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1.
J Cutan Pathol ; 50(10): 897-902, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36790018

RESUMO

Microsecretory adenocarcinoma (MSA) is a newly described salivary gland tumor harboring a characteristic balanced chromosomal translocation resulting in MEF2C::SS18 gene fusion. Six primary cutaneous MSA cases have been recently described. We report three additional cases confirming the relevance of this recently identified entity of primary cutaneous adnexal tumor. Three patients aged 53-, 64- and 78-year-old were retrospectively diagnosed with MSA of the skin (MSAS) as consultation cases of the CARADERM (CAncers RAres DERMatologiques) national network. The clinical presentation was an indolent nodule on the upper extremities. There was no history of salivary gland tumor. Histopathologically, the tumors presented as dermal nodular proliferation with slightly infiltrative borders, composed of cribriform and microcystic structures with abundant myxoid intraluminal secretion embedded in a fibromyxoid stroma. They diffusely expressed cytokeratin 8 and SOX10, focally p63 and heterogeneously smooth muscle actin. All tumors harbored the MEF2C::SS18 gene fusion. A complete surgical excision was performed. No local recurrence or distant metastases were observed so far (follow-up: 17, 38, and 45 months). MSAS is the cutaneous homologue of MSA of the salivary gland, a low-grade adnexal neoplasm whose prognosis seems to be excellent once the complete removal of the tumor is assured.


Assuntos
Adenocarcinoma de Células Claras , Carcinoma de Apêndice Cutâneo , Neoplasias das Glândulas Salivares , Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Neoplasias das Glândulas Sudoríparas/patologia , Neoplasias Cutâneas/patologia , Neoplasias das Glândulas Salivares/genética , Biomarcadores Tumorais/genética , Glândulas Sudoríparas/patologia
2.
Nat Immunol ; 9(6): 650-7, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18454150

RESUMO

Interleukin 17 (IL-17)-producing T helper 17 cells (T(H)-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T(H)-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1beta and IL-6) were all essential for human T(H)-17 differentiation. However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T(H)-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T(H)-17 differentiation and provide a framework for the global analysis of T helper responses.


Assuntos
Diferenciação Celular/imunologia , Interleucina-17/biossíntese , Interleucina-23/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Fator de Crescimento Transformador beta/metabolismo , Citocinas/metabolismo , Humanos , Linfócitos T Auxiliares-Indutores/imunologia
3.
J Allergy Clin Immunol ; 134(2): 373-81, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24910175

RESUMO

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a major proallergic cytokine that promotes TH2 responses through dendritic cell (DC) activation. Whether it also plays a role in human autoimmune inflammation and associated pathways is not known. OBJECTIVE: In this study we investigated the potential role of several epithelium-derived factors, including TSLP, in inducing IL-23 production by human DCs. We further dissected the role of TSLP in patients with psoriasis, an IL-23-associated skin autoimmune disease. METHODS: The study was performed in human subjects using primary cells and tissue samples from patients with psoriasis and healthy donors. We analyzed the production of IL-23 in vitro by blood and skin DCs. We studied the function for TSLP and its interaction with other components of the inflammatory microenvironment in situ and ex vivo. RESULTS: We found that TSLP synergized with CD40 ligand to promote DC activation and pathogenic IL-23 production by primary blood and skin DCs. In situ TSLP was strongly expressed by keratinocytes of untreated psoriatic lesions but not in normal skin. Moreover, we could demonstrate that IL-4, an important component of the TH2 inflammation seen in patients with atopic dermatitis, inhibited IL-23 production induced by TSLP and CD40 ligand in a signal transducer and activator of transcription 6-independent manner. CONCLUSION: Our results identify TSLP as a novel player within the complex psoriasis cytokine network. Blocking TSLP in patients with psoriasis might contribute to decreasing DC activation and shutting down the production of pathogenic IL-23.


Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Interleucina-23/imunologia , Queratinócitos/imunologia , Psoríase/imunologia , Pele/imunologia , Adulto , Ligante de CD40/genética , Ligante de CD40/imunologia , Citocinas/genética , Células Dendríticas/patologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Regulação da Expressão Gênica , Humanos , Interleucina-23/genética , Interleucina-4/genética , Interleucina-4/imunologia , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Psoríase/genética , Psoríase/patologia , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Pele/patologia , Células Th2/imunologia , Células Th2/patologia , Linfopoietina do Estroma do Timo
4.
J Allergy Clin Immunol ; 130(1): 233-40.e5, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22664159

RESUMO

BACKGROUND: The interplay between allergy and autoimmunity has been a matter of long debate. Epidemiologic studies point to a decreased frequency of allergy in patients with autoimmune diseases. However, recent studies suggest that IL-17 and related cytokines, which play a central role in autoimmunity, might also promote allergy. OBJECTIVE: To address this controversy, we systematically studied the interactions between T(H)17-related cytokines and the thymic stromal lymphopoietin (TSLP)-mediated proallergic pathway. METHODS: We used human primary dendritic cells (DCs), T cells, and skin explants. A novel geometric representation and multivariate ANOVA were used to analyze the T(H) cytokine profile. RESULTS: We show that IL-17A specifically inhibits TSLP production but increases proinflammatory IL-8 production in human skin explants exposed to TNF-α and IL-4. This inhibitory activity was confirmed in cultured skin explants of atopic dermatitis lesions. At the T-cell level, T(H)17-polarizing cytokines (IL-1ß, IL-6, TGF-ß, and IL-23) inhibited T(H)2 differentiation induced by TSLP-activated DCs. This led to a global dominance of a T(H)17-polarizing environment over TSLP-activated DCs, as revealed by clustering and computational analysis. CONCLUSIONS: Our data indicate that T(H)17-related cytokines are negative regulators of the TSLP immune pathway. This might explain the decreased frequency of allergy in patients with autoimmunity and suggests new means of manipulating proallergic responses.


Assuntos
Citocinas/antagonistas & inibidores , Interleucina-17/farmacologia , Células Th17/imunologia , Células Th2/metabolismo , Autoimunidade , Diferenciação Celular , Células Cultivadas , Citocinas/biossíntese , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/fisiopatologia , Humanos , Interleucina-17/metabolismo , Pele/imunologia , Pele/metabolismo , Pele/fisiopatologia , Células Th17/metabolismo , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Linfopoietina do Estroma do Timo
5.
ASAIO J ; 68(4): e69-e72, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34039885

RESUMO

The implantation of left ventricular assist devices (LVADs) in patients with end-stage heart failure can be associated with some forms of immune dysregulation and systemic inflammatory response. These abnormalities may be related to impaired T-lymphocyte-dependent immunity and B-lymphocyte hyper-reactivity and may lead to the development of autoimmune processes and the occurrence of severe infections. We present here the first observation of a peculiar immune complication associated with the implantation of an LVAD, characterized by an IgA vasculitis clinically manifested as Henoch-Schönlein purpura. The vasculitis was biologically associated with a significant increase of the plasma levels of C-X-C motif chemokine ligand (CXCL)13, a CXC motif chemokine produced by follicular dendritic cells, which targets CXCR5, a receptor primarily expressed by B lymphocytes, to promote their chemotaxis and expansion. Spontaneous resolution of the vasculitis occurred over time, concomitantly to a decrease of CXCL13 expression. These findings suggest that CXCL13 might be an interesting biomarker to detect auto-antigen sampling and the risk of secondary immune complications following LVAD implantation.


Assuntos
Coração Auxiliar , Vasculite por IgA , Vasculite , Biomarcadores , Coração Auxiliar/efeitos adversos , Humanos , Vasculite por IgA/complicações , Imunoglobulina A , Vasculite/etiologia
6.
Front Immunol ; 12: 656407, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767715

RESUMO

Pansclerotic morphea (PSM) is a rare skin disease characterized by progressive stiffening of the skin with or without the typical superficial skin changes usually seen in morphea (localized scleroderma). Standard therapy, consisting of a combination of systemic glucocorticoids and methotrexate or mycophenolate mofetil, does rarely stop disease progression, which may lead to severe cutaneous sclerosis and secondary contractures. Little is known about the efficacy of newer biologicals such as abatacept, a fusion protein antibody against CTLA-4, or tocilizumab, a fully humanized IL-6R antibody, in the treatment of this pathology. We present the case of an 8 years old girl with an unusual, progressive stiffening of the skin, which was eventually diagnosed as pansclerotic morphea. A treatment with systemic glucocorticoids and methotrexate combined with tocilizumab led to a good clinical response within 2 months after initiation. In this paper, we discuss differential diagnoses to be considered and this new promising treatment option based on a case review of the literature.


