Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Autoanticuerpos/efectos de los fármacos , Autoantígenos/inmunología , Colágenos no Fibrilares/inmunología , Penfigoide Ampolloso/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Humanos , Masculino , Penfigoide Ampolloso/sangre , Penfigoide Ampolloso/complicaciones , Psoriasis/sangre , Psoriasis/complicaciones , Resultado del Tratamiento , Colágeno Tipo XVIIRESUMEN
Systemic sclerosis (SSc) is a systemic disorder that typically results in fibrosis of the skin and multiple internal organ systems. Although the precise mechanism is unknown, overproduction of extracellular matrix proteins, including collagens and fibronectins, and aberrant immune activation might be involved in the pathogenesis. The soluble cluster of differentiation 21 (sCD21) represents the extracellular portion of the CD21 glycoprotein that is released by shedding from the cell surfaces into plasma. sCD21 binds complement fragments and activates monocytes through binding to membrane CD23. The present study was undertaken to investigate the serum levels of sCD21 in patients with SSc. Serum sCD21 levels were reduced with age both in patients with SSc and normal controls. Serum sCD21 levels in patients with SSc were significantly decreased compared to those in control subjects. When we divided patients with SSc into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), patients with lcSSc had lower levels of serum sCD21 than those with dcSSc. Moreover, the prevalence of pulmonary fibrosis in the patients with dcSSc inversely correlated with serum sCD21 levels. Our finding may support the notion that B-cell activation is involved in the mechanism for pulmonary fibrosis and skin sclerosis.
Asunto(s)
Receptores de Complemento 3d/sangre , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/epidemiología , Adulto , Anciano , Regulación hacia Abajo/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fibrosis Pulmonar/sangre , Fibrosis Pulmonar/epidemiología , Fibrosis Pulmonar/inmunología , Esclerodermia Sistémica/inmunología , Piel/inmunología , Piel/patología , SolubilidadRESUMEN
In this pilot study, the effect of low-dose imatinib mesylate (100 mg/day) on cutaneous involvement in patients with systemic sclerosis (SSc) was analyzed. Three patients with SSc were treated with 100 mg/day of imatinib mesylate for 6 months because of pulmonary arterial hypertension refractory to conventional treatments, including beraprost, bosentan, sildenafil, and epoprostenol. Changes in cutaneous involvement were evaluated at 1, 3, and 6 months. During the treatment, the total skin score gradually improved in all of the patients. Contracture of phalanges was attenuated in two patients, one of whom also experienced the partial restoration of large-joint mobility. Nailfold bleeding, initially seen in two patients, was gradually attenuated and had completely disappeared at 6 months. In all patients, Raynaud's phenomenon was attenuated at around 3 months and had completely disappeared at 6 months. Although transient renal dysfunction was observed in one patient, none of the patients experienced common adverse effects of imatinib, such as edema, nausea, rash, and musculoskeletal pain. These clinical data indicate the tolerability and efficacy of low-dose imatinib in SSc, especially against cutaneous vascular involvement, including Raynaud's phenomenon and nailfold bleeding.
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Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Piel/efectos de los fármacos , Anciano , Benzamidas , Contractura/tratamiento farmacológico , Contractura/etiología , Contractura/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Hemorragia/fisiopatología , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Enfermedades de la Uña/tratamiento farmacológico , Enfermedades de la Uña/etiología , Enfermedades de la Uña/fisiopatología , Uñas/irrigación sanguínea , Uñas/patología , Rango del Movimiento Articular , Enfermedad de Raynaud/tratamiento farmacológico , Enfermedad de Raynaud/etiología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/fisiopatología , Piel/irrigación sanguínea , Piel/fisiopatología , Resultado del TratamientoRESUMEN
Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y(6) receptors, stimulated normal human keratinocytes (NHK) to produce IL-1α, IL-8/CXCL8, and IL-6. P2Y(6) receptor expression increased in MSU-stimulated NHK. Both P2Y(6)-specific antagonist and P2Y(6) antisense oligonucleotides significantly inhibited the production of IL-1α, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y(6)-specific antagonist completely inhibited the MSU-induced production of IL-1ß by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y(6)-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y(6) receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.
