RESUMO
In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4+ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX+ CD4+ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Interleucina-4/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Cutâneas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Citotoxicidade Imunológica , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-4/genética , Células Jurkat , Linfócitos do Interstício Tumoral/imunologia , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/imunologia , México , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fenótipo , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologiaRESUMO
The role of Mycobacterium tuberculosis in the etiology and pathogenesis of cutaneous tuberculosis is controversial because of the difficulties associated with demonstrating the presence of these mycobacteria in tuberculid cutaneous lesions by routinely available microbiological and histological techniques. In this study, we aimed to demonstrate the presence of M. tuberculosis in cutaneous tuberculosis. Multiple polymerase chain reaction (PCR) followed by nested PCR was used to amplify genomic fragments from 3 different mycobacteria species. DNA was isolated from 30 paraffin-embedded skin biopsies. Samples were selected randomly from patients with a clinical and histopathological diagnosis of the most frequent groups of cutaneous tuberculosis in Mexico as follows: 5 cases of scrofuloderma tuberculosis; 2 cases of lupus vulgaris tuberculosis; and 5 cases of tuberculosis verrucosa cutis. The other cases denominated tuberculids in some countries such as Mexico and included the following: 7 cases of rosacea-like tuberculosis; one case of papulonecrotic tuberculosis; and 10 cases of erythema induratum of Bazin. Four normal skin biopsies were included as controls. M. tuberculosis DNA was amplified successfully by nested PCR in 80% of the samples (24 of the 30 samples) assayed. Mycobacterial DNA was not detected in the normal skin biopsies used as controls. Detection of M. tuberculosis DNA in 80% of cutaneous tuberculosis analyzed implicates this mycobacterium in the pathogenesis of multiple clinical forms of cutaneous tuberculosis.
Assuntos
DNA Bacteriano/análise , Mycobacterium tuberculosis , Reação em Cadeia da Polimerase/métodos , Tuberculose Cutânea/microbiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The diagnostic approaches and therapeutic strategies of atopic dermatitis (AD) are generally inconsistent among physicians and health institutions. OBJECTIVE: To develop a consensus statement among experts to reduce the variations in practice regarding the diagnosis and treatment of patients ≥ 12 years with AD to improve their care. METHODS: Systematic literature search in PubMed and GREAT. With methodological support and using the Delphi method, a formal consensus was developed among 16 experts in Dermatology and Allergology, based on the current evidence and its applicability in the Mexican context. Apart from intense electronic communication, several issues of disagreement were discussed in two face-to-face meetings. RESULTS: The clinical experts reached consensus on 46 statements related to the definition, classification, diagnostic strategies and treatment of AD. For the diagnosis we suggest the Williams criteria and for severity scoring the SCORAD (by the doctor) and POEM (by the patient). In addition to general care and treatment education (workshops), we suggest four steps for treatment, depending on severity: 1. Topical treatment with anti-inflammatory agents (and systemic: antihistamines/antileukotrienes -low level evidence-) 2. Phototherapy, 3. Cyclosporin A and 4. Dupilumab, with the possibility of managing this biological earlier on if a fast effect is needed. In extrinsic AD we suggest evaluating the addition of allergen immunotherapy or an elimination diet, if there is an IgE-mediated respiratory or food allergy, respectively. CONCLUSION: The panel of experts reached consensus on relevant aspects of AD with a focus on the transcultural adaptation of recent evidence.
Antecedentes: Los abordajes diagnósticos y las estrategias terapéuticas de la dermatitis atópica generalmente son inconsistentes entre los médicos y entre las instituciones de salud. Objetivo: Consensar las opiniones de expertos para reducir las variaciones en la práctica respecto al diagnóstico y tratamiento de pacientes ≥ 12 años con dermatitis atópica para mejorar su cuidado. Métodos: Búsqueda sistemática de la literatura en PubMed y GREAT. Con apoyo metodológico y utilizando el método Delphi se desarrolló un consenso formal entre 16 expertos en dermatología y alergología, basándose en la evidencia actual y su aplicabilidad en el contexto mexicano. A parte de una comunicación electrónica intensa, se discutieron los puntos en desacuerdo en dos reuniones presenciales. Resultados: Los expertos clínicos alcanzaron consenso en 46 declaraciones relacionadas con la definición, clasificación, estrategias de diagnóstico y tratamiento de la dermatitis atópica. Para el diagnóstico sugerimos se usan los criterios de Williams y el SCORAD (por parte del médico) y POEM (por parte del paciente) para definir la gravedad. Aunado a cuidados generales y educación terapéutica, sugerimos cuatro pasos para tratamiento, según gravedad: 1. Manejo tópico con antiinflamatorio (y sistémico: antihistamínico/antileucotrieno evidencia reducida) 2. Fototerapia, 3. Ciclosporina A y 4. Dupilumab, con la posibilidad de manejarlo antes si se necesita efecto rápido. En la dermatitis atópica extrínseca sugerimos agregar inmunoterapia con alérgenos o una dieta de eliminación si existe una alergia IgE-mediada, inhalatoria o alimentaria, respectivamente. Conclusión: El panel de expertos realizó consenso en aspectos relevantes de la dermatitis atópica con enfoque en la adaptación transcultural de evidencia reciente.