Assuntos
Esclerodermia Localizada/diagnóstico , Dermatopatias/diagnóstico , Biomarcadores , Biópsia , Criança , Diagnóstico Diferencial , Gerenciamento Clínico , Feminino , Humanos , Imuno-Histoquímica , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Pele/patologia , Avaliação de Sintomas , Resultado do Tratamento
7.
Transplantation ; 85(6): 911-5, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18360276

RESUMO

Immunopathology of acute graft-versus-host disease (aGVHD) involves secretion of proinflammatory cytokines with subsequent expression of danger signals by injured host tissues. This explanation, however, does not explain the cluster of aGVHD target organs (skin, gut, and liver). NKG2D ligands (MICA/B and ULBP1-3 proteins) are stress-induced molecules that act as danger signals to alert NK and alphabeta or gammadelta CD8 T cells through engagement of the activating NKG2D receptor. We observed a strong and reversible induction of MICA/B expression in skin and liver sections during aGVHD. Tumor necrosis factor-alpha and gamma-radiation up-regulated expression of MICA/B and ULBP proteins in vitro on skin and intestine epithelial cell lines and ex vivo in normal skin explants. This NKG2D-ligand induction was regulated by a complex interplay between NFkB and JNK activation pathways. Our data suggest that NKG2D ligand induction might participate in the amplification loop that leads to tissue damage during aGVHD.


Assuntos
Raios gama , Doença Enxerto-Hospedeiro/patologia , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/efeitos da radiação , Fator de Necrose Tumoral alfa/farmacologia , Doença Aguda , Biópsia , Linhagem Celular , Células Epiteliais/fisiologia , Células Epiteliais/efeitos da radiação , Proteínas Ligadas por GPI , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Pele/citologia , Pele/efeitos da radiação
8.
Dermatol Pract Concept ; 12(2): e2022070, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35646466
9.
J Exp Med ; 214(5): 1529-1546, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28428203

RESUMO

T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells. TSLP-induced T cells expressed CXCR5, CXCL13, ICOS, PD1, BCL6, BTLA, and SAP, among other Tfh markers. Functionally, TSLP-DC-polarized T cells induced IgE secretion by memory B cells, and this depended on IL-4Rα. TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13. Mechanistically, TSLP-induced Tfh differentiation depended on OX40-ligand, but not on ICOS-ligand. Our results delineate a pathway of human Tfh differentiation in Th2 environments.


Assuntos
Citocinas/fisiologia , Células Dendríticas/fisiologia , Ligante OX40/fisiologia , Células Th2/fisiologia , Diferenciação Celular/fisiologia , Quimiocina CXCL13/metabolismo , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/metabolismo , Receptores Imunológicos/metabolismo , Linfopoietina do Estroma do Timo
10.
J Immunol ; 178(6): 3373-7, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17339431

RESUMO

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that strongly activates dendritic cells (DC) and can initiate allergic inflammation. The factors inducing the production of human TSLP are not known. In this study, we show that proinflammatory (TNF-alpha or IL-1alpha) and Th2 (IL-4 or IL-13) cytokines synergized to induce the production of TSLP in human skin explants. TSLP production in situ was restricted to epidermal keratinocytes of the suprabasal layer. TSLP production could not be inhibited by factors regulating Th2 inflammation, such as IL-10, TGF-beta, or IFN-gamma. Cytokine-treated skin culture supernatants induced the maturation of blood CD11c(+) DC in a TSLP-dependent manner. Our data provide the first evidence of TSLP induction and subsequent DC activation in human skin. Blocking TSLP-inducing cytokines could represent a novel strategy for the treatment of allergic diseases.


Assuntos
Citocinas/agonistas , Mediadores da Inflamação/agonistas , Queratinócitos/imunologia , Pele/imunologia , Adulto , Idoso , Antígeno CD11c/imunologia , Células Cultivadas , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/imunologia , Feminino , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Hipersensibilidade/terapia , Mediadores da Inflamação/imunologia , Queratinócitos/metabolismo , Pessoa de Meia-Idade , Transdução de Sinais/imunologia , Pele/metabolismo , Linfopoietina do Estroma do Timo
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