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As communities of color are disproportionately affected by COVID-19, there is an urgent need for dissemination of timely and accurate information to community members. In this article, we describe a stakeholder approach for the implementation, evaluation, and lessons learned from COVID-19 Conversations, a program developed and delivered virtually by researchers and academics at Northwell Health. The goal of the program was to address the mental, physical, and psychosocial needs of community members. The program used Zoom/Facebook Live to deliver interactive discussions on topics ranging from health education on COVID-19 and mental health to resources for unmet social needs. This interprofessional, cross-sector collaboration highlights the importance of public health interventions aimed at reducing the spread of COVID-19 through easy online access and culturally relevant community education and outreach.
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COVID-19 , Medios de Comunicación Sociales , Humanos , Grupos Minoritarios , Salud Pública , SARS-CoV-2RESUMEN
BACKGROUND: In March 2020, the greater New York metropolitan area became an epicenter for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The initial evolution of case incidence has not been well characterized. METHODS: Northwell Health Laboratories tested 46â 793 persons for SARS-CoV-2 from 4 March through 10 April. The primary outcome measure was a positive reverse transcription-polymerase chain reaction test for SARS-CoV-2. The secondary outcomes included patient age, sex, and race, if stated; dates the specimen was obtained and the test result; clinical practice site sources; geolocation of patient residence; and hospitalization. RESULTS: From 8 March through 10 April, a total of 26â 735 of 46â 793 persons (57.1%) tested positive for SARS-CoV-2. Males of each race were disproportionally more affected than females above age 25, with a progressive male predominance as age increased. Of the positive persons, 7292 were hospitalized directly upon presentation; an additional 882 persons tested positive in an ambulatory setting before subsequent hospitalization, a median of 4.8 days later. Total hospitalization rate was thus 8174 persons (30.6% of positive persons). There was a broad range (>10-fold) in the cumulative number of positive cases across individual zip codes following documented first caseincidence. Test positivity was greater for persons living in zip codes with lower annual household income. CONCLUSIONS: Our data reveal that SARS-CoV-2 incidence emerged rapidly and almost simultaneously across a broad demographic population in the region. These findings support the premise that SARS-CoV-2 infection was widely distributed prior to virus testing availability.
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COVID-19 , SARS-CoV-2 , Adulto , Femenino , Hospitalización , Humanos , Incidencia , Masculino , New YorkRESUMEN
Objective: To assess the relationships between systemic IFN type I (IFN-I) and II (IFN-II) activity and disease manifestations in primary SS (pSS). Methods: RT-PCR of multiple IFN-induced genes followed by principal component analysis of whole blood RNA of 50 pSS patients was used to identify indicator genes of systemic IFN-I and IFN-II activities. Systemic IFN activation levels were analysed in two independent European cohorts (n = 86 and 55, respectively) and their relationships with clinical features were analysed. Results: Three groups could be stratified according to systemic IFN activity: IFN inactive (19-47%), IFN-I (53-81%) and IFN-I + II (35-55%). No patient had isolated IFN-II activation. IgG levels were highest in patients with IFN-I + II, followed by IFN-I and IFN inactive patients. The prevalence of anti-SSA and anti-SSB was higher among those with IFN activation. There was no difference in total-EULAR SS Disease Activity Index (ESSDAI) or ClinESSDAI between the three subject groups. For individual ESSDAI domains, only the biological domain scores differed between the three groups (higher among the IFN active groups). For patient reported outcomes, there were no differences in EULAR Sjögren's syndrome patient reported index (ESSPRI), fatigue or dryness between groups, but pain scores were lower in the IFN active groups. Systemic IFN-I but not IFN-I + II activity appeared to be relatively stable over time. Conclusions: Systemic IFN activation is associated with higher activity only in the ESSDAI biological domain but not in other domains or the total score. Our data raise the possibility that the ESSDAI biological domain score may be a more sensitive endpoint for trials targeting either IFN pathway.