Assuntos
Dermatite Atópica , Guias de Prática Clínica como Assunto , Adolescente , Adulto , Produtos Biológicos/uso terapêutico , Terapia Combinada , Comorbidade , Dermatite Atópica/diagnóstico , Dermatite Atópica/psicologia , Dermatite Atópica/terapia , Fármacos Dermatológicos/classificação , Fármacos Dermatológicos/uso terapêutico , Dermatologia/métodos , Diagnóstico Diferencial , Gerenciamento Clínico , Feminino , Humanos , Imunoterapia/métodos , Lactação , Masculino , México , Fototerapia/métodos , Gravidez , Complicações na Gravidez/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Dermatopatias Infecciosas/complicações , Inquéritos e Questionários , Irrigação Terapêutica , Transição para Assistência do AdultoRESUMO
Innate lymphoid cells (ILC) are members of a heterogeneous family with a lymphoid origin that mimics the T helper (Th) cytokine profile. ILC are involved in early effector cytokine-mediated responses during infections in peripheral tissues. ILC also play an important role in chronic skin inflammatory diseases, including psoriasis. Although classical ILC express CD127, it has been recently reported that the presence of non-classical CD127- ILC populations and an early ILC precursor (EILP) CD127low. ILC development has predominately been investigated in mouse models. However, in humans, different transcription factors have been described for ILC identification. NFIL3 (nuclear factor, IL-3 regulated) is crucial for ILC development in response to IL-7. CD123 (IL-3Rα) is usually used to exclude basophils during ILC identification, however, it is unknown if in response to IL-3, NFIL3 could be relevant to induce ILC features in Lin- CD123+ populations in addition, is also unknown whether peripheral blood (PB) population with ILC features may have skin-homing potential to participate in skin inflammatory chronic diseases. Here, we report a Lin- CD123+ CD127low CD7+ CLA+ population that share some phenotypic properties with basophils, but expresses several transcription factors for ILC commitment such as inhibitor of DNA binding 2 (Id2), NFIL3, promyelocytic leukemia zinc finger (PLZF), thymocyte selection-associated high-mobility group box protein (TOX), and T cell factor-1 (TCF-1). In addition, this population expresses different ILC markers: CD132, CD90, CD161, α4 integrin, c-Kit, CRTH2, AhR, and IL-23R. IL-3 prevents apoptosis and increases their NFIL3, TOX, and PLZF expression. In PB, the CD123+ CD127low population is predominantly a conspicuous population that expresses T-bet and RORγt. The Lin- CD123+ CD127low population in PB has a limited Th type cytokine expression and highly expresses IL-8. The Lin- CD123+ CD127low population expresses skin-homing receptors (cutaneous lymphocyte antigen and CXCR4) and transmigrates through endothelial cells in response to SDF-1. An equivalent Lin- CD123low population was identified in control skin, which shows a broader phenotypic diversity and cytokine production, including IL-22 and IL-17. Remarkably, the CD123low population in the lesion and non-lesion skin of psoriasis patients expresses IL-17 and IL-22. Our findings suggest the identification of an alternative Lin- CD123+ CD127low population with ILC features endowed with migratory capabilities that might contribute to immunopathological hallmarks of psoriasis.
RESUMO
Psoriasis is a chronic inflammatory disease with a worldwide prevalence between 6 and 39% in moderate to severe forms. In European countries like Germany and England was identified that only one third of patients with moderate to severe forms will receive systemic management, this fact motivated to integrate into Europe an international consensus on treatment goals with the aim of providing support to the dermatologist by algorithms that serve as a therapeutic guide that allows you to gain control short and long term effects of this disease. The European group met to develop the definitions of severity of psoriasis, treatment goals for moderate to severe disease, and optimization options and / or therapeutic transition than a paper published in 2011 was obtained. In Mexico a working group of experts on biological therapy (GTEB), made up of 10 members and an extended group of 150 dermatologists' voters in the country for the purpose of issuing Mexico's position on the proposals of the European group was formed. In this document the findings of the Working Group of Experts on Biological Therapy in Mexico are listed.
La psoriasis es una enfermedad crónica inflamatoria, con una prevalencia mundial entre 6 y 39% en las formas moderadas a severas. En países europeos como Alemania e Inglaterra se identificó que solo la tercera parte de los pacientes que padecen formas moderadas a severas reciben manejo sistémico; este hecho motivó la integración en Europa de un consenso internacional sobre metas de tratamiento con el objetivo de brindar apoyo al dermatólogo con algoritmos que sirvan como guía terapéutica para lograr el control a corto y largo plazo de esta enfermedad. El grupo europeo se reunió para elaborar las definiciones de severidad de la psoriasis, las metas de tratamiento en la enfermedad moderada a severa, entre otros temas, de lo que se obtuvo un documento publicado en el 2011. En México se conformó un grupo de trabajo de expertos en terapia biológica (GTEB), formado por 10 integrantes y un grupo extendido de 150 dermatólogos votantes del país, con la finalidad de emitir la posición de México sobre las propuestas del grupo europeo. En el presente documento se enumeran las conclusiones del grupo de trabajo de expertos en terapia biológica en México.
