Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 19.002
Filtrar
Más filtros

Intervalo de año de publicación
1.
Annu Rev Immunol ; 42(1): 347-373, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38941603

RESUMEN

Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic acids through endosomal Toll-like receptors and the ensuing production of type I interferon and other soluble mediators, which orchestrate innate and adaptive responses. We review several aspects of pDC biology that have recently come to the fore. We discuss emerging questions regarding the lineage affiliation and origin of pDCs and argue that these cells constitute an integral part of the dendritic cell lineage. We emphasize the specific function of pDCs as innate sentinels of virus infection, particularly their recognition of and distinct response to virus-infected cells. This essential evolutionary role of pDCs has been particularly important for the control of coronaviruses, as demonstrated by the recent COVID-19 pandemic. Finally, we highlight the key contribution of pDCs to systemic lupus erythematosus, in which therapeutic targeting of pDCs is currently underway.


Asunto(s)
COVID-19 , Células Dendríticas , Inmunidad Innata , Lupus Eritematoso Sistémico , SARS-CoV-2 , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , COVID-19/inmunología , Animales , SARS-CoV-2/inmunología , SARS-CoV-2/fisiología , Lupus Eritematoso Sistémico/inmunología , Receptores Toll-Like/metabolismo , Diferenciación Celular , Linaje de la Célula
2.
Annu Rev Immunol ; 41: 1-15, 2023 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-37126416

RESUMEN

I have been a scientific grasshopper throughout my career, moving from question to question within the domain of lupus. This has proven to be immensely gratifying. Scientific exploration is endlessly fascinating, and succeeding in studies you care about with colleagues and trainees leads to strong and lasting bonds. Science isn't easy; being a woman in science presents challenges, but the drive to understand a disease remains strong.


Asunto(s)
Selección de Profesión , Lupus Eritematoso Sistémico , Femenino , Humanos , Investigación Biomédica
3.
Annu Rev Immunol ; 41: 533-560, 2023 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-36854182

RESUMEN

Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.


Asunto(s)
Interferones , Lupus Eritematoso Sistémico , Humanos , Animales , Interferones/uso terapéutico , Linfocitos B , Linfocitos T Colaboradores-Inductores , Autoanticuerpos
4.
Annu Rev Immunol ; 35: 313-336, 2017 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-28142323

RESUMEN

Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. The existence of these sensors raises fundamental questions about self/nonself discrimination because of the abundance of self-DNA and self-RNA that occupy these same compartments. Recent advances have revealed that enzymes that metabolize or modify endogenous nucleic acids are essential for preventing inappropriate activation of the innate antiviral response. In this review, we discuss rare human diseases caused by dysregulated nucleic acid sensing, focusing primarily on intracellular sensors of nucleic acids. We summarize lessons learned from these disorders, we rationalize the existence of these diseases in the context of evolution, and we propose that this framework may also apply to a number of more common autoimmune diseases for which the underlying genetics and mechanisms are not yet fully understood.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Autoinmunidad , Lupus Eritematoso Sistémico/inmunología , Malformaciones del Sistema Nervioso/inmunología , Ácidos Nucleicos/inmunología , Virosis/inmunología , Animales , Humanos , Inmunidad Innata , Interferón Tipo I/metabolismo , Receptores Toll-Like/metabolismo
5.
Cell ; 185(18): 3375-3389.e21, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35998627

RESUMEN

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple immune cells. To elucidate SLE pathogenesis, it is essential to understand the dysregulated gene expression pattern linked to various clinical statuses with a high cellular resolution. Here, we conducted a large-scale transcriptome study with 6,386 RNA sequencing data covering 27 immune cell types from 136 SLE and 89 healthy donors. We profiled two distinct cell-type-specific transcriptomic signatures: disease-state and disease-activity signatures, reflecting disease establishment and exacerbation, respectively. We then identified candidate biological processes unique to each signature. This study suggested the clinical value of disease-activity signatures, which were associated with organ involvement and therapeutic responses. However, disease-activity signatures were less enriched around SLE risk variants than disease-state signatures, suggesting that current genetic studies may not well capture clinically vital biology. Together, we identified comprehensive gene signatures of SLE, which will provide essential foundations for future genomic and genetic studies.