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Regulación de la Expresión Génica , Interferón Tipo I/genética , Interferón gamma/genética , ARN/genética , Síndrome de Sjögren/genética , Adulto , Femenino , Humanos , Interferón Tipo I/biosíntesis , Interferón gamma/biosíntesis , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/metabolismoRESUMEN
OBJECTIVE: The interferon (IFN) type I signature is present in over half of patients with primary Sjögren's syndrome (pSS) and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered as the main source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of patients with pSS. METHODS: Blood samples from 42 healthy controls (HC) and 115 patients with pSS were stratified according to their IFN type I signature. CD123+BDCA4+ pDCs and CD14+ monocytes were isolated from peripheral blood mononuclear cells (PBMCs). Genome-wide microarray analysis was conducted on sorted pDCs in a small sample set, followed by validation of differentially expressed genes of interest in pDCs and monocytes. RESULTS: We found an upregulation of endosomal toll-like receptor (TLR) 7, but not TLR9, in IFN-positive (IFNpos) pDCs (p<0.05) and monocytes (p=0.024). Additionally, the downstream signalling molecules MyD88, RSAD2 and IRF7 were upregulated, as were the cytoplasmic RNA-sensing receptors DDX58/retinoic acid inducible gene-I (RIG-I) and IFIH1/melanoma differentiation associated gene-5 (MDA5). In vitro triggering of the TLR7-pathway in HC PBMCs induced upregulation of DDX58/RIG-I and IFIH1/MDA5, and downregulated TLR9. The upregulation of TLR7, its downstream signalling pathway, DDX58/RIG-I and IFIH1/MDA5 were confined to patients with IFN-positive pSS. IFN-negative patients had a contrasting expression pattern-TLR7 normal, and decreased TLR9, RIG-I and MDA5. CONCLUSIONS: Here we conclude a contrasting expression pattern of the RNA-sensing receptors TLR7, RIG-I and MDA5 in pDCs and monocytes of patients with IFNpos pSS. This profile could explain the pathogenic IFN production and might reveal novel therapeutic targets in these patients.
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Interferón Tipo I/sangre , ARN Mensajero/análisis , Transducción de Señal , Síndrome de Sjögren/sangre , Síndrome de Sjögren/genética , Receptor Toll-Like 7/genética , Adulto , Anciano , Células Cultivadas , Proteína 58 DEAD Box/análisis , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/metabolismo , Células Dendríticas , Femenino , Humanos , Factor 7 Regulador del Interferón/análisis , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/metabolismo , Helicasa Inducida por Interferón IFIH1/análisis , Helicasa Inducida por Interferón IFIH1/genética , Helicasa Inducida por Interferón IFIH1/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Fosforilación , Proteínas/genética , Receptores Inmunológicos , Glándulas Salivales/química , Síndrome de Sjögren/metabolismo , Receptor Toll-Like 7/análisis , Receptor Toll-Like 7/metabolismo , Regulación hacia ArribaRESUMEN
PURPOSE OF REVIEW: The purpose of the study was to review the characteristics of renal macrophages and dendritic cells during homeostasis and disease, with a particular focus on lupus nephritis. RECENT FINDINGS: Resident renal macrophages derive from embryonic sources and are long-lived and self-renewing; they are also replaced from the bone marrow with age. The unique characteristics of macrophages in each tissue are imposed by the microenvironment and reinforced by epigenetic modifications. In acute renal injury, inflammatory macrophages are rapidly recruited and then replaced by those with a wound healing/resolution phenotype. In lupus nephritis, dendritic cells infiltrate the kidneys and function to present antigen and organize tertiary lymphoid structures that amplify inflammation. In addition, both infiltrating and resident macrophages contribute to ongoing injury. These cells have a mixed inflammatory and alternatively activated phenotype that may reflect failed resolution, potentially leading to tissue fibrosis and irreversible damage. A further understanding of the renal inflammatory cells that mediate tissue injury and fibrosis should lead to new therapies to help preserve renal function in patients with lupus nephritis.