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Antioxidantes/efectos adversos , Queratinocitos/inmunología , Psoriasis/inmunología , Antagonistas del Receptor Purinérgico P2/inmunología , Transducción de Señal/efectos de los fármacos , Ácido Úrico/efectos adversos , Animales , Antioxidantes/farmacología , Línea Celular , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Gota/inmunología , Gota/metabolismo , Gota/patología , Humanos , Hiperuricemia/inmunología , Hiperuricemia/metabolismo , Hiperuricemia/patología , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Ratones Endogámicos BALB C , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/inmunología , Peritonitis/inmunología , Peritonitis/metabolismo , Peritonitis/patología , Psoriasis/inducido químicamente , Psoriasis/metabolismo , Psoriasis/patología , Antagonistas del Receptor Purinérgico P2/metabolismo , Receptores Purinérgicos P2 , Transducción de Señal/inmunología , Ácido Úrico/farmacologíaRESUMEN
Systemic sclerosis (SSc) is characterized by vascular injuries, and bosentan has recently been proved to be efficacious for the prevention of new digital ulcers in SSc. We herein report a case of SSc in a patient with refractory digital ulcers and gangrene treated with bosentan. Stenosis of the ulnar artery, evaluated by magnetic resonance angiography, was attenuated by the bosentan treatment, suggesting that bosentan exerts a reverse remodeling effect against the pathological organic changes of arteries in SSc.
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Dedos/irrigación sanguínea , Flujo Sanguíneo Regional/efectos de los fármacos , Esclerodermia Difusa/tratamiento farmacológico , Úlcera Cutánea/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Antihipertensivos/uso terapéutico , Bosentán , Femenino , Dedos/patología , Gangrena/tratamiento farmacológico , Gangrena/etiología , Gangrena/patología , Humanos , Persona de Mediana Edad , Esclerodermia Difusa/complicaciones , Esclerodermia Difusa/patología , Úlcera Cutánea/etiología , Úlcera Cutánea/patologíaRESUMEN
BACKGROUND: Semaphorin 7A (Sema7A) expressed on activated T cells stimulates cytokine production in monocytes through its receptor, α1ß1 integrin. OBJECTIVE: To study the significance of Sema7A expressed on keratinocytes in skin inflammation where interaction between keratinocytes and ß1-integrin expressing inflammatory cells, such as monocytes, takes place. METHODS: The regulation of Sema7A expression on keratinocytes by various cytokines was studied by flow cytometry and immunoblot. ß1-integrin expressing human monocyte cell line, THP-1 cells, were co-cultured with paraformaldehyde-fixed normal human epidermal keratinocytes (NHK) and IL-8 production by THP-1 cells was studied. The significance of ß1-integrin or Sema7A within this cell interaction was examined by the experiments using ß1-integrin blocking antibody or Sema7A siRNA. RESULTS: IFN-γ and TNF-α slightly increased Sema7A expression, while IL-4 decreased it. Among cytokines tested, TGF-ß1 most strikingly increased the Sema7A expression on NHK. When NHK was stimulated by TGF-ß1, paraformaldehyde-fixed, and co-cultured with THP-1 cells, IL-8 production by THP-1 cells was increased compared to THP-1 cells only. When THP-1 cells were pretreated with ß1-integrin blocking antibody, this increase in IL-8 production by THP-1 cells was inhibited. Likewise, when NHK were pretreated with Sema7A siRNA before fixation and co-cultured with THP-1 cells, increase in IL-8 production by THP-1 cells was inhibited. CONCLUSION: Our results suggest that Sema7A on keratinocytes and ß1-integrin on monocytes contribute to monocyte activation by keratinocytes within skin inflammation, such as psoriasis or wound.
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Antígenos CD/fisiología , Integrina beta1/metabolismo , Interleucina-8/metabolismo , Queratinocitos/citología , Monocitos/metabolismo , Semaforinas/fisiología , Técnicas de Cocultivo , Citocinas/metabolismo , Cartilla de ADN/química , Ensayo de Inmunoadsorción Enzimática/métodos , Citometría de Flujo/métodos , Proteínas Ligadas a GPI/fisiología , Humanos , Inflamación , Monocitos/citología , Psoriasis/metabolismo , ARN Interferente Pequeño/metabolismo , Cicatrización de HeridasAsunto(s)
Artritis Reumatoide/etiología , Periodo Posparto , Complicaciones del Embarazo , Dermatosis del Cuero Cabelludo/complicaciones , Esclerodermia Localizada/complicaciones , Adulto , Artritis Reumatoide/diagnóstico , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Embarazo , Dermatosis del Cuero Cabelludo/diagnóstico , Esclerodermia Localizada/diagnósticoAsunto(s)
Calcinosis/patología , Esclerodermia Sistémica/patología , Antibacterianos/uso terapéutico , Calcinosis/diagnóstico , Calcinosis/tratamiento farmacológico , Calcinosis/etiología , Femenino , Humanos , Persona de Mediana Edad , Esclerodermia Difusa/complicaciones , Esclerodermia Difusa/patología , Esclerodermia Sistémica/complicaciones , Tomografía Computarizada por Rayos XAsunto(s)
Anticuerpos Antinucleares/inmunología , Autoanticuerpos/inmunología , Enfermedades del Tejido Conjuntivo/inmunología , Hipersensibilidad a las Drogas/inmunología , Ribonucleoproteína Nuclear Pequeña U1/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Biomarcadores/sangre , Comorbilidad , Enfermedades del Tejido Conjuntivo/sangre , Enfermedades del Tejido Conjuntivo/epidemiología , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Ribonucleoproteína Nuclear Pequeña U1/sangre , Adulto JovenAsunto(s)
Quimiocina CCL17/sangre , Dermatomiositis/sangre , Enfermedades Pulmonares Intersticiales/sangre , Adulto , Anciano , Ciclosporina/uso terapéutico , Dermatomiositis/complicaciones , Dermatomiositis/tratamiento farmacológico , Femenino , Humanos , L-Lactato Deshidrogenasa/sangre , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mucina-1/sangre , Prednisolona/uso terapéutico , Proteína D Asociada a Surfactante Pulmonar/sangre , Regulación hacia ArribaRESUMEN
Dendritic cells (DCs) are a group of professional antigen-presenting cells, and many genes are known to be associated with their maturation. We compared the transcriptional profiles of immature and mature mouse Langerhans cells using the suppressive, subtractive hybridization method and identified a novel gene of unknown function, termed herein transmembrane protein 123 (Tmem123), of which mRNA expression was enhanced in mature but not in immature Langerhans cells. Its expression was also enhanced in other mature DCs such as bone marrow-derived DCs (BMDCs) and splenic DCs. Interestingly, CD40 expression was up-regulated on mature BMDCs cultured with colchicine concurrently with the enhanced expression of Tmem123 compared with that of fresh BMDCs. Furthermore, the expression of CD40 was enhanced on Tmem123-transfected DC2.4 cells, a mouse BMDC-derived cell line, compared with that on mock-transfected DC2.4 cells. This enhancement of CD40 expression did not occur after deletion of lysosome/endosome targeting YXXÏ motifs (where X is any amino acid and Ï is a bulky hydrophobic amino acid) in the Tmem123 cytoplasmic tail. By stimulation with anti-CD40 monoclonal antibody, these transfectants secreted an increased amount of IL-12/23 p40 compared with mock-transfected DC2.4 cells. Thus, our study demonstrates that Tmem123 may be used as a new maturation marker in DCs and that this molecule may be closely associated with the cell surface expression of CD40.