Asunto(s)
Lupus Eritematoso Sistémico , Transcriptoma , Humanos , Lupus Eritematoso Sistémico/genética , Análisis de Secuencia de ARN
6.
Cell ; 184(17): 4464-4479.e19, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34384544

RESUMEN

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.


Asunto(s)
Interferón Tipo I/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Mitocondrias/metabolismo , Células Mieloides/metabolismo , Adolescente , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Niño , Preescolar , Eritroblastos/metabolismo , Eritroblastos/ultraestructura , Eritrocitos/metabolismo , Eritropoyesis , Humanos , Mitofagia , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo
7.
Cell ; 184(11): 3006-3021.e17, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-33930287

RESUMEN

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.


Asunto(s)
Regulación de la Expresión Génica/genética , Expresión Génica/inmunología , Enfermedades del Sistema Inmune/genética , Adulto , Femenino , Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/metabolismo , Enfermedades del Sistema Inmune/metabolismo , Enfermedades del Sistema Inmune/fisiopatología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Sitios de Carácter Cuantitativo/inmunología , Transcriptoma/genética , Secuenciación Completa del Genoma/métodos
8.
Cell ; 177(4): 865-880.e21, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-31031002

RESUMEN

Circular RNAs (circRNAs) produced from back-splicing of exons of pre-mRNAs are widely expressed, but current understanding of their functions is limited. These RNAs are stable in general and are thought to have unique structural conformations distinct from their linear RNA cognates. Here, we show that endogenous circRNAs tend to form 16-26 bp imperfect RNA duplexes and act as inhibitors of double-stranded RNA (dsRNA)-activated protein kinase (PKR) related to innate immunity. Upon poly(I:C) stimulation or viral infection, circRNAs are globally degraded by RNase L, a process required for PKR activation in early cellular innate immune responses. Augmented PKR phosphorylation and circRNA reduction are found in peripheral blood mononuclear cells (PBMCs) derived from patients with autoimmune disease systemic lupus erythematosus (SLE). Importantly, overexpression of the dsRNA-containing circRNA in PBMCs or T cells derived from SLE can alleviate the aberrant PKR activation cascade, thus providing a connection between circRNAs and SLE.


Asunto(s)
ARN Circular/metabolismo , ARN Circular/fisiología , eIF-2 Quinasa/metabolismo , Adolescente , Adulto , Enfermedades Autoinmunes/genética , Línea Celular , Endorribonucleasas/metabolismo , Femenino , Humanos , Inmunidad Innata/genética , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/genética , Persona de Mediana Edad , Fosforilación , ARN/metabolismo , Empalme del ARN/genética , Estabilidad del ARN/fisiología , ARN Circular/genética , ARN Bicatenario/metabolismo , Virosis/metabolismo , eIF-2 Quinasa/inmunología
9.
Immunity ; 57(9): 2232-2250.e10, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39137779

RESUMEN

Due to its stimulatory potential for immunomodulatory CD4+ regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) immunotherapy has gained considerable attention for the treatment of autoimmune diseases. In this investigator-initiated single-arm non-placebo-controlled phase-2 clinical trial of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients, we generated a comprehensive atlas of in vivo human immune responses to low-dose IL-2. We performed an in-depth study of circulating and cutaneous immune cells by imaging mass cytometry, high-parameter flow cytometry, transcriptomics, and targeted serum proteomics. Low-dose IL-2 stimulated various circulating immune cells, including Treg cells with a skin-homing phenotype that appeared in the skin of SLE patients in close interaction with endothelial cells. Analysis of surface proteins and transcriptomes revealed different IL-2-driven Treg cell activation programs, including gut-homing CD38+, skin-homing HLA-DR+, and highly proliferative inflammation-homing CD38+ HLA-DR+ Treg cells. Collectively, these data define the distinct human Treg cell subsets that are responsive to IL-2 immunotherapy.


