RESUMO
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.
Assuntos
COVID-19 , Células Dendríticas , Imunidade Inata , Lúpus Eritematoso Sistêmico , SARS-CoV-2 , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , COVID-19/imunologia , Animais , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores Toll-Like/metabolismo , Diferenciação Celular , Linhagem da CélulaRESUMO
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.
Assuntos
Escolha da Profissão , Lúpus Eritematoso Sistêmico , Feminino , Humanos , Pesquisa BiomédicaRESUMO
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.
Assuntos
Doenças Autoimunes do Sistema Nervoso/imunologia , Autoimunidade , Lúpus Eritematoso Sistêmico/imunologia , Malformações do Sistema Nervoso/imunologia , Ácidos Nucleicos/imunologia , Viroses/imunologia , Animais , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Receptores Toll-Like/metabolismoRESUMO
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.
Assuntos
Lúpus Eritematoso Sistêmico , Transcriptoma , Humanos , Lúpus Eritematoso Sistêmico/genética , Análise de Sequência de RNARESUMO
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/metabolismoRESUMO
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.
Assuntos
Regulação da Expressão Gênica/genética , Expressão Gênica/imunologia , Doenças do Sistema Imunitário/genética , Adulto , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Locos de Características Quantitativas/imunologia , Transcriptoma/genética , Sequenciamento Completo do Genoma/métodosRESUMO
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.
Assuntos
RNA Circular/metabolismo , RNA Circular/fisiologia , eIF-2 Quinase/metabolismo , Adolescente , Adulto , Doenças Autoimunes/genética , Linhagem Celular , Endorribonucleases/metabolismo , Feminino , Humanos , Imunidade Inata/genética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/genética , Pessoa de Meia-Idade , Fosforilação , RNA/metabolismo , Splicing de RNA/genética , Estabilidade de RNA/fisiologia , RNA Circular/genética , RNA de Cadeia Dupla/metabolismo , Viroses/metabolismo , eIF-2 Quinase/imunologiaRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteína Coestimuladora de Linfócitos T Induzíveis , Lúpus Eritematoso Sistêmico , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-6 , Proteínas Proto-Oncogênicas c-cbl , Células T Auxiliares Foliculares , Animais , Feminino , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Autofagia/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/genética , Camundongos Endogâmicos C57BL , Proteólise , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Proto-Oncogênicas c-cbl/deficiência , Transdução de Sinais/imunologia , Células T Auxiliares Foliculares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , UbiquitinaçãoRESUMO
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.
Assuntos
Linfócitos B/imunologia , Evolução Clonal , Centro Germinativo/citologia , Centro Germinativo/imunologia , Tolerância Imunológica , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Linfócitos B/citologia , Quimera/imunologia , Epitopos/imunologia , Rim/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular , DNA/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interferon Tipo I/metabolismo , Animais , Anticorpos Antinucleares/imunologia , Autoantígenos/imunologia , Autoimunidade , Biomarcadores , Ligante de CD40/deficiência , Comunicação Celular/genética , Comunicação Celular/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Endodesoxirribonucleases/deficiência , Imunofluorescência , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Knockout , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismoRESUMO
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.
Assuntos
Proteínas de Transporte/imunologia , Retrovirus Endógenos/imunologia , Glicoproteínas/imunologia , Nefrite Lúpica/imunologia , Chaperonas Moleculares/imunologia , Proteínas Nucleares/imunologia , Proteínas Repressoras/imunologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Camundongos Knockout , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
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.
Assuntos
Diferenciação Celular/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteína Proto-Oncogênica c-ets-1/imunologia , Células Th2/imunologia , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Células Th2/metabolismoRESUMO
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.
Assuntos
Autoimunidade , Lúpus Eritematoso Sistêmico , Humanos , Proteômica , Granulócitos/patologia , NeutrófilosRESUMO
Genome-wide association studies (GWAS) have provided insights into the genetic basis of complex diseases. In the next step, integrative multi-omics approaches can characterize molecular profiles in relevant primary tissues to reveal the mechanisms that underlie disease development. Here, we highlight recent progress in four examples of complex diseases generated by integrative studies: type 2 diabetes (T2D), osteoarthritis, Alzheimer's disease (AD), and systemic lupus erythematosus (SLE). High-resolution methodologies such as single-cell and spatial omics techniques will become even more important in the future. Furthermore, we emphasize the urgent need to include as yet understudied cell types and increase the diversity of studied populations.
Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Humanos , Diabetes Mellitus Tipo 2/genética , MultiômicaRESUMO
A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins, autoantibody, and complement. This uptake, mediated through CD21, triggered endosomal TLR7 and led to the secretion of interferon (IFN) α via an IRF5-dependent pathway. Blocking of FDC secretion of IFN-α restored B cell tolerance and reduced the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical source of the IFN-α driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in systemic lupus erythematosus.
Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Células Dendríticas Foliculares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Autoantígenos/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Interferon-alfa/biossíntese , Interferon-alfa/imunologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Reação em Cadeia da Polimerase , Receptor 7 Toll-Like/imunologia , TranscriptomaRESUMO
Antibodies to non-protein antigens such as nucleic acids, polysaccharides, and glycolipids play important roles in both host defense against microbes and development of autoimmune diseases. Although non-protein antigens are not recognized by T cells, antibody production to non-protein antigens involve T cell-independent mechanisms such as signaling through TLR7 and TLR9 in antibody production to nucleic acids. Although self-reactive B cells are tolerized by various mechanisms including deletion, anergy, and receptor editing, T cell tolerance is also crucial in self-tolerance of B cells to protein self-antigen because self-reactive T cells induce autoantibody production to these self-antigens. However, presence of T cell-independent mechanism suggests that T cell tolerance is not able to maintain B cell tolerance to non-protein self-antigens. Lines of evidence suggest that B cell response to non-protein self-antigens such as nucleic acids and gangliosides, sialic acid-containing glycolipids, are suppressed by inhibitory B cell co-receptors CD72 and Siglec-G, respectively. These inhibitory co-receptors recognize non-protein self-antigens and suppress BCR signaling induced by these antigens, thereby inhibiting B cell response to these self-antigens. Inhibitory B cell co-receptors appear to be involved in B cell self-tolerance to non-protein self-antigens that can activate B cells by T cell-independent mechanisms.
Assuntos
Doenças Autoimunes , Receptores de Antígenos de Linfócitos B , Linfócitos B , Humanos , Tolerância Imunológica , Tolerância a Antígenos PrópriosRESUMO
The recognition of pathogen-associated nucleic acid (NA) promotes effective immunity against invading pathogens. However, endosomal Toll-like receptor (TLR) activation by self-NA also underlies the pathogenesis of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). For this reason, the activation thresholds of NA-sensing TLRs must be tightly regulated to balance protective and pathogenic immune responses. In this study, we will provide an overview of the evolutionary mechanisms designed to limit the aberrant activation of endosomal TLRs by self-ligands, focusing on four broad strategies. These include the following: 1) the production of nucleases able to degrade self-DNA and RNA; 2) the cell-specific regulation of endosomal TLR expression; 3) the spatial and temporal control of TLR positioning at a sub-cellular level; and 4) the modulation of downstream TLR signaling cascades. Given the critical role of B cells in lupus pathogenesis, where possible, we will describe evidence for B cell-specific induction of these regulatory mechanisms. We will also highlight our own work showing how modulation of B cell endolysosomal flux tunes NA-sensing TLR activation signals. In the face of inevitable generation of self-NA during normal cellular turnover, these parallel mechanisms are vital to protect against pathogenic inflammation.
Assuntos
Linfócitos B , Receptores Toll-Like , Linfócitos B/imunologia , Endossomos/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Transdução de Sinais , Receptores Toll-Like/metabolismoRESUMO
Using data from single-cell RNA sequencing and flow cytometry, we initially examined the expression of FCRL3, finding it to be elevated and positively associated with TIGIT expression in the regulatory T cells of patients with systemic lupus erythematosus. This also suggests that the co-expression of FCRL3 and TIGIT warrants further attention.
Assuntos
Lúpus Eritematoso Sistêmico , Receptores Imunológicos , Linfócitos T Reguladores , Humanos , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/genética , Linfócitos T Reguladores/imunologia , Regulação para Cima/imunologia , Feminino , Masculino , AdultoRESUMO
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune-mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B-lymphoma-2 (BCL-2) family and interferon-induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL-15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL-2 family and ISGs. Further, treatment with ABT-263 (a senolytic BCL-2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L-PD-1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T-bet+ age-related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL-2 inhibitor ABT-263 may be the potential treatment in ameliorating lupus phenotypes.
Assuntos
Linfócitos T CD4-Positivos , Senescência Celular , Lúpus Eritematoso Sistêmico , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Senescência Celular/imunologia , Senescência Celular/efeitos dos fármacos , Sulfonamidas/farmacologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Adulto , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Camundongos Endogâmicos MRL lpr , Pessoa de Meia-Idade , Masculino , Senoterapia/farmacologiaRESUMO
Langerhans cells (LCs) are the key antigen-presenting cells in the epidermis in normal conditions and respond differentially to environmental and/or endogenous stimuli, exerting either proinflammatory or anti-inflammatory effects. Current knowledge about LCs mainly originates from studies utilizing mouse models, whereas with the development of single-cell techniques, there has been significant progress for human LCs, which has updated our understanding of the phenotype, ontogeny, differentiation regulation, and function of LCs. In this review, we delineated the progress of human LCs and summarized LCs' function in inflammatory skin diseases, providing new ideas for precise regulation of LC function in the prevention and treatment of skin diseases.