Single-cell transcriptomics reveals peripheral immune responses in anti-synthetase syndrome-associated interstitial lung disease
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ABSTRACT:
PROVIDER: PRJNA787316 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17173429_1.fastq.gz | Fastqsanger.gz | |||
| SRR17173429_2.fastq.gz | Fastqsanger.gz | |||
| SRR17173430_1.fastq.gz | Fastqsanger.gz | |||
| SRR17173430_2.fastq.gz | Fastqsanger.gz | |||
| SRR17173431_1.fastq.gz | Fastqsanger.gz |
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Project description:Objective: Interstitial lung diseases (ILDs) secondary to anti-synthetase syndrome (ASS) greatly influence the prognoses of patients with ASS. Here we aimed to investigate the peripheral immune responses to understand the pathogenesis of this condition. Methods: We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from 5 patients with ASS-ILD and 3 healthy donors (HDs). Flow cytometry of PBMCs was performed to replenish the results of scRNA-seq. Results: We used scRNA-seq to depict a high-resolution visualization of cellular landscape in PBMCs from patients with ASS-ILD. Patients showed upregulated interferon responses among all cell types. And the ratio of effector memory CD8 T cells to naïve CD8 T cells was significantly higher than that in HDs. Additionally, Th1, Th2, and Th17 cell differentiation signaling pathways were enriched in T cells, and antigen processing and presentation was enhanced in NK cells. Flow cytometry analyses showed increased proportions of Th17 cells and Th2 cells, and decreased proportion of Th1 cells in patients with ASS-ILD when compared with HDs. Conclusions: Our study reveals that ASS-ILD is characterized by upregulated interferon responses, altered CD8 T cell homeostasis, involvement of differentiation signaling pathways of CD4 T cells, and enhanced antigen processing and presentation ability in NK cells by scRNA-seq data. And the proportions of Th17 cells and Th2 cells are higher in patients with ASS-ILD than those in HDs using flow cytometry, while the proportion of Th1 cells is lower. These findings may provide foundations of novel therapeutic targets for patients with this condition.
2021-12-10 | GSE190510 | GEO
Project description:ObjectiveInterstitial lung diseases (ILDs) secondary to anti-synthetase syndrome (ASS) greatly influence the prognoses of patients with ASS. Here we aimed to investigate the peripheral immune responses to understand the pathogenesis of this condition.MethodsWe performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from 5 patients with ASS-ILD and 3 healthy donors (HDs). Flow cytometry of PBMCs was performed to replenish the results of scRNA-seq.ResultsWe used scRNA-seq to depict a high-resolution visualization of cellular landscape in PBMCs from patients with ASS-ILD. Patients showed upregulated interferon responses among NK cells, monocytes, T cells, and B cells. And the ratio of effector memory CD8 T cells to naïve CD8 T cells was significantly higher in patients than that in HDs. Additionally, Th1, Th2, and Th17 cell differentiation signaling pathways were enriched in T cells. Flow cytometry analyses showed increased proportions of Th17 cells and Th2 cells, and decreased proportion of Th1 cells in patients with ASS-ILD when compared with HDs, evaluated by the expression patterns of chemokine receptors.ConclusionsThe scRNA-seq data analyses reveal that ASS-ILD is characterized by upregulated interferon responses, altered CD8 T cell homeostasis, and involvement of differentiation signaling pathways of CD4 T cells. The flow cytometry analyses show that the proportions of Th17 cells and Th2 cells are increased and the proportion of Th1 cells is decreased in patients with ASS-ILD. These findings may provide foundations of novel therapeutic targets for patients with this condition.