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Células Dendríticas/patología , Riñón/patología , Nefritis Lúpica/patología , Macrófagos/patología , Células Dendríticas/inmunología , Humanos , Riñón/inmunología , Nefritis Lúpica/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunologíaRESUMEN
BACKGROUND: Interferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in SSc before overt skin fibrosis develops. METHODS: The expression of 11 IFN type I inducible genes was tested in whole-blood samples from 30 healthy controls (HCs), 12 subjects with primary Raynaud's phenomenon (RP), 19 patients with EaSSc, 7 patients with definite SSc without cutaneous fibrosis, 21 limited cutaneous SSc and 10 diffuse cutaneous SSc subjects. The correlation between IFN activity in monocytes, B cell activating factor (BAFF) mRNA expression and type III procollagen N-terminal propeptide (PIIINP) serum levels was tested. RESULTS: In all the SSc groups, higher IFN scores were observed compared with HC. An IFN score ≥7.09 discriminated HCs from patients with SSc (sensitivity=0.7, specificity=0.88, area under receiving operating characteristic (AUROC)=0.82); the prevalence of an elevated IFN score was: HC=3.3%; RP=33.3%, EaSSc=78.9%, definite SSc=100%, limited cutaneous SSc=42.9%, diffuse cutaneous SSc=70.0%. In monocytes an IFN score ≥4.12 distinguished HCs from patients with fibrotic SSc (sensitivity=0.62, specificity=0.85, AUROC=0.76). Compared with IFN-negative subjects, IFN-positive subjects had higher monocyte BAFF mRNA levels (19.7±5.2 vs 15.20±4.0, p=2.1×10(-5)) and serum PIIINP levels (median=6.0 (IQR 5.4-8.9) vs median=3.9 (IQR 3.3-4.7), p=0.0004). CONCLUSIONS: An IFN type I signature is observed in patients with SSc from the earliest phases of the disease, even before overt skin fibrosis. The presence of IFN type I signature in monocytes is correlated with BAFF mRNA expression and serum PIIINP levels, supporting a contribution in the pathogenesis and progression of SSc.
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Factor Activador de Células B/biosíntesis , Interferón Tipo I/genética , Esclerodermia Sistémica/genética , Adulto , Anciano , Factor Activador de Células B/genética , Estudios de Casos y Controles , Femenino , Fibrosis , Regulación de la Expresión Génica , Humanos , Interferón Tipo I/biosíntesis , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/sangre , Procolágeno/biosíntesis , Procolágeno/sangre , ARN Mensajero/genética , Esclerodermia Sistémica/metabolismo , Piel/patología , TranscriptomaRESUMEN
Primary Sjögren's syndrome (pSS) can be complicated by distal renal tubular acidosis (dRTA), which may contribute to low bone mineral density (BMD). Our objective was to evaluate BMD in pSS patients with and without dRTA as compared with healthy controls. BMD of lumbar spine (LS) and femoral neck (FN) was measured in 54 pSS patients and 162 healthy age- and sex-matched controls by dual-energy X-ray absorptiometry (DXA). dRTA was defined as inability to reach urinary pH <5.3 after an ammonium chloride (NH4Cl) test. LS- and FN-BMD were significantly higher in pSS patients compared with controls (1.18 ± 0.21 g/cm(2) for patients vs. 1.10 ± 0.18 g/cm(2) for controls, P = 0.008 and 0.9 ± 0.16 g/cm(2) for patients vs. 0.85 ± 0.13 g/cm(2) for controls, P = 0.009, respectively). After adjustment for BMI and smoking, the LS- and FN-BMD remained significantly higher. Patients with dRTA (N = 15) did not have a significantly different LS- and FN-BMD compared with those without dRTA (N = 39) after adjustment for BMI, age, and gender. Thirty-seven (69 %) pSS patients were using hydroxychloroquine (HCQ). Unexpectedly, pSS patients had a significantly higher LS- and FN-BMD compared with healthy controls. Patients with dRTA had similar BMD compared with patients without dRTA. We postulate that an explanation for the higher BMD in pSS patients may be the frequent use of HCQ.
