Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
Ann Rheum Dis ; 82(7): 887-896, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36987655

RESUMO

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.


Assuntos
Síndrome de Behçet , Espondilartrite , Uveíte , Humanos , Predisposição Genética para Doença , Síndrome de Behçet/genética , Antígenos de Histocompatibilidade Classe I/genética , Aminopeptidases/genética , Antígenos de Histocompatibilidade Menor/genética
2.
J Immunol ; 207(9): 2235-2244, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34580106

RESUMO

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 , Risco
3.
Int J Cancer ; 134(10): 2393-402, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24243586

RESUMO

Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non-treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan-Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log-rank test. Patients with higher numbers of CD8(+) TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis-free period. The total number of primary TILs (CD4 plus CD8) and CD8(+) primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8(+) effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8(+) T cells producing IFN-γ in PBMC were significantly higher in patients with angiosarcoma (n = 10) compared not only with that of healthy controls (n = 20) but also patients with advanced melanoma (n = 11). These results suggest that anti-tumor immunity is clinically relevant in angiosarcoma.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hemangiossarcoma/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Cutâneas/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Hemangiossarcoma/metabolismo , Hemangiossarcoma/patologia , Humanos , Imuno-Histoquímica , Interferon gama/imunologia , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Contagem de Leucócitos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Metástase Linfática , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
4.
Front Immunol ; 15: 1374581, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38524140

RESUMO

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.


Assuntos
Autoimunidade , Psoríase , Humanos , Linfócitos T CD8-Positivos , Antígenos HLA-C , Autoantígenos , Peptídeos , Receptores de Antígenos de Linfócitos T , Proteínas ADAMTS
5.
Development ; 137(19): 3293-302, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20823067

RESUMO

During early embryogenesis, the neural plate is specified along the anterior-posterior (AP) axis by the action of graded patterning signals. In particular, the attenuation of canonical Wnt signals plays a central role in the determination of the anterior brain region. Here, we show that the extracellular matrix (ECM) protein Del1, expressed in the anterior neural plate, is essential for forebrain development in the Xenopus embryo. Overexpression of Del1 expands the forebrain domain and promotes the formation of head structures, such as the eye, in a Chordin-induced secondary axis. Conversely, the inhibition of Del1 function by a morpholino oligonucleotide (MO) represses forebrain development. Del1 also augments the expression of forebrain markers in neuralized animal cap cells, whereas Del1-MO suppresses them. We previously reported that Del1 interferes with BMP signaling in the dorsal-ventral patterning of the gastrula marginal zone. By contrast, we demonstrate here that Del1 function in AP neural patterning is mediated mainly by the inhibition of canonical Wnt signaling. Wnt-induced posteriorization of the neural plate is counteracted by Del1, and the Del1-MO phenotype (posteriorization) is reversed by Dkk1. Topflash reporter assays show that Del1 suppresses luciferase activities induced by Wnt1 and beta-catenin. This inhibitory effect of Del1 on canonical Wnt signaling, but not on BMP signaling, requires the Ror2 pathway, which is implicated in non-canonical Wnt signaling. These findings indicate that the ECM protein Del1 promotes forebrain development by creating a local environment that attenuates the cellular response to posteriorizing Wnt signals via a unique pathway.


Assuntos
Proteínas de Membrana/metabolismo , Placa Neural/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Transdução de Sinais , Proteínas de Xenopus/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Padronização Corporal , Cabeça/embriologia , Proteínas de Membrana/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Proteínas Wnt/metabolismo , Proteínas de Xenopus/genética , beta Catenina/metabolismo
6.
Pediatr Dermatol ; 30(1): 105-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22211668