Assuntos
Psoríase/terapia , Assistência ao Convalescente , Terapia Combinada , Técnica Delphi , Fármacos Dermatológicos/uso terapêutico , Objetivos , Humanos , México , Fototerapia , Psoríase/diagnóstico , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Discoid lupus erythematosus (DLE) is a cutaneous autoimmune inflammatory disease in which the role of conventional dendritic cells (cDCs) in skin damage has not been evaluated. OBJECTIVE: To evaluate the involvement of cDCs in DLE pathogenesis. MATERIAL & METHODS: Skin biopsies from 42 patients with DLE were embedded in paraffin or placed in culture. The dermis was separated and cell suspensions were characterized by flow cytometry. RESULTS: We found an increase in cDCs with inflammatory characteristics in the skin of DLE patients, compared with control skins. Interestingly, cDCs from the DLE patients expressed low levels of the inhibitory molecule PD-L1 and showed a high expression of CCR6, which correlated with disease activity. Increased cellular death was observed in the skin of DLE patients compared with control skin and remarkably we found that damage-associated molecular patterns could be responsible for CCR6 expression on cDCs in the skin. CONCLUSIONS: Our results indicate the presence of pathogenic CCR6+ cDCs in the skin lesions of DLE patients, which could result from in situ phenotypic changes.
Assuntos
Células Dendríticas/metabolismo , Lúpus Eritematoso Discoide/metabolismo , Lúpus Eritematoso Discoide/patologia , Receptores CCR6/metabolismo , Adolescente , Adulto , Idoso , Apoptose , Antígeno B7-H1/metabolismo , Antígeno CD11c/análise , Antígenos CD40/análise , Contagem de Células , Movimento Celular , Células Cultivadas , Células Dendríticas/química , Feminino , Antígenos de Histocompatibilidade Classe II/análise , Humanos , Lúpus Eritematoso Discoide/sangue , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/análise , Receptores CCR6/análise , Pele/química , Pele/metabolismo , Fator de Necrose Tumoral alfa/análise , Adulto JovemRESUMO
BACKGROUND: Acanthosis nigricans (AN) is a skin condition commonly present on the neck of obese subjects. Obesity is often accompanied by insulin resistance and/or hyperinsulinemia. Metformin and rosiglitazone are 2 pharmacologic agents useful in conditions characterized by insulin resistance. OBJECTIVE: The aim of our study was to compare the efficacy of metformin versus rosiglitazone on AN lesions of the neck as well as their effects on metabolic and anthropometric variables. METHODS: This 12-week randomized, open-label pilot study involved overweight or obese subjects with AN treat with either metformin (n=4) or rosiglitazone (n=3). RESULTS: Only the rosiglitazone group showed a significant reduction in insulin levels. No effect on the severity of AN was observed, but modest improvements of skin texture occurred in both treatment groups. CONCLUSIONS: Metformin and rosiglitazone were well-tolerated. Although efficacy on skin lesions was very modest, their use in acanthotic subjects might be useful during longer treatment periods.
Assuntos
Acantose Nigricans/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Metformina/uso terapêutico , Tiazolidinedionas/uso terapêutico , Acantose Nigricans/sangue , Acantose Nigricans/patologia , Administração Oral , Adulto , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/sangue , Masculino , Metformina/administração & dosagem , Obesidade , Projetos Piloto , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Resultado do TratamentoRESUMO
Background. Guttate psoriasis is associated with infections by Streptococcus pyogenes and cross-reaction between skin and streptococcal antigens have been reported, suggesting an autoimmune component in the disease. Methods. In this work, the authors looked for antibodies against S. pyogenes M-5 antigens by immunoblot in 52 sera of psoriasis patients and in 52 sera of normal individuals. Histological and immunohistochemical analysis in skin biopsies from lesions of another group of 16 clinically diagnosed guttate psoriasis patients and four healthy controls were also carried out. Results. All guttate psoariasis patients studied (11) had IgG antibodies that intensively recognized three different proteins of 70,60 and 14 kDa, as compared to sera from patients with other forms of psoriasis or from healthy controls. The diagnosis of psoariasis was confirmed in 14 of the patients by hematoxylin-eosin staining. Of the other two patients, one was diagnosed as parapsoriasis and the other as liquen. By indirect immunofluorescence (IFI), all 14 psoriatic patients had autoantibodies against their own lesional skin that did not recognized normal skin from control subjects or from the two non-psoriatic patients. The parapsoriatic and the liquen patients did not have autoantibodies. A rabbit immune serum against S. pyogenes antigens reacted with lesional skin from the 14 guttate psoriatic patients, but not with normal skin from controls or with lesional skin from the 2 non-psoriatic patients. Conclusions. The recognition by immunoblot of streptococcal antigens by serum of guttate psoriasis patients, the presence of autoantibodies against their own skin, and recognition of the same skin antigens by anti-streptococcal rabbit antibodies confirm the participation of the immune system and of streptococcal infection in guttate psoriasis