Asunto(s)
Inmunoterapia , Interleucina-2 , Lupus Eritematoso Sistémico , Piel , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Interleucina-2/inmunología , Piel/inmunología , Inmunoterapia/métodos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/terapia , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Activación de Linfocitos/inmunología , Femenino , Adulto , Masculino
10.
Immunity ; 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39378884

RESUMEN

Opsonization of red blood cells that retain mitochondria (Mito+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1ß (mIL-1ß) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1ß (IL-1ß) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1ß secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1ß into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1ß and expanded in SLE patients with active disease.

11.
Immunity ; 57(7): 1603-1617.e7, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38761804

RESUMEN

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteína Coestimuladora de Linfocitos T Inducibles , Lupus Eritematoso Sistémico , Ratones Noqueados , Proteínas Proto-Oncogénicas c-bcl-6 , Proteínas Proto-Oncogénicas c-cbl , Células T Auxiliares Foliculares , Animales , Femenino , Humanos , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Autofagia/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/genética , Ratones Endogámicos C57BL , Proteolisis , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Proteínas Proto-Oncogénicas c-cbl/genética , Proteínas Proto-Oncogénicas c-cbl/deficiencia , Transducción de Señal/inmunología , Células T Auxiliares Foliculares/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Ubiquitinación
12.
Cell ; 170(5): 913-926.e19, 2017 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-28841417

RESUMEN

Germinal centers (GCs) are the primary sites of clonal B cell expansion and affinity maturation, directing the production of high-affinity antibodies. This response is a central driver of pathogenesis in autoimmune diseases, such as systemic lupus erythematosus (SLE), but the natural history of autoreactive GCs remains unclear. Here, we present a novel mouse model where the presence of a single autoreactive B cell clone drives the TLR7-dependent activation, expansion, and differentiation of other autoreactive B cells in spontaneous GCs. Once tolerance was broken for one self-antigen, autoreactive GCs generated B cells targeting other self-antigens. GCs became independent of the initial clone and evolved toward dominance of individual clonal lineages, indicating affinity maturation. This process produced serum autoantibodies to a breadth of self-antigens, leading to antibody deposition in the kidneys. Our data provide insight into the maturation of the self-reactive B cell response, contextualizing the epitope spreading observed in autoimmune disease.


Asunto(s)
Linfocitos B/inmunología , Evolución Clonal , Centro Germinal/citología , Centro Germinal/inmunología , Tolerancia Inmunológica , Animales , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Linfocitos B/citología , Quimera/inmunología , Epítopos/inmunología , Riñón/inmunología , Ratones , Ratones Endogámicos C57BL
13.
Immunity ; 52(6): 1022-1038.e7, 2020 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-32454024

RESUMEN

Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet mechanisms of their development remain poorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA responses in Dnase1l3-/- mice require CD40L-mediated T cell help, but proceed independently of germinal center formation via short-lived antibody-forming cells (AFCs) localized to extrafollicular regions. Type I interferon (IFN-I) signaling and IFN-I-producing plasmacytoid dendritic cells (pDCs) facilitate the differentiation of DNA-reactive AFCs in vivo and in vitro and are required for downstream manifestations of autoimmunity. Moreover, the endosomal DNA sensor TLR9 promotes anti-dsDNA responses and SLE-like disease in Dnase1l3-/- mice redundantly with another nucleic acid-sensing receptor, TLR7. These results establish extrafollicular B cell differentiation into short-lived AFCs as a key mechanism of anti-DNA autoreactivity and reveal a major contribution of pDCs, endosomal Toll-like receptors (TLRs), and IFN-I to this pathway.


Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Comunicación Celular , ADN/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interferón Tipo I/metabolismo , Animales , Anticuerpos Antinucleares/inmunología , Autoantígenos/inmunología , Autoinmunidad , Biomarcadores , Ligando de CD40/deficiencia , Comunicación Celular/genética , Comunicación Celular/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Endodesoxirribonucleasas/deficiencia , Técnica del Anticuerpo Fluorescente , Centro Germinal/inmunología , Centro Germinal/metabolismo , Centro Germinal/patología , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/metabolismo , Ratones , Ratones Noqueados , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 9/metabolismo
14.
Immunity ; 50(2): 334-347.e9, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30709743