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Acidosis Tubular Renal/etiología , Densidad Ósea/fisiología , Síndrome de Sjögren/complicaciones , Absorciometría de Fotón , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To establish an easy and practical assay for identifying systemic interferon (IFN) type I bioactivity in patients with primary Sjögren's syndrome (pSS). The IFN type I signature is present in over half of the pSS patients and identifies a subgroup with a higher disease activity. This signature is currently assessed via laborious expression profiles of multiple IFN type I-inducible genes. METHODS: In a cohort of 35 pSS patients, myxovirus-resistance protein A (MxA) was assessed as a potential biomarker for type I IFN activity, using an enzyme immunoassay (EIA) on whole-blood and flow cytometric analyses (fluorescence-activated cell sorting, FACS) of isolated CD14 monocytes. In addition, potential biomarkers such as CD64, CD169 and B cell-activating factor (BAFF) were simultaneously analysed in CD14 monocytes using FACS. The IFNscore, a measure for total type I IFN bioactivity, was calculated using expression values of the IFN type I signature genes--IFI44, IFI44L, IFIT3, LY6E and MX1--in CD14 monocytes, determined by real-time quantitative PCR. RESULTS: IFNscores correlated the strongest with monocyte MxA protein (r=0.741, p<0.001) and whole-blood MxA levels (r=0.764, p<0.001), weaker with CD169 (r=0.495, p<0.001) and CD64 (r=0.436, p=0.007), and not at all with BAFF protein. In particular, whole blood MxA levels correlated with EULAR Sjögren's Syndrome Disease Activity Index scores and numerous clinical pSS parameters. Interestingly, patients on hydroxychloroquine showed reduced MxA levels (EIA, p=0.04; FACS p=0.001). CONCLUSIONS: The MxA assays were excellent tools to assess IFN type I activity in pSS, MxA-EIA being the most practical. MxA levels associate with features of active disease and are reduced in hydroxychloroquine-treated patients, suggesting the clinical applicability of MxA in stratifying patients according to IFN positivity.
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Interferón Tipo I/metabolismo , Proteínas de Resistencia a Mixovirus/metabolismo , Síndrome de Sjögren/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos/genética , Antígenos de Superficie/genética , Biomarcadores/metabolismo , Estudios de Cohortes , Proteínas del Citoesqueleto/genética , Femenino , Proteínas Ligadas a GPI/genética , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Interferón Tipo I/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Persona de Mediana Edad , Proteínas de Resistencia a Mixovirus/genética , ARN Mensajero/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Síndrome de Sjögren/genéticaRESUMEN
OBJECTIVE: To determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called 'IFN type I signature', in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and expression of B cell activating factor (BAFF). METHODS: Expression of IFI44L, IFI44, IFIT3, LY6E and MX1 was measured using real time quantitative PCR in monocytes. Expression values were used to calculate IFN type I scores for each subject. pSS patients positive for the IFN type I signature (IFN score≥10) and patients negative for the signature (IFN score<10) were then compared for clinical disease manifestations and BAFF expression. A bioassay using a monocytic cell line was performed to study whether BAFF mRNA expression was inducible by IFN type I activity in serum of patients with pSS. RESULTS: An IFN type I signature was present in 55% of patients with pSS compared with 4.5% of HC. Patients with the IFN type I signature showed: (a) higher EULAR Sjögren's Syndrome Disease Activity Index scores; higher anti-Ro52, anti-Ro60 and anti-La autoantibodies; higher rheumatoid factor; higher serum IgG; lower C3, lower absolute lymphocyte and neutrophil counts; (b)higher BAFF gene expression in monocytes. In addition, serum of signature-positive patients induced BAFF gene expression in monocytes. CONCLUSIONS: The monocyte IFN type I signature identifies a subgroup of patients with pSS with a higher clinical disease activity together with higher BAFF mRNA expression. Such patients might benefit from treatment blocking IFN type I production or activity.
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Factor Activador de Células B/genética , Interferón Tipo I/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Monocitos/metabolismo , Síndrome de Sjögren/epidemiología , Síndrome de Sjögren/inmunología , Adulto , Anciano , Biomarcadores/metabolismo , Femenino , Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Prevalencia , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia Arriba/inmunologíaRESUMEN
The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis.
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Anemia commonly occurs in systemic lupus erythematosus, a disease characterized by innate immune activation by nucleic acids. Overactivation of cytoplasmic sensors by self-DNA or RNA can cause erythroid cell death, while sparing other hematopoietic cell lineages. Whereas chronic inflammation is involved in this mechanism, less is known about the impact of systemic lupus erythematosus on the BM erythropoietic niche. We discovered that expression of the endosomal ssRNA sensor human TLR8 induces fatal anemia in Sle1.Yaa lupus mice. We observed that anemia was associated with a decrease in erythromyeloblastic islands and a block in differentiation at the CFU-E to proerythroblast transition in the BM. Single-cell RNAseq analyses of isolated BM erythromyeloblastic islands from human TLR8-expressing mice revealed that genes associated with essential central macrophage functions including adhesion and provision of nutrients were down-regulated. Although compensatory stress erythropoiesis occurred in the spleen, red blood cell half-life decreased because of hemophagocytosis. These data implicate the endosomal RNA sensor TLR8 as an additional innate receptor whose overactivation causes acquired failure of erythropoiesis via myeloid cell dysregulation.
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Anemia , Lupus Eritematoso Sistémico , Animales , Humanos , Ratones , Anemia/etiología , Médula Ósea/metabolismo , ARN , Receptor Toll-Like 8RESUMEN
ABSTRACT: Olfactory dysfunction related to SARS-CoV-2 infection and COVID-19 disease is now well established in the literature. In December 2020, the FDA approved the Pfizer-BioNTech and Moderna vaccines for use in preventing COVID-19 in the United States. To the best of our knowledge, this is the first report of a phantosmia post-Pfizer COVID-19 vaccination, with positive magnetic resonance imaging radiographic findings in a patient with documented absence of infection by SARS-CoV-2 virus or concomitant sinonasal disease.
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Vacunas contra la COVID-19/efectos adversos , Alucinaciones/diagnóstico por imagen , Alucinaciones/etiología , Trastornos del Olfato/diagnóstico por imagen , Trastornos del Olfato/etiología , Humanos , Imagen por Resonancia Magnética , RadiografíaRESUMEN
The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with very few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which - by leveraging available transcriptomic and proteomic databases - allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both > 96%) the viral effects on cellular host-immune response, resulting in a specific cellular SARS-CoV-2 signature and ii) utilize this specific signature to narrow down promising repurposable therapeutic strategies. Powered by this tool, coupled with domain expertise, we have identified several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential new druggable targets in COVID-19 pathogenesis.
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The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and advise potential therapeutic targets.
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Inmunidad Adaptativa/inmunología , COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Inmunidad Innata/inmunología , Síndrome de Dificultad Respiratoria/inmunología , Formación de Anticuerpos , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/sangre , COVID-19/fisiopatología , Inactivadores del Complemento/uso terapéutico , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Endotelio Vascular/inmunología , Endotelio Vascular/fisiopatología , Humanos , Inmunidad Humoral/inmunología , Inmunoglobulina G/inmunología , Factores Inmunológicos/uso terapéutico , Memoria Inmunológica , Inmunosupresores/uso terapéutico , Interferones/inmunología , Células Asesinas Naturales/inmunología , Linfopenia/inmunología , Activación de Macrófagos/inmunología , Infiltración Neutrófila/inmunología , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Trombofilia/sangre , Trombofilia/inmunología , Trombosis/sangre , Trombosis/inmunología , Tratamiento Farmacológico de COVID-19RESUMEN
Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Although the prognosis of LN has improved substantially over the past 50 years, outcomes have plateaued in the USA in the past 20 years as immunosuppressive therapies have failed to reverse disease in more than half of treated patients. This failure might reflect disease complexity and heterogeneity, as well as social and economic barriers to health-care access that can delay intervention until after damage has already occurred. LN progression is still poorly understood and involves multiple cell types and both immune and non-immune mechanisms. Single-cell analysis of intrinsic renal cells and infiltrating cells from patients with LN is a new approach that will help to define the pathways of renal injury at a cellular level. Although many new immune-modulating therapies are being tested in the clinic, the development of therapies to improve regeneration of the injured kidney and to prevent fibrosis requires a better understanding of the mechanisms of LN progression. This mechanistic understanding, together with the development of clinical measures to evaluate risk and detect early disease and better access to expert health-care providers, should improve outcomes for patients with LN.
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Riñón/citología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/complicaciones , Biomarcadores/análisis , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Diagnóstico Precoz , Fibrosis/prevención & control , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Humanos , Inmunosupresores/uso terapéutico , Riñón/lesiones , Riñón/metabolismo , Riñón/patología , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/prevención & control , Lupus Eritematoso Sistémico/epidemiología , Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Pronóstico , Regeneración/efectos de los fármacos , Regeneración/fisiología , Factores Socioeconómicos , Estados Unidos/epidemiologíaRESUMEN
We write to introduce our novel group formed to confront some of the issues raised by the COVID-19 pandemic. Information about the group, which we named "cure COVid for Ever and for All" (RxCOVEA), its dynamic membership (changing regularly), and some of its activities-described in more technical detail for expert perusal and commentary-are available upon request.
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Recent advances in the field of autoimmunity have identified numerous dysfunctional pathways in Systemic Lupus Erythematosus (SLE), including aberrant clearance of nucleic-acid-containing debris and immune complexes, excessive innate immune activation leading to overactive type I IFN signalling, and abnormal B and T cell activation. On the background of genetic polymorphisms that reset thresholds for immune responses, multiple immune cells contribute to inflammatory amplification circuits. Neutrophils activated by immune complexes are a rich source of immunogenic nucleic acids. Identification of new B subsets suggests several mechanisms for induction of autoantibody producing effector cells. Disordered T cell regulation involves both CD4 and CD8 cells. An imbalance in immunometabolism in immune cells amplifies autoimmunity and inflammation. These new advances in understanding of disease pathogenesis provide fertile ground for therapeutic development.
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Lupus Eritematoso Sistémico/terapia , Animales , Autoinmunidad/genética , Autoinmunidad/inmunología , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunologíaRESUMEN
BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is an incurable multi-systemic autoimmune disease. Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. The objective of this study was to assess the prevalence of the IFN-I signature and the contribution of cytosolic nucleic acid receptors to IFN-I activation in a cohort of primarily white cSLE patients. METHODS: The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs). Innate immune receptor expression was determined by RT-PCR and flow cytometry. To clarify the contribution of RNA-binding RIG-like receptors (RLRs) and DNA-binding receptors (DBRs) to IFN-I activation, peripheral blood mononuclear cells (PBMCs) from patients were treated with BX795, a TANK-binding kinase 1 (TBK1) inhibitor blocking RLR and DBR pathways. RESULTS: The IFN-I signature was positive in 57% of cSLE patients and 15% of the HCs. Upregulated gene expression of TLR7, RLRs (IFIH1, DDX58, DDX60, DHX58) and DBRs (ZBP-1, IFI16) was observed in CD14+ monocytes of the IFN-I-positive cSLE patients. Additionally, RIG-I and ZBP-1 protein expression was upregulated in these cells. Spontaneous IFN-I stimulated gene (ISG) expression in PBMCs from cSLE patients was inhibited by a TBK1-blocker. CONCLUSIONS: IFN-I activation, assessed as ISG expression, in cSLE is associated with increased expression of TLR7, and RNA and DNA binding receptors, and these receptors contribute to IFN-I activation via TBK1 signaling. TBK1-blockers may therefore be a promising treatment target for SLE.