| S-EPMC8891123 | biostudies-literature
Project description:Background: A 58-year-old male with anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD) underwent bilateral lung transplantation (LTx) but experienced ILD progression and myositis worsening 38 weeks post-transplant, despite glucocorticoids, tacrolimus, and mycophenolic acid treatment. High-dose glucocorticoids led to adverse effects and ILD exacerbation upon tapering. Objective: To identify persistent inflammatory pathways despite anti-rejection therapy. Methods: Two sets of single-cell RNA-seq (scRNA-seq) analyses were conducted on peripheral blood mononuclear cells (PBMCs) from our patient who experienced recurrent ASS-ILD following bilateral LTx: one before regimen adjustment and one after. The goal these analyses is to investigate systemic inflammatory profiles. Results: In comparison to five ASS-ILD patients without LTx, our patient following bilateral LTx (before regimen adjustment) displayed a higher proportion of CD14⁺ and CD16⁺ monocytes, alongside reduced T, B, and NK cells. Notably, interferon- and JAK-STAT–associated pathways were significantly enriched, as evidenced by marked up-regulation of key genes (e.g. JAK1, JAK2, STAT1, STAT2, STAT3, IL4R, IL6R) in the patient’s monocytes. Elevated serum ferritin levels and the enrichment of macrophage and neutrophil activation pathways further underscored hyperactivation of the mononuclear phagocyte system. Due to poor tolerance of high-dose steroids, limited efficacy of tacrolimus and MPA, and the need to manage post-transplant rejection while controlling ASS, the patient’s regimen was modified. Considering the activation of the mononuclear phagocyte system in the patient, tacrolimus was replaced with cyclosporine A, which is more widely used in macrophage activation syndrome (target trough concentration 120-150 ng/ml). Given the significant activation of the interferon and JAK-STAT pathways in the patient’s activated monocytes, we replaced EC-MPS with the Janus kinase inhibitor (JAKi) tofacitinib at 5 mg twice daily. Short-term high-dose glucocorticoids (methylprednisolone 120 mg/d for 3 days) were also administered before rapid tapering. After regimen adjustment, scRNA-seq was conducted again, which indicated a reduction in CD14⁺ and CD16⁺ monocytes, with T, B, and NK cells rebounding. Neutrophils, characterized by high S100A8, S100A9, and DEFA3 expression, became more prominent. Interferon-related gene expression decreased in monocytes and neutrophils, indicating successful suppression of the interferon pathway. Conclusions: We presented a complicated case of a patient with early recurrence of underlying ASS-ILD after bilateral lung transplantation. We used two sets of scRNA-seq analyses to investigate the systemic inflammatory responses.
2025-01-09 | GSE286228 | GEO
Project description:Background: A 58-year-old male with anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD) underwent bilateral lung transplantation (LTx) but experienced ILD progression and myositis worsening 38 weeks post-transplant, despite glucocorticoids, tacrolimus, and mycophenolic acid treatment. High-dose glucocorticoids led to adverse effects and ILD exacerbation upon tapering. Objective: To identify persistent inflammatory pathways despite anti-rejection therapy. Methods: 10X Visium HD spatial transcriptomic analysis was conducted on lung tissues from two distinct patients: one untreated patient with ASS-ILD without LTx serving as a control, and another patient who experienced bilateral LTx. This analysis aims to investigate the inflammatory profiles within the lung tissues and to explore the correlation between pulmonary lesions and systemic inflammation. Results: In comparison to the control patient, the lung tissue from the post-transplant patient appeared to have an increased proportion of macrophages, with a concurrent decrease in the proportions of plasma cells and T cells. Among the macrophages of interest, the post-transplant patient appeared to have an elevated proportion of alveolar macrophages, whereas the control patient seemed to have a larger proportion of monocyte-derived macrophages. Considering that interstitial pneumonia is often driven by alveolar epithelial cell injury, we observed that the post-transplant patient appeared to have a higher proportion of transitional AT2 cells, which were appeared to express both AT2-specific markers (SFTPC, SFTPD) and AT1-specific markers (AGER, RTKN2, GPRC5A). Conclusions: We presented a complicated case of a patient with early recurrence of underlying ASS-ILD after bilateral LTx. We used spatial transcriptomic analysis to investigate the differences between systemic inflammatory responses and lung tissue responses.
2025-01-09 | GSE286227 | GEO
Project description:Heterozygous mutations in six tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT-mutant glycyl- or tyrosyl-tRNA synthetases inhibit global protein synthesis by an unknown mechanism, independent of aminoacylation activity. We report that tRNAGly overexpression rescues protein synthesis and peripheral neuropathy phenotypes in Drosophila and mouse models of CMT caused by glycyl-tRNA synthetase (GlyRS) mutations (CMT2D). Kinetic experiments revealed that CMT-mutant GlyRS bind tRNAGly, but display markedly slow release rates. This tRNAGly sequestration may deplete the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome and translation deficit.