RESUMEN

Elevated endogenous retrovirus (ERV) transcription and anti-ERV antibody reactivity are implicated in lupus pathogenesis. Overproduction of non-ecotropic ERV (NEERV) envelope glycoprotein gp70 and resultant nephritis occur in lupus-prone mice, but whether NEERV mis-expression contributes to lupus etiology is unclear. Here we identified suppressor of NEERV (Snerv) 1 and 2, Krüppel-associated box zinc-finger proteins (KRAB-ZFPs) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1. Germline Snerv1/Snerv2 deletion increased activating chromatin modifications, transcription, and gp70 expression from NEERV loci. F1 crosses of lupus-prone New Zealand Black (NZB) and 129 mice to Snerv1/Snerv2-/- mice failed to restore NEERV repression, demonstrating that loss of SNERV underlies the lupus autoantigen gp70 overproduction that promotes nephritis in susceptible mice and that SNERV encodes for Sgp3 (in NZB mice) and Gv-1 loci (in 129 mice). Increased ERV expression in lupus patients inversely correlated with three putative ERV-suppressing KRAB-ZFPs, suggesting that loss of KRAB-ZFP-mediated ERV control may contribute to human lupus pathogenesis.


Asunto(s)
Proteínas Portadoras/inmunología , Retrovirus Endógenos/inmunología , Glicoproteínas/inmunología , Nefritis Lúpica/inmunología , Chaperonas Moleculares/inmunología , Proteínas Nucleares/inmunología , Proteínas Represoras/inmunología , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Regulación de la Expresión Génica/inmunología , Predisposición Genética a la Enfermedad/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Nefritis Lúpica/genética , Nefritis Lúpica/metabolismo , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos NZB , Ratones Noqueados , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
15.
Immunity ; 51(3): 573-589.e8, 2019 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-31474513

RESUMEN

Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5-CD163+CD14+ cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies.


Asunto(s)
Biomarcadores/sangre , Células Dendríticas/inmunología , Inflamación/sangre , Inflamación/inmunología , Leucocitos Mononucleares/inmunología , Fagocitos/inmunología , Antígenos CD/sangre , Antígenos CD/inmunología , Células Cultivadas , Citometría de Flujo/métodos , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Monocitos/inmunología , Fenotipo , Análisis de la Célula Individual
16.
Immunol Rev ; 325(1): 77-89, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38873851

RESUMEN

Systemic lupus erythematosus is a complex autoimmune disease resulting from a dysregulation of the immune system that involves gut dysbiosis and an altered host cellular metabolism. This review highlights novel insights and expands on the interactions between the gut microbiome and the host immune metabolism in lupus. Pathobionts, invasive pathogens, and even commensal microbes, when in dysbiosis, can all trigger and modulate immune responses through metabolic reprogramming. Changes in the microbiota's global composition or individual taxa may trigger a cascade of metabolic changes in immune cells that may, in turn, reprogram their functions. Factors contributing to dysbiosis include changes in intestinal hypoxia, competition for glucose, and limited availability of essential nutrients, such as tryptophan and metal ions, all of which can be driven by host metabolism changes. Conversely, the accumulation of some host metabolites, such as itaconate, succinate, and free fatty acids, could further influence the microbial composition and immune responses. Overall, mounting evidence supports a bidirectional relationship between host immunometabolism and the microbiota in lupus pathogenesis.


Asunto(s)
Disbiosis , Microbioma Gastrointestinal , Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/microbiología , Microbioma Gastrointestinal/inmunología , Animales , Disbiosis/inmunología , Sistema Inmunológico/metabolismo , Sistema Inmunológico/inmunología , Sistema Inmunológico/microbiología , Microbiota/inmunología
17.
Immunity ; 49(6): 1034-1048.e8, 2018 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-30566881

RESUMEN

Single-nucleotide polymorphisms in ETS1 are associated with systemic lupus erythematosus (SLE). Ets1-/- mice develop SLE-like symptoms, suggesting that dysregulation of this transcription factor is important to the onset or progression of SLE. We used conditional deletion approaches to examine the impact of Ets1 expression in different immune cell types. Ets1 deletion on CD4+ T cells, but not B cells or dendritic cells, resulted in the SLE autoimmunity, and this was associated with the spontaneous expansion of T follicular helper type 2 (Tfh2) cells. Ets1-/- Tfh2 cells exhibited increased expression of GATA-3 and interleukin-4 (IL-4), which induced IgE isotype switching in B cells. Neutralization of IL-4 reduced Tfh2 cell frequencies and ameliorated disease parameters. Mechanistically, Ets1 suppressed signature Tfh and Th2 cell genes, including Cxcr5, Bcl6, and Il4ra, thus curbing the terminal Tfh2 cell differentiation process. Tfh2 cell frequencies in SLE patients correlated with disease parameters, providing evidence for the relevance of these findings to human disease.


