RESUMEN
Several proteins have been proposed as candidate auto-antigens in the pathogenesis of Behçet's disease (BD). In this study, we aimed to confirm the cellular responses to candidate peptide autoantigens with high affinity for the HLA-B*51:01 molecule using computerized binding predictions and molecular dynamics simulations. We identified two new candidate peptides (HSP65PD, derived from heat shock protein-65, and B51PD, derived from HLA-B*51:01) with high-affinity to the HLA-B*51:01 binding pocket using the Immune Epitope Database for Major Histocompatibility Complex-I Binding Prediction and molecular dynamics simulations. The peptide-induced proliferation of lymphocytes from patients with BD, sarcoidosis, Vogt-Koyanagi-Harada disease (VKH) with panuveitis, systemic scleroderma (SSc) without uveitis, and healthy controls (HC) was investigated using the bromodeoxyuridine assay. The proliferative response of leukocytes to HSP65PD was significantly higher in BD (SI 1.92 ± 0.65) than that in sarcoidosis (SI 1.38 ± 0.46), VKH (SI 1.40 ± 0.33), SSc (SI 1.32 ± 0.31), and HC (SI 1.27 ± 0.28) (P = 0.0004, P = 0.0007, P < 0.0001, P < 0.0001, respectively, Mann-Whitney's U-test). The proliferative response of leukocytes to B51PD was also higher in BD than that in sarcoidosis, VKH, SSc without uveitis, and HC, whereas no significant differences were observed among the five groups in response to a control peptide derived from topoisomerase 1. A significantly higher response to HPS65PD and B51PD was observed in the HLA-B*51:01-positive patients with BD than in the HLA-B*51:01-negative patients. In conclusion, two peptides that had high affinity to HLA-B*51:01 in computerized binding prediction showed significantly higher response in HLA-B*51:01-positive patients with BD, indicating the usefulness of computerized simulations for identifying autoreactive peptides to HLAs.
Asunto(s)
Síndrome de Behçet/inmunología , Antígenos HLA-B/inmunología , Linfocitos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Síndrome de Behçet/metabolismo , Proliferación Celular/fisiología , Simulación por Computador , Femenino , Antígenos HLA-B/metabolismo , Humanos , Activación de Linfocitos/inmunología , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Simulación de Dinámica Molecular , Péptidos/farmacología , Péptidos/uso terapéutico , Uveítis/inmunologíaRESUMEN
OBJECTIVE: To determine the role of tumor necrosis factor receptor p55 (TNFRp55)-mediated signaling in the pathogenesis of scleroderma. METHODS: A murine model of scleroderma that closely resembles systemic sclerosis in humans was used. Wild-type and TNFRp55-deficient (TNFRp55(-/-)) mice received a subcutaneous injection of bleomycin each day. The extent of skin fibrosis was determined by measurements of the dermal thickness, as well as histologic examinations. Expression levels of fibrogenic cytokines, procollagen alpha1, and matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-9 messenger RNA (mRNA) were analyzed, both in vivo and in vitro, by reverse transcriptase-polymerase chain reaction assay or Western blotting. RESULTS: TNFRp55(-/-) mice began to develop severe sclerotic changes of the dermis on day 3 of the subcutaneous injections of bleomycin, while wild-type mice did not. The expression levels of fibrogenic cytokines, procollagen alpha1, and MMP-2 and MMP-9 mRNA were unaffected in the skin of both wild-type and TNFRp55(-/-) mice, with or without bleomycin treatment. Induction of MMP-1 expression was significantly inhibited in the skin from bleomycin-treated TNFRp55(-/-) mice, and this phenomenon was also observed in vitro. CONCLUSION: These results indicated that signaling mediated by TNFRp55 plays an essential role in MMP-1 expression and a key role in the collagen degradation process in this murine model. This study might provide a basis for understanding the pathogenesis of scleroderma and formulating therapeutic intervention.
Asunto(s)
Colágeno/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Esclerodermia Sistémica/metabolismo , Piel/metabolismo , Animales , Bleomicina/toxicidad , Western Blotting , Citocinas/genética , Citocinas/metabolismo , Cartilla de ADN/química , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/inducido químicamente , Fibrosis/metabolismo , Fibrosis/patología , Ratones , Ratones Noqueados , ARN Mensajero/metabolismo , Receptores del Factor de Necrosis Tumoral/deficiencia , Receptores del Factor de Necrosis Tumoral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/patología , Transducción de Señal , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
We report a 66-year-old woman with localized argyria caused by embedding of acupuncture needles. Ten years after she had received acupuncture, she noticed two asymptomatic bluish macules on her right arm. A biopsied specimen from the macule revealed many brownish-black granules mainly located around the sweat glands and the blood vessels in the dermis. The X-ray examination of the extremities revealed numerous needle-like fragments around her extremities. "Embedding of needles" induces some serious adverse events. We should know the adverse events for the safety and health of patients.