Asunto(s)
Perfilación de la Expresión Génica , Interferón Tipo I/genética , Lupus Eritematoso Sistémico/genética , Monocitos/metabolismo , Adolescente , Adulto , Niño , Preescolar , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/metabolismo , ADN/genética , ADN/metabolismo , Femenino , Humanos , Interferón Tipo I/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Masculino , ARN/genética , ARN/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme that converts tryptophan to kynurenine, is driven in part by type I and type II interferons (IFNs). Naive T cells are polarized into FoxP3+ Treg cells upon exposure to either IDO+ cells or kynurenine. Recent studies have suggested that the kynurenine pathway reflects a crucial interface between the immune and nervous system. The aims of the present study were to evaluate whether Treg cell levels are elevated, in conjunction with increased IDO activity, in patients with primary Sjögren's syndrome (SS) who are positive for the IFN gene expression signature, and to investigate the downstream kynurenine pathway in these patients. METHODS: Serum from 71 healthy controls, 58 IFN-negative patients with primary SS, and 66 IFN-positive patients with primary SS was analyzed using high-performance liquid chromatography to measure the levels of tryptophan and kynurenine. Expression levels of messenger RNA (mRNA) for IDO and downstream enzymes in the kynurenine pathway were assessed in CD14+ monocytes using real-time quantitative polymerase chain reaction. CD4+CD45RO+ T helper memory cell populations were analyzed by flow cytometry. RESULTS: Significantly increased levels of IDO activity (assessed as the kynurenine:tryptophan ratio) (P = 0.0054) and percentages of CD25(high) FoxP3+ Treg cells (P = 0.039) were observed in the serum from IFN-positive patients with primary SS, and these parameters were significantly correlated with one another (r = 0.511, P = 0.002). In circulating monocytes from IFN-positive patients with primary SS, the expression of IDO1 mRNA was up-regulated (P < 0.0001), and this was correlated with the IFN gene expression score (r = 0.816, P < 0.0001). Interestingly, the proapoptotic and neurotoxic downstream enzyme kynurenine 3-monooxygenase was up-regulated (P = 0.0057), whereas kynurenine aminotransferase I (KATI) (P = 0.0003), KATIII (P = 0.016), and KATIV (P = 0.04) were down-regulated in IFN-positive patients with primary SS compared to healthy controls. CONCLUSION: These findings demonstrate enhanced IDO activity in conjunction with increased percentages of CD25(high) FoxP3+ Treg cells in primary SS patients who carry the IFN signature. In addition, IFN-positive patients with primary SS exhibit an imbalanced kynurenine pathway, with evidence of a shift toward potentially more proapoptotic and neurotoxic metabolites. Intervening in these IFN- and IDO-induced immune system imbalances may offer a new array of possibilities for therapeutic interventions in patients with primary SS.
Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferones/sangre , Quinurenina/fisiología , Síndrome de Sjögren/sangre , Síndrome de Sjögren/inmunología , Linfocitos T Reguladores/enzimología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transducción de SeñalRESUMEN
Mouse models have been widely used to elucidate the pathogenic mechanisms of human diseases. The advantages of using these models include the ability to study different stages of the disease with particular respect to specific target organs, to focus on the role of specific pathogenic factors and to investigate the effect of possible therapeutic interventions. Sjögren's syndrome (SS) is a systemic autoimmune disease, characterised by lymphocytic infiltrates in the salivary and lacrimal glands. To date, effective therapy is not available and treatment has been mainly symptomatic. Ongoing studies in murine models are aimed at developing more effective and targeted therapies in SS. The heterogeneity of SS will most probably benefit from optimising therapies, tailored to specific subgroups of the disease. In this review, we provide our perspective on the importance of subdividing SS patients according to their interferon signature, and recommend choosing appropriate mouse models for interferon-positive and interferon-negative SS subtypes. Murine models better resembling human-disease phenotypes will be essential in this endeavour.