Asunto(s)
Diferenciación Celular/inmunología , Lupus Eritematoso Sistémico/inmunología , Proteína Proto-Oncogénica c-ets-1/inmunología , Células Th2/inmunología , Animales , Autoinmunidad/genética , Autoinmunidad/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Expresión Génica/inmunología , Perfilación de la Expresión Génica , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína Proto-Oncogénica c-ets-1/genética , Proteína Proto-Oncogénica c-ets-1/metabolismo , Células Th2/metabolismo
18.
Immunity ; 49(4): 725-739.e6, 2018 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-30314758

RESUMEN

Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Lupus Eritematoso Sistémico/inmunología , Receptor Toll-Like 7/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Femenino , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Masculino , Persona de Mediana Edad , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Transcriptoma/genética , Transcriptoma/inmunología , Adulto Joven
19.
Proc Natl Acad Sci U S A ; 121(24): e2322009121, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38843187

RESUMEN

Follicular helper T (TFH) cells mediate germinal center reactions to generate high affinity antibodies against specific pathogens, and their excessive production is associated with the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). ETV5, a member of the ETS transcription factor family, promotes TFH cell differentiation in mice. In this study, we examined the role of ETV5 in the pathogenesis of lupus in mice and humans. T cell-specific deletion of Etv5 alleles ameliorated TFH cell differentiation and autoimmune phenotypes in lupus mouse models. Further, we identified SPP1 as an ETV5 target that promotes TFH cell differentiation in both mice and humans. Notably, extracellular osteopontin (OPN) encoded by SPP1 enhances TFH cell differentiation by activating the CD44-AKT signaling pathway. Furthermore, ETV5 and SPP1 levels were increased in CD4+ T cells from patients with SLE and were positively correlated with disease activity. Taken together, our findings demonstrate that ETV5 is a lupus-promoting transcription factor, and secreted OPN promotes TFH cell differentiation.


Asunto(s)
Diferenciación Celular , Lupus Eritematoso Sistémico , Osteopontina , Factores de Transcripción , Animales , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Osteopontina/metabolismo , Osteopontina/genética , Ratones , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Femenino , Modelos Animales de Enfermedad , Ratones Noqueados
20.
Immunol Rev ; 314(1): 313-325, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36305174

RESUMEN

A body of evidence has re-energized the interest on the role neutrophils in inflammatory and autoimmune conditions. For decades, neutrophils have been considered a homogenous population. Nevertheless, accumulating evidence suggests that neutrophils are more versatile and heterogeneous than initially considered. The notion of neutrophil heterogeneity has been supported by the identification of low-density granulocytes (LDGs) in systemic lupus erythematosus (SLE) and other systemic autoimmune and autoinflammatory conditions. Transcriptomic, epigenetic, proteomic, and functional analyses support that LDGs are a distinct subset of proinflammatory neutrophils implicated in the pathogenesis of SLE and other autoimmune diseases. Importantly, it remains incompletely characterized whether LDGs detected in other inflammatory/autoimmune conditions display the same phenotype that those present in SLE. A shared feature of LDGs across diseases is their association with vascular damage, an important contributor to morbidity and mortality in chronic inflammatory conditions. Additionally, the lack of specific markers to identify LDGs in circulation or in tissue, makes it a challenge to elucidate their role in the pathogenesis of inflammatory and autoimmune conditions. In this review, we aim to examine the evidence on the biology and the putative pathogenic role of LDGs in systemic autoimmune diseases.


Asunto(s)
Autoinmunidad , Lupus Eritematoso Sistémico , Humanos , Proteómica , Granulocitos/patología , Neutrófilos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA