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1.
Cell ; 184(17): 4464-4479.e19, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34384544

RESUMO

Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.


Assuntos
Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Mitocôndrias/metabolismo , Células Mieloides/metabolismo , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Eritroblastos/metabolismo , Eritroblastos/ultraestrutura , Eritrócitos/metabolismo , Eritropoese , Humanos , Mitofagia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo
2.
Arthritis Rheumatol ; 75(7): 1246-1261, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36648920

RESUMO

OBJECTIVE: This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management. METHODS: The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses. RESULTS: Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH). CONCLUSION: These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.


Assuntos
Dermatomiosite , Humanos , Dermatomiosite/metabolismo , Leucócitos Mononucleares , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Aldeído Liases/metabolismo
3.
J Exp Med ; 216(5): 1154-1169, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30962246

RESUMO

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4+ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes.


Assuntos
Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Complicações na Gravidez/sangue , Complicações na Gravidez/genética , Transcriptoma , Adulto , Biomarcadores , Implantação do Embrião/genética , Feminino , Humanos , Estudos Longitudinais , Pré-Eclâmpsia/genética , Gravidez , Estudos Prospectivos , RNA-Seq
4.
J Exp Med ; 214(11): 3449-3466, 2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-28935693

RESUMO

The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1ß after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.


Assuntos
Artrite Juvenil/genética , Diferenciação Celular/genética , Macrófagos/metabolismo , Monócitos/metabolismo , Adulto , Artrite Juvenil/sangue , Artrite Juvenil/imunologia , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Citocinas/sangue , Citocinas/genética , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica/métodos , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Ligantes , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Monócitos/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Nat Commun ; 5: 5283, 2014 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-25335753

RESUMO

The mechanisms by which microbial vaccines interact with human APCs remain elusive. Herein, we describe the transcriptional programs induced in human DCs by pathogens, innate receptor ligands and vaccines. Exposure of DCs to influenza, Salmonella enterica and Staphylococcus aureus allows us to build a modular framework containing 204 transcript clusters. We use this framework to characterize the responses of human monocytes, monocyte-derived DCs and blood DC subsets to 13 vaccines. Different vaccines induce distinct transcriptional programs based on pathogen type, adjuvant formulation and APC targeted. Fluzone, Pneumovax and Gardasil, respectively, activate monocyte-derived DCs, monocytes and CD1c+ blood DCs, highlighting APC specialization in response to vaccines. Finally, the blood signatures from individuals vaccinated with Fluzone or infected with influenza reveal a signature of adaptive immunity activation following vaccination and symptomatic infections, but not asymptomatic infections. These data, offered with a web interface, may guide the development of improved vaccines.


Assuntos
Células Dendríticas/citologia , Células Dendríticas/microbiologia , Transcrição Gênica , Vacinas/química , Algoritmos , Animais , Antígenos CD1/metabolismo , Antígenos de Superfície/metabolismo , Análise por Conglomerados , Citocinas/metabolismo , Células Dendríticas/metabolismo , Cães , Perfilação da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1 , Interleucina-4/metabolismo , Células Madin Darby de Rim Canino , Monócitos/citologia , Monócitos/metabolismo , Análise de Componente Principal , Salmonella enterica , Staphylococcus aureus , Trombomodulina , Transcriptoma
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