RESUMEN
Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0's cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Herpesvirus Humano 1 , Inflamasomas , Proteínas NLR , Ubiquitina-Proteína Ligasas , Humanos , Inflamasomas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Herpesvirus Humano 1/fisiología , Proteínas NLR/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Inmediatas-Precoces/metabolismo , Células HEK293 , Replicación Viral , Queratinocitos/virología , Queratinocitos/metabolismo , Herpes Simple/virología , Herpes Simple/inmunología , Herpes Simple/metabolismo , AnimalesRESUMEN
The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.
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Proteína ADAM17 , Células de Langerhans , Lupus Eritematoso Sistémico , Piel , Proteína ADAM17/metabolismo , Proteína ADAM17/genética , Animales , Humanos , Células de Langerhans/metabolismo , Ratones , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Lupus Eritematoso Sistémico/metabolismo , Rayos Ultravioleta/efectos adversos , Femenino , Modelos Animales de Enfermedad , Trastornos por Fotosensibilidad/metabolismo , Interferones/metabolismo , Ratones Endogámicos MRL lprRESUMEN
Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using Olink targeted proteomics. Flow and Olink data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Spatial and Olink data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. Our Olink data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3.
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Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.
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Inhibidores de las Cinasas Janus , Vitíligo , Ratones , Animales , Humanos , ARN Interferente Pequeño/genética , Linfocitos T CD8-positivos/metabolismo , Autoinmunidad/genética , Vitíligo/tratamiento farmacológico , Vitíligo/genética , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , ARN BicatenarioRESUMEN
The melanocyte-keratinocyte transplantation procedure (MKTP) treats stable and recalcitrant vitiligo. Despite careful selection of candidates based on clinical stability, the success of the procedure is unpredictable. The aim of our study was to define the immunological profile of stable vitiligo lesions undergoing MKTP and correlate them with clinical outcomes. We included 20 MKTP candidates with vitiligo and a patient with piebaldism as a control. Prior to MKTP, T-cell subsets and chemokines in the recipient skin were measured by flow cytometry and ELISA. During MKTP, melanocytes in the donor skin were quantified by flow cytometry. After MKTP, patients were followed for 12 months and repigmentation was assessed clinically and by ImageJ analysis of clinical photographs. Baseline immunologic biomarkers, duration of clinical stability, and transplanted melanocyte number were correlated to postsurgical repigmentation scores. CD8+ T cells were elevated in 43% of the clinically stable vitiligo lesions. CD8+ T-cell number negatively correlated with postsurgical repigmentation scores (r = -0.635, P = 0.002). Duration of clinical stability, skin chemokines, and transplanted melanocyte number did not influence postsurgical repigmentation. This study demonstrates that CD8+ T-cell number correlates negatively with success of postsurgical repigmentation and can be a biomarker to identify ideal surgical candidates.
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INTRODUCTION: Connective tissue diseases (CTDs) are a category of conditions that affect tissues that support and provide structure to the body. These diseases include rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, and sclerosing diseases. CTDs can be caused by dysregulation of inflammatory pathways, specifically an upregulation of interferons and JAK/STAT pathway activation. AREAS COVERED: While CTDs have historically been treated with broadly immunosuppressant medications such as corticosteroids and disease-modifying antirheumatic drugs (DMARDS), newer and more targeted immunomodulating medications called Janus kinase inhibitors (JAKi) have emerged as potential treatments. EXPERT OPINION: While most studies regarding JAKi for CTDs have focused on adult populations, pediatric patients with CTDs may also benefit from JAKi therapy. Moreover, the JAK/STAT inhibitor tofacitinib has been approved by the FDA for the treatment of active polyarticular course juvenile idiopathic arthritis. In this review, we have summarized what has been published on the use of JAKi for various pediatric CTDs.
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Antirreumáticos , Enfermedades del Tejido Conjuntivo , Inhibidores de las Cinasas Janus , Adulto , Antirreumáticos/efectos adversos , Niño , Enfermedades del Tejido Conjuntivo/tratamiento farmacológico , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Quinasas Janus , Factores de Transcripción STAT/metabolismo , Transducción de SeñalRESUMEN
Morphea (localized scleroderma) is a rare autoimmune connective tissue disease with variable clinical presentations, with an annual incidence of 0.4-2.7 cases per 100,000. Morphea occurs most frequently in children aged 2-14 years, and the disease exhibits a female predominance. Insights into morphea pathogenesis are often extrapolated from studies of systemic sclerosis due to their similar skin histopathologic features; however, clinically they are two distinct diseases as evidenced by different demographics, clinical features, disease course and prognosis. An interplay between genetic factors, epigenetic modifications, immune and vascular dysfunction, along with environmental hits are considered as the main contributors to morphea pathogenesis. In this review, we describe potential new therapies for morphea based on both preclinical evidence and ongoing clinical trials. We focus on different classes of therapeutics, including antifibrotic, anti-inflammatory, cellular and gene therapy, and antisenolytic approaches, and how these target different aspects of disease pathogenesis.
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Esclerodermia Localizada , Esclerodermia Sistémica , Niño , Progresión de la Enfermedad , Femenino , Humanos , Pronóstico , Esclerodermia Localizada/tratamiento farmacológico , PielRESUMEN
A unique and sudden need for virtual medical visits created by the coronavirus disease 2019 (COVID-19) pandemic has led to an unprecedented expansion of telemedicine across nearly all medical specialties in the United States. In addition to providing essential medical services during the pandemic, telemedicine has the potential to expand health care access to underserved populations by eliminating traditional barriers to care such as transportation needs, distance from specialty providers, and approved time off from work. However, the literature regarding telehealth accessibility for low-income, non-English-speaking, and minority patients remains limited. Through a cross-sectional analysis comparing 2019 clinic visits with 2020 telehealth visits at the UMass Memorial Medical Center, we demonstrate specialty-specific changes in patient demographics, including a younger population, fewer non-English-speaking patients, and a relative preservation of minority, Medicaid, and Medicare patients among telehealth visits in comparison to clinic visits. We also demonstrate that nonsurgical specialties had significantly lower no-show rates and the greatest number of telehealth visits. Overall, our findings highlight the potential shortcomings of telemedicine in servicing non-English-speaking patients, while maintaining that it is an important tool with the potential to improve access to health care, particularly in nonprocedural specialties.
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COVID-19 , Telemedicina , Anciano , Estudios Transversales , Humanos , Medicare , Pandemias , SARS-CoV-2 , Estados Unidos , Poblaciones VulnerablesAsunto(s)
Dermatología/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/estadística & datos numéricos , Pacientes no Presentados/estadística & datos numéricos , Telemedicina/estadística & datos numéricos , COVID-19/epidemiología , COVID-19/prevención & control , Control de Enfermedades Transmisibles/normas , Dermatología/métodos , Dermatología/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias/prevención & control , Estudios Retrospectivos , Factores Socioeconómicos , Telemedicina/normasAsunto(s)
Dermatología , Derivación y Consulta/estadística & datos numéricos , Enfermedades de la Piel , Telemedicina , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consulta Remota/estadística & datos numéricos , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/terapia , Telemedicina/estadística & datos numéricos , Telemedicina/tendencias , Centros de Atención TerciariaAsunto(s)
Dermatología/legislación & jurisprudencia , Equidad en Salud/legislación & jurisprudencia , Política de Salud/legislación & jurisprudencia , Cobertura del Seguro/legislación & jurisprudencia , Telemedicina/legislación & jurisprudencia , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/transmisión , Dermatología/economía , Dermatología/métodos , Dermatología/tendencias , Equidad en Salud/economía , Equidad en Salud/tendencias , Política de Salud/economía , Política de Salud/tendencias , Humanos , Cobertura del Seguro/economía , Cobertura del Seguro/tendencias , Distanciamiento Físico , Racismo/economía , Racismo/prevención & control , Telemedicina/economía , Telemedicina/tendencias , Poblaciones Vulnerables/legislación & jurisprudenciaRESUMEN
Cutaneous Lupus Erythematosus (CLE) is a clinically diverse group of autoimmune skin diseases with shared histological features of interface dermatitis and autoantibodies deposited at the dermal-epidermal junction. Various genetic and environmental triggers of CLE promote infiltration of T cells, B cells, neutrophils, antigen presenting cells, and NK cells into lesional skin. In this mini-review, we will discuss the clinical features of CLE, insights into CLE immunopathogenesis, and novel treatment approaches.
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Lupus Eritematoso Cutáneo/tratamiento farmacológico , Lupus Eritematoso Cutáneo/inmunología , Lupus Eritematoso Cutáneo/patología , HumanosRESUMEN
An 80-year-old woman presented with a several-year history of progressive hair loss and scalp pruritus. No other rashes or muscle weakness were noted on examination. Scalp biopsy showed interface dermatitis, dense perivascular and periadnexal lymphocytic infiltrate, mucin and scarring alopecia. Laboratory analysis did not show evidence of myositis. The patient was started on hydroxychloroquine for possible cutaneous lupus erythematosus. On follow-up, she presented with a new violaceous rash on the superior eyelids and a well-defined oval patch on the mid-hard palate suspicious for dermatomyositis. Myositis-specific autoantibodies revealed presence of anti-transcriptional intermediary factor-1γ (anti-TIF1γ) in the serum. Anti-TIF1γ autoantibody-positive dermatomyositis is a newly recognised subtype of dermatomyositis that is highly associated with amyopathic disease and has an increased risk of malignancy, making prompt diagnosis crucial. This case highlights the utility of a thorough oral exam in patients suspected to have connective tissue disease as the distinctive ovoid palatal patch is nearly pathognomonic for anti-TIF1γ dermatomyositis.
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Autoanticuerpos/sangre , Dermatomiositis/diagnóstico , Eritema/patología , Exantema/patología , Paladar Duro/patología , Anciano de 80 o más Años , Fármacos Dermatológicos/uso terapéutico , Dermatomiositis/tratamiento farmacológico , Diagnóstico Diferencial , Femenino , Humanos , Metotrexato/uso terapéutico , Factores de Transcripción/inmunologíaRESUMEN
Progressive Macular Hypomelanosis (PMH) is a common but often misdiagnosed disorder of acquired hypopigmentation. An adolescent female presented with irregular, hypopigmented patches ultimately diagnosed as PMH. Complete repigmentation was achieved with narrowband UVB phototherapy, benzoyl peroxide wash, and clindamycin lotion.
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Tissue resident memory T cells (Trm) form in the skin in vitiligo and persist to maintain disease, as white spots often recur rapidly after discontinuing therapy. We and others have recently described melanocyte-specific autoreactive Trm in vitiligo lesions. Here, we characterize the functional relationship between Trm and recirculating memory T cells (Tcm) in our vitiligo mouse model. We found that both Trm and Tcm sensed autoantigen in the skin long after stabilization of disease, producing IFN-γ, CXCL9, and CXCL10. Blockade of Tcm recruitment to the skin with FTY720 or depletion of Tcm with low-dose Thy1.1 antibody reversed disease, indicating that Trm cooperate with Tcm to maintain disease. Taken together, our data provide characterization of skin memory T cells in vitiligo, demonstrate that Trm and Tcm work together during disease, and indicate that targeting their survival or function may provide novel, durable treatment options for patients.
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Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Melanocitos/inmunología , Piel/inmunología , Vitíligo/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Melanocitos/patología , Ratones , Ratones Transgénicos , Piel/patología , Vitíligo/patologíaRESUMEN
The pathogenesis of vitiligo involves interplay between intrinsic and extrinsic melanocyte defects, innate immune inflammation, and T-cell-mediated melanocyte destruction. The goal of treatment is to not only halt disease progression but also promote repigmentation through melanocyte regeneration, proliferation, and migration. Treatment strategies that address all aspects of disease pathogenesis and repigmentation are likely to have greatest efficacy, a strategy that may require combination therapies. Current treatments generally involve nontargeted suppression of autoimmunity, whereas emerging treatments are likely to use a more targeted approach based on in-depth understanding of disease pathogenesis, which may provide higher efficacy with a good safety profile.
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Autoinmunidad/inmunología , Melanocitos/inmunología , Linfocitos T Citotóxicos/inmunología , Vitíligo/inmunología , Inmunidad Adaptativa/inmunología , Antioxidantes/uso terapéutico , Humanos , Inmunidad Innata/inmunología , Inmunosupresores/uso terapéutico , Melanocitos/metabolismo , Estrés Oxidativo , Fototerapia , Regeneración , Autotolerancia/inmunología , Vitíligo/terapiaRESUMEN
BACKGROUND: Vitiligo is an autoimmune disease of the skin with limited treatment options; there is an urgent need to identify and validate biomarkers of disease activity to support vitiligo clinical studies. OBJECTIVE: To investigate potential biomarkers of disease activity directly in the skin of vitiligo subjects and healthy subjects. METHODS: Patient skin was sampled via a modified suction-blister technique, allowing for minimally invasive, objective assessment of cytokines and T-cell infiltrates in the interstitial skin fluid. Potential biomarkers were first defined and later validated in separate study groups. RESULTS: In screening and validation, CD8+ T-cell number and C-X-C motif chemokine ligand (CXCL) 9 protein concentration were significantly elevated in active lesional compared to nonlesional skin. CXCL9 protein concentration achieved greater sensitivity and specificity by receiver operating characteristic analysis. Suction blistering also allowed for phenotyping of the T-cell infiltrate, which overwhelmingly expresses C-X-C motif chemokine receptor 3. LIMITATIONS: A small number of patients were enrolled for the study, and only a single patient was used to define the treatment response. CONCLUSION: Measuring CXCL9 directly in the skin might be effective in clinical trials as an early marker of treatment response. Additionally, use of the modified suction-blister technique supports investigation of inflammatory skin diseases using powerful tools like flow cytometry and protein quantification.