2021-09-07 | GSE160584 | GEO
Project description:Anti-synthetase syndrome (ASS), a subtype of idiopathic inflammatory myopathy (IMM), is characterized by distinctive skin rashes, proximal muscle weakness, and interstitial lung disease (ILD). The etiology of ASS remains largely unknown, and patients endure a poor quality of life and are prone to pulmonary infection. Recent studies have highlighted the potential role of aberrant glycosylation of immunoglobulin G (IgG) in the development of autoimmune diseases. However, the specific N-glycosylation patterns of IgG in ASS have not yet been fully elucidated. In this study, we employed GlycoQuant, a method for intact glycopeptide analysis, to investigate the intact N-glycopeptides of IgG from 30 ASS patients and 30 healthy controls (HC). Our analysis revealed 13 differentially expressed intact N-glycopeptides in ASS. Furthermore, we observed a significant increase in fucose alongside a marked decrease in N-acetylneuraminic acid levels among ASS patients. Crucially, alterations in IgG N-glycosylation correlated with the disease severity. In conclusion, this study provides a thorough overview of IgG N-glycosylation patterns in ASS, laying a solid foundation for future research in this area.
2024-11-20 | PXD058077 |
Project description:BackgroundRecognition of Anti-tRNA synthetase (ARS) related interstitial lung disease (ILD) is key to ensuring patients have prompt access to immunosuppressive therapies. The purpose of this retrospective cohort study was to identify factors that may delay recognition of ARS-ILD.MethodsPatients seen at Vanderbilt University Medical Center between 9/17/2017-10/31/2018 were included in this observational cohort. Clinical and laboratory features were obtained via chart abstraction. Kruskal-Wallis ANOVA, Mann-Whitney U, and Fisher's exact t tests were utilized to determine statistical significance.ResultsPatients with ARS were found to have ILD in 51.9% of cases, which was comparable to the frequency of ILD in systemic sclerosis (59.5%). The severity of FVC reduction in ARS (53.2%) was comparable to diffuse cutaneous systemic sclerosis (56.8%, p = 0.48) and greater than dermatomyositis (66.9%, p = 0.005) or limited cutaneous systemic sclerosis (71.8%, p = 0.005). Frank honeycombing was seen with ARS antibodies but not other myositis autoantibodies. ARS patients were more likely to first present to a pulmonary provider in a tertiary care setting (53.6%), likely due to fewer extrapulmonary manifestations. Only 33% of ARS-ILD were anti-nuclear antibody, rheumatoid factor, or anti-cyclic citrullinated peptide positive. Patients with ARS-ILD had a two-fold longer median time to diagnosis compared to other myositis-ILD patients (11.0 months, IQR 8.5-43 months vs. 5.0 months, IQR 3.0-9.0 months, p = 0.003).ConclusionsARS patients without prominent extra-pulmonary manifestations are at high risk for not being recognized as having a connective tissue disease related ILD and miscategorized as usual interstitial pneumonia/idiopathic pulmonary fibrosis without comprehensive serologies.
| S-EPMC8566329 | biostudies-literature
Project description:tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase
| PRJNA673697 | ENA
Project description:Interstitial cystitis (IC) and bladder pain syndrome are terms used to describe a heterogenous chronic pelvic and bladder pain disorder of unknown etiology. The goal of this pilot study was to determine if gene expression profiling of bladder biopsy tissue from patients experiencing symptoms could be used to separate the patients based on some clinical parameter.
2014-05-13 | GSE57560 | GEO
Project description:Anti-synthetase syndrome (AS) is a rare autoimmune disorder characterized by the presence of aminoacyl-transfer RNA synthetase antibodies in conjunction with clinical features such as interstitial lung disease (ILD), Raynaud's phenomenon, nonerosive arthritis, and myopathy. AS distinguishes itself from other inflammatory myopathies by its significant lung involvement and rapidly progressive interstitial lung disease (AS-ILD), therefore the management of AS-ILD requires careful clinical, serologic and radiologic assessment. Glucocorticoids are considered the mainstay of therapy; however, additional immunosuppressive agents are often required to achieve disease control. Patient prognosis is highly dependent on early diagnosis and symptom recognition as the antibody profile is thought to influence therapy response. Since progressive ILD is the leading cause of morbidity and mortality, this review will discuss the clinical approach to patient with suspected AS, with particular emphasis on diagnosis and management of AS-ILD.
| S-EPMC8482343 | biostudies-literature