RESUMO

Treatment of infantile acute lymphocytic leukemia (ALL) may cause failure to thrive and hypogonadism due to hypopituitarism induced by chemotherapy and whole-brain radiotherapy. We report the case of a 22-year-old girl with a genetic predisposition to pattern hair loss who developed inveterate diffuse alopecia. The patient had onset of ALL at 8 years old and underwent bone marrow transplantation (BMT). Diffuse alopecia gradually advanced over her whole body. Her vellus scalp hair gradually came out, and hair loss progressed again at 8 years, after BMT. She later developed iatrogenic failure of secretion of estrogen and was treated with estrogen substitution therapy for 14 months from the age of 20. There was a small increase in the volume of hair during therapy, but alopecia returned to the former level after the therapy was suspended. Histopathologic examinations of the scalp performed during estrogen substitution therapy and 2 years after suspension of the therapy showed a 60% decrease in the number of hair follicles and prominent development of vellus hair. We conclude that estrogen influenced hair growth in the context of a genetic predisposition for pattern hair loss in this case.


Assuntos
Alopecia/etiologia , Transplante de Medula Óssea/efeitos adversos , Estrogênios/metabolismo , Doença Iatrogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Alopecia/tratamento farmacológico , Alopecia/fisiopatologia , Transplante de Medula Óssea/métodos , Quimioterapia Adjuvante/efeitos adversos , Progressão da Doença , Estrogênios/deficiência , Feminino , Seguimentos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Radioterapia Adjuvante/efeitos adversos , Medição de Risco , Índice de Gravidade de Doença , Falha de Tratamento , Adulto Jovem
7.
Children (Basel) ; 8(2)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33562038

RESUMO

We describe a patient who developed multiple granulomatous skin lesions after Bacille de Calmette et Guérin (BCG) vaccination without significant effect by topical corticosteroid, followed by painless cystic tumors on the bilateral knees and hands and inflammatory changes on ophthalmologic examination. A functional mutation in NOD2 was detected by a genetic analysis, and he was diagnosed as sporadic Blau syndrome. Since NOD2 acts as a sensor for the BCG component, it is possible that BCG vaccination may trigger granuloma formation in Blau syndrome patients with such genetic background.

8.
J Dermatol Sci ; 100(2): 129-138, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33039243

RESUMO

BACKGROUND: It is widely accepted that NKG2D+cells are critically involved in alopecia areata (AA) pathogenesis. However, besides being expressed in CD8+T-cells and NK cells, NKG2D is also found in human γδT-cells. AA lesional hair follicles (HFs) overexpress NKG2D and γδTCR activating ligands, e.g. MICA and CD1d, and chemoattractants for γδT-cells, such as CXCL10. OBJECTIVE: To investigate whether abnormal activities of γδT-cells may be involved in AA pathogenesis. METHODS: We analyzed the number and activation status of γδT-cells in human healthy, lesional and non-lesional AA scalp biopsies by FACS and/or quantitative (immuno-)histomorphometry. RESULTS: In healthy human scalp skin, the few skin-resident γδT-cells were found to be mostly Vδ1+, non-activated (CD69-NKG2Ddim) and positive for CXCL10, and CXCL12 receptors. These Vδ1+T-cells predominantly localized in/around the HF infundibulum. In striking contrast, the number of Vδ1+T-cells was significantly higher around and even inside the proximal (suprabulbar and bulbar) epithelium of lesional AA HFs. These cells also showed a pro-inflammatory phenotype, i.e. higher NKG2D, and IFN-γ and lower CD200R expression. Importantly, more pro-inflammatory Vδ1+T-cells were seen also around non-lesional AA HFs. Lesional AA HFs also showed significantly higher expression of CXCL12. CONCLUSION: Our pilot study introduces skin-resident γδT-cells as a previously overlooked, but potentially important, mostly (auto-)antigen-independent, new innate immunity protagonist in AA pathobiology. The HF infiltration of these activated, IFN-γ-releasing cells already around non-lesional AA HFs suggest that Vδ1+T-cells are involved in the early stages of human AA pathobiology, and may thus deserve therapeutic targeting for optimal AA management.


Assuntos
Alopecia em Áreas/imunologia , Folículo Piloso/patologia , Linfócitos Intraepiteliais/imunologia , Alopecia em Áreas/patologia , Biópsia , Folículo Piloso/citologia , Folículo Piloso/imunologia , Voluntários Saudáveis , Humanos , Imunidade Inata , Projetos Piloto
9.
Front Immunol ; 10: 1336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275310

RESUMO

Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vß-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4+ and extensively restricted in CD8+ T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4+ and CD8+ TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Melanoma/imunologia , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/imunologia
10.
J Invest Dermatol ; 138(6): 1338-1347, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29288651

RESUMO

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4+ T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4+ T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4+ T cells. Moreover, GPP patients showed preferences for HLA-DRB1∗14, HLA-DQB1∗05, and HLA-DQB1∗03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell-mediated inflammation in GPP.


Assuntos
Autoimunidade , Interleucina-17/metabolismo , Interleucina-1/metabolismo , Psoríase/imunologia , Células Th17/imunologia , Adulto , Idoso , Autoantígenos/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Interleucina-1/imunologia , Interleucina-17/imunologia , Interleucinas/genética , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Psoríase/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Pele/imunologia , Pele/metabolismo , Pele/patologia , Células Th17/metabolismo , Adulto Jovem
13.
JAMA Dermatol ; 152(7): 825-8, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27096382

RESUMO

IMPORTANCE: Generalized pustular psoriasis von Zumbusch type (GPP) is the most severe manifestation of psoriasis. The etiology of GPP is only partially understood, and GPP lacks approved treatments. Loss-of-function mutations in the interleukin 36 (IL-36) receptor antagonist (IL36RN), an inhibitor of innate immune activation in the skin, and therapeutic efficacy of IL-1 blockade in a subset of patients with GPP are viewed as evidence for an autoinflammatory pathogenesis. A pathogenic role of T cells has not been considered. OBJECTIVE: To test whether ustekinumab, a monoclonal antibody blocking IL-12 and IL-23, is an effective treatment modality for patients in whom GPP treatment with conventional psoriasis drugs or antagonists of tumor necrosis factor (TNF) has not been sufficiently effective, is contraindicated, or has lost efficacy. DESIGN, SETTING, AND PARTICIPANTS: We treated a series of 4 patients with GPP with ustekinumab, which was applied on an outpatient basis according to the dosing regimen approved for psoriasis vulgaris. In 3 patients it was combined with low doses of the retinoid acitretin. IL36RN mutations were determined in all 4 patients by means of targeted sequencing of genomic DNA. MAIN OUTCOME MEASURES: The response to therapy was assessed by clinical examination. RESULTS: The 4 patients were female. Sequencing of IL36RN identified a homozygous mutation in case 1 (Pro76Leu). The other 3 patients carried no rare IL36RN variants. Overall GPP duration ranged from 50 to 146 months. Ustekinumab treatment is currently ongoing in all 4 patients without loss of efficacy, currently reaching treatment durations of 17 (case 1) to 44 months (case 3). Ustekinumab treatment induced sustained remissions in all 4 GPP patients. This response was independent of IL36RN mutations and consolidated by combination with low doses of the retinoid acitretin. CONCLUSIONS AND RELEVANCE: Ustekinumab-induced remissions suggest that T cells play a crucial role in GPP pathogenesis based on the documented role that IL-12 and IL-23 play in autoimmune diseases through differentiating helper T cell 1 (TH1) and maintaining TH17 responses. Acitretin treatment may support ustekinumab efficacy, possibly by suppressing TH17 responses through the retinoid-related orphan receptors, RORγt and RORα. Combining IL-12/IL-23 blockade and acitretin may constitute an efficient treatment modality interfering with GPP pathomechanisms.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Interleucinas/genética , Psoríase/tratamento farmacológico , Psoríase/genética , Ustekinumab/uso terapêutico , Acitretina/uso terapêutico , Adulto , Quimioterapia de Consolidação , Quimioterapia Combinada , Feminino , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Ceratolíticos/uso terapêutico , Pessoa de Meia-Idade , Mutação , Indução de Remissão
15.
J Exp Med ; 212(13): 2203-12, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26621454

RESUMO

Psoriasis vulgaris is a common T cell-mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8(+) T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02-restricted psoriatic T cell response. We found that a Vα3S1/Vß13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8(+) T cell clone of an HLA-C*06:02-positive psoriasis patient specifically recognizes HLA-C*06:02-positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02-presented melanocytic autoantigen of the Vα3S1/Vß13S1 TCR. Consistent with the Vα3S1/Vß13S1-TCR reactivity, we observed numerous CD8(+) T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8(+) T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8(+) T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Melanócitos/metabolismo , Psoríase/imunologia , Proteínas ADAM/metabolismo , Proteínas ADAMTS , Adulto , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Epiderme/metabolismo , Epiderme/patologia , Epitopos/química , Epitopos/imunologia , Feminino , Antígenos HLA-C/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Peptídeos/química , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
17.
J Child Neurol ; 29(9): NP69-73, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24072019

RESUMO

Acute disseminated encephalomyelitis confined to the brainstem is associated with poor prognosis. We describe a case of a 10-year-old boy with acute disseminated encephalomyelitis in the brainstem that developed after influenza A infection. A 10-year-old boy presented with fever and prolonged disturbance of consciousness and was admitted to our hospital. Magnetic resonance imaging (MRI) of the midbrain, with T2-weighted and fluid-attenuated inversion recovery images, suggested acute disseminated encephalomyelitis accompanied by a brainstem lesion. Lumbar puncture showed pleocytosis and increased protein content, including myelin basic protein, interleukin-6, and immunoglobulin G, all suggestive of acute disseminated encephalomyelitis. Treatments such as methylprednisolone pulse therapy, intravenous immunoglobulin, and therapeutic hypothermia were performed. Although the patient presented with anisocoria with increased intracranial pressure monitoring during hypothermia, prompt therapy with d-mannitol and dopamine was effective. Our case results suggest that hypothermia could be included in the choice of therapy for acute disseminated encephalomyelitis with brainstem lesions.


Assuntos
Tronco Encefálico/patologia , Encefalomielite Aguda Disseminada/fisiopatologia , Encefalomielite Aguda Disseminada/terapia , Hipotermia Induzida/métodos , Pressão Intracraniana , Monitorização Neurofisiológica/métodos , Criança , Encefalomielite Aguda Disseminada/patologia , Humanos , Vírus da Influenza A , Influenza Humana/complicações , Imageamento por Ressonância Magnética , Masculino
18.
Eur J Dermatol ; 22(4): 531-6, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22743283

RESUMO

Alopecia areata (AA) is a common hair loss disorder that frequently follows a chronic course. Although AA is apparently associated with disturbance of quality of life (QoL), no disease-specific instrument to measure the QoL has been developed. This study was conducted to develop a disease-specific self-administered instrument to measure AA patients' QoL (AAQ). A two-step cross-sectional study was conducted. Items were generated from qualitative interviews with five patients with AA (two men and three women, age 28±6.4 years). Then, a preliminary questionnaire was produced and delivered to the patients (n=122). The AAQ was examined in terms of statistical performance. The AAQ included 7 items in the following three subscales: 'restriction of activity', 'concealment' and 'adaptation'. The reliability of internal consistency was fair with Cronbach's alpha coefficients of 0.59-81 for each subscale. Confirmatory factor analysis and correlation analysis demonstrated that the AAQ had good construct validity. Interestingly, the AAQ was only correlated with subjective severity scores as rated by the patients, but not with objective disease severity assessed by investigators.


Assuntos
Alopecia em Áreas , Qualidade de Vida , Inquéritos e Questionários , Adulto , Alopecia em Áreas/diagnóstico , Estudos Transversais , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA