS. Immunostaining for PRAME was performed on paraffin-embedded formalin-fixed diagnostic tissue using a rabbit monoclonal antibody to PRAME (Abcam), with a 1:3200 dilution on a Leica Bond detection system. RESULTS: Our search identified 21 cases of melanocytic pseudonests (n = 21, 46%) encountered in lichenoid dermatoses and 24 cases of inflamed MIS (n = 24, 53%). Each method of evaluating PRAME immunohistochemistry (PRAME+ clusters, PRAME % of melanocytes by four categories and PRAME+ melanocyte counts per linear mm of epidermal basal layer) showed statistically significant differences between the MIS and the pseudonest cohorts (respectively, p < 0.001; p < 0.001; and p < 0.001). Receiver operating characteristics analysis for PRAME+ melanocyte counts per linear mm of epidermal basal layer revealed an area under the curve of 0.9 ± 0.05 (95% confidence interval 0.9-1.0). When determining an optimal cut-off point for the best Youden index [sensitivity (%) + specificity (%) - 100], the cut-off of 1.0 PRAME+ melanocytes per linear mm showed a sensitivity of 79.2% and specificity of 85.7% (Youden index 0.65) to distinguish MIS from pseudonests. CONCLUSION: PRAME immunohistochemistry may constitute an additional tool for this challenging differential diagnosis.
Assuntos
Imuno-Histoquímica , Ceratose Actínica , Erupções Liquenoides , Melanoma , Neoplasias Cutâneas , Humanos , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Estudos de Casos e Controles , Diagnóstico Diferencial , Imuno-Histoquímica/métodos , Ceratose Actínica/diagnóstico , Erupções Liquenoides/diagnóstico , Erupções Liquenoides/patologia , Melanócitos/citologia , Melanócitos/imunologia , Melanoma/diagnóstico , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Melanoma Maligno CutâneoRESUMO
The skin serves as a physical barrier and an immunological interface that protects the body from the external environment1-3. Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body4-6. Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8+ T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8+ cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fibroblastos/imunologia , Pele/imunologia , Pele/patologia , Vitiligo/imunologia , Vitiligo/patologia , Adolescente , Adulto , Animais , Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/imunologia , Criança , Modelos Animais de Doenças , Feminino , Fibroblastos/patologia , Humanos , Interferon gama/imunologia , Masculino , Melanócitos/imunologia , Melanócitos/patologia , Camundongos , Pessoa de Meia-Idade , Comunicação Parácrina , RNA-Seq , Análise de Célula Única , Células Estromais/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto JovemAssuntos
Imunidade Inata , Receptores CXCR3/metabolismo , Vitiligo/imunologia , Adulto , Apoptose/imunologia , Biópsia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Voluntários Saudáveis , Humanos , Masculino , Melanócitos/imunologia , Melanócitos/patologia , Pessoa de Meia-Idade , Pele/imunologia , Pele/metabolismo , Pele/patologia , Vitiligo/patologia , Adulto JovemRESUMO
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.
Assuntos
Aminopeptidases/metabolismo , Linfócitos T CD8-Positivos/imunologia , Antígenos HLA-C/metabolismo , Melanócitos/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Psoríase/imunologia , Aminopeptidases/genética , Apresentação de Antígeno , Autoantígenos/imunologia , Autoimunidade , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Células HEK293 , Antígenos HLA-C/genética , Humanos , Antígenos de Histocompatibilidade Menor/genética , Terapia de Alvo Molecular , Psoríase/genética , Receptores de Antígenos de Linfócitos T/metabolismo , RiscoRESUMO
Although surgical interventions have become optional for refractory vitiligo, grafting related injuries is inevitable. Embryonic stem cell (ESC) derivatives can be used in transplantation to address this issue, but the immune rejection due to allogeneic transplantation is of great concern. To investigate the immunogenicity of ESC derived melanocytes (ES-MC), we established a co-culture system of ES-MC and allogeneic PBMC. The results showed that ES-MC were similar to human primary melanocytes, with low expression of immune related molecules, and limited capability of stimulating allogeneic lymphocytes in vitro. Taken together, our findings confirm that ES-MC are of limited immunogenicity, providing new insights into the application of ES-MC in the regenerative medicine such as treating vitiligo.
Assuntos
Células-Tronco Embrionárias Humanas/imunologia , Melanócitos/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Células-Tronco Embrionárias Humanas/citologia , Humanos , Melanócitos/citologia , Medicina RegenerativaRESUMO
Immune dysregulation is critical in vitiligo pathogenesis. Although the presence and roles of numerous CD4+ T-cell subsets have been described, the presence of Th9 cells and more importantly, roles of IL-9 on melanocyte functions are not explored yet. Here, we quantified the T helper cell subsets including Th9 cells in vitiligo patients by multicolor flowcytometry. There was an increased frequency of skin-homing (CLA+ ) and systemic (CLA- ) Th9 cells in vitiligo patients compared to healthy donors. However, there was no difference in Th9 cell frequency in vitiligo patients with early and chronic disease. There was negligible IL-9 receptor (IL-9R) expression on human primary melanocytes (HPMs); however, IFNγ upregulated IL-9R expression on HPMs. Functionally, IL-9/IL-9R signaling reduced the production of IFNγ-induced toxic reactive oxygen species (ROS) in HPMs. There was no effect of IL-9 on expression of genes responsible for melanosome formation (MART1, TYRP1, and DCT), melanin synthesis (TYR), and melanocyte-inducing transcription factor (MITF) in HPMs. In conclusion, this study identifies the presence of Th9 cells in vitiligo and their roles in reducing the oxidative stress of melanocytes, which might be useful in designing effective therapeutics.
Assuntos
Regulação da Expressão Gênica/imunologia , Interleucina-9/imunologia , Melanócitos/imunologia , Pele/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vitiligo/imunologia , Adulto , Humanos , Masculino , Melanócitos/patologia , Pessoa de Meia-Idade , Receptores de Interleucina-9/imunologia , Pele/patologia , Linfócitos T Auxiliares-Indutores/patologia , Vitiligo/patologiaRESUMO
SUMMARY: Inflammatory infiltrates are frequently present in melanocytic lesions, with different distribution and composition. Much attention has been devoted to tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment, establishing their prognostic and predictive value in many malignancies, including melanoma. However, lymphocytes, albeit the most numerous and consistent presence, constitute only part of the immune microenvironment. Other inflammatory cells, including neutrophils, plasma cells, eosinophils and mast cells, are found in melanoma and other melanocytic lesions.Few studies offer a detailed count of these inflammatory infiltrates across the spectrum of melanocytic lesions. By using whole slide image analysis and open source software, in the present study we report the enumeration of different inflammatory infiltrates in benign melanocytic nevi, dysplastic nevi, melanoma in situ and invasive malignant melanomas. Significant higher numbers of plasma cells and neutrophils were observed in melanoma. These results indicate that composition of the inflammatory infiltrate may contribute to the diagnostic algorithm of melanocytic lesions.
RESUMEN: Los infiltrados inflamatorios están presentes con frecuencia en las lesiones melanocíticas, con diferente distribución y composición. Se ha prestado mucha atención a los linfocitos infiltrantes de tumores (TIL) en el microambiente tumoral, estableciendo su valor pronóstico y predictivo en muchas neoplasias malignas, incluido el melanoma. Sin embargo, los linfocitos de presencia más numerosa y constante, constituyen solo una parte del microambiente inmunológico. Otras células inflamatorias, incluidos neutrófilos, células plasmáticas, eosinófilos y mastocitos, se encuentran en el melanoma y otras lesiones melanocíticas. Pocos estudios ofrecen un recuento detallado de estos infiltrados inflamatorios en todo el espectro de lesiones melanocíticas. Mediante el uso de análisis de imágenes de diapositivas completas y software de código abierto, en el presente estudio informamos la enumeración de diferentes infiltrados inflamatorios en nevos melanocíticos benignos, nevos displásicos, melanoma in situ y melanomas malignos invasivos. Se observaron números significativamente más altos de células plasmáticas y neutrófilos en el melanoma. Estos resultados indican que la composición del infiltrado inflamatorio puede contribuir al algoritmo diagnóstico de las lesiones melanocíticas.
Assuntos
Humanos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Melanócitos/imunologia , Melanócitos/patologia , Melanoma/imunologia , Melanoma/patologia , Plasmócitos , Linfócitos do Interstício Tumoral , Inflamação , Neutrófilos/imunologia , Neutrófilos/patologiaRESUMO
Vitiligo is a disease of the skin characterized by the appearance of white spots. Significant progress has been made in understanding vitiligo pathogenesis over the past 30 years, but only through perseverance, collaboration, and open-minded discussion. Early hypotheses considered roles for innervation, microvascular anomalies, oxidative stress, defects in melanocyte adhesion, autoimmunity, somatic mosaicism, and genetics. Because theories about pathogenesis drive experimental design, focus, and even therapeutic approach, it is important to consider their impact on our current understanding about vitiligo. Animal models allow researchers to perform mechanistic studies, and the development of improved patient sample collection methods provides a platform for translational studies in vitiligo that can also be applied to understand other autoimmune diseases that are more difficult to study in human samples. Here we discuss the history of vitiligo translational research, recent advances, and their implications for new treatment approaches.
Assuntos
Melanócitos , Pigmentação da Pele , Pele , Pesquisa Translacional Biomédica , Vitiligo , Animais , Autoimunidade , Fármacos Dermatológicos/uso terapêutico , Modelos Animais de Doenças , Testes Genéticos , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/imunologia , Melanócitos/metabolismo , Estresse Oxidativo , Fenótipo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Pigmentação da Pele/efeitos dos fármacos , Vitiligo/tratamento farmacológico , Vitiligo/genética , Vitiligo/imunologia , Vitiligo/metabolismoRESUMO
Vitiligo is an acquired multifactorial disease that affects melanocytes and results in skin depigmentation. In this review, we examine the role of cells stress and self-reactive T cells responses. Given the canonical and non-canonical functions of NKG2D, such as authenticating stressed target and enhance TCR signaling, we examine how melanocyte stress leads to the expression of ligands that are recognized by the activating receptor NKG2D, and how its signaling results in the turning of T cells against self (melanocyte suicide by proxy). We also discuss how this initiation phase is followed by T cell perpetuation, as NKG2D signaling results in self-sustained long-lasting T cells, with improved cytolytic properties.
Assuntos
Autoimunidade , Linfócitos T CD8-Positivos/metabolismo , Melanócitos/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Pigmentação da Pele , Pele/metabolismo , Vitiligo/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Microambiente Celular , Citotoxicidade Imunológica , Humanos , Melanócitos/imunologia , Melanócitos/patologia , Estresse Oxidativo , Transdução de Sinais , Pele/imunologia , Pele/patologia , Vitiligo/genética , Vitiligo/imunologia , Vitiligo/patologiaRESUMO
Melanocytes are static, minimally proliferative cells. This leaves them vulnerable in vitiligo. Yet upon malignant transformation, they form vicious tumors. This profound switch in physiology is accompanied by genetic change and is driven by environmental factors. If UV exposure in younger years supports malignant transformation and melanoma formation, it can likewise impart mutations on melanocytes that reduce their viability, to initiate vitiligo. A wide variety of microbes can influence these diametrically opposed outcomes before either disease takes hold. These microbes are vehicles of change that we are only beginning to study. Once a genetic modification occurs, there is a wide variety of immune cells ready to respond. Though it does not act alone, the T cell is among the most decisive responders in this process. The same biochemical process that offered the skin protection by producing melanin can become an Achilles heel for the cell when the T cells target melanosomal enzymes or, on occasion, neoantigens. T cells are precise, determined, and consequential when they strike. Here, we probe the relationship between the microbiome and its metabolites, epithelial integrity, and the activation of T cells that target benign and malignant melanocytes in vitiligo and melanoma.
Assuntos
Melaninas/metabolismo , Melanócitos/patologia , Melanoma/patologia , Microbiota , Transtornos da Pigmentação/patologia , Linfócitos T/imunologia , Distinções e Prêmios , Humanos , Melanócitos/imunologia , Melanócitos/microbiologia , Melanoma/imunologia , Melanoma/microbiologia , Transtornos da Pigmentação/imunologia , Transtornos da Pigmentação/microbiologia , Linfócitos T/classificaçãoAssuntos
Procedimentos Clínicos , Fatores Imunológicos/administração & dosagem , Pigmentação da Pele/efeitos da radiação , Terapia Ultravioleta/métodos , Vitiligo/terapia , Administração Cutânea , Administração Oral , Terapia Combinada/métodos , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/imunologia , Melanócitos/efeitos da radiação , Pele/citologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Pigmentação da Pele/efeitos dos fármacos , Pigmentação da Pele/imunologia , Resultado do Tratamento , Vitiligo/imunologiaAssuntos
Dermatite Atópica/diagnóstico , Interleucina-13/análise , Subunidade alfa de Receptor de Interleucina-4/análise , Pele/patologia , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/metabolismo , Biópsia , Estudos de Casos e Controles , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Feminino , Voluntários Saudáveis , Humanos , Imuno-Histoquímica , Interleucina-13/metabolismo , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Masculino , Melanócitos/imunologia , Melanócitos/metabolismo , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Pele/citologia , Pele/imunologia , Adulto JovemRESUMO
The epidermis is located in the outermost layer of the living body and is the place where external stimuli such as ultraviolet rays and microorganisms first come into contact. Melanocytes and melanin play a wide range of roles such as adsorption of metals, thermoregulation, and protection from foreign enemies by camouflage. Pigmentary disorders are observed in diseases associated with immunodeficiency such as Griscelli syndrome, indicating molecular sharing between immune systems and the machineries of pigment formation. Melanocytes express functional toll-like receptors (TLRs), and innate immune stimulation via TLRs affects melanin synthesis and melanosome transport to modulate skin pigmentation. TLR2 enhances melanogenetic gene expression to augment melanogenesis. In contrast, TLR3 increases melanosome transport to transfer to keratinocytes through Rab27A, the responsible molecule of Griscelli syndrome. TLR4 and TLR9 enhance tyrosinase expression and melanogenesis through p38 MAPK (mitogen-activated protein kinase) and NFκB signaling pathway, respectively. TLR7 suppresses microphthalmia-associated transcription factor (MITF), and MITF reduction leads to melanocyte apoptosis. Accumulating knowledge of the TLRs function of melanocytes has enlightened the link between melanogenesis and innate immune system.