Transcriptomes of peripheral blood mononuclear cells from juvenile dermatomyositis patients show elevated inflammation even when clinically inactive

Roberson, Elisha D.O.; Mesa, Rosana; Morgan, Gabrielle; Cao, Li; Marin, Wilfredo; Pachman, Lauren M

doi:10.1038/s41598-021-04302-8

Cited by 16 publications

(25 citation statements)

References 63 publications

(65 reference statements)

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“…As previously reported (8,9), juvenile DM patients had a markedly distinctive transcriptional signature. Juvenile DM patients had 1,426 differentially expressed genes compared with healthy controls ( P ≤ 0.05).…”

Section: Resultssupporting

confidence: 81%

“…Thus, whether Th2 cells play a pathogenic role in juvenile DM or they expand in response to muscle damage remains to be addressed. Importantly, expansion of CXCR5 low/− CM B cells correlated with increased ISG transcriptional expression, a known feature of juvenile DM (8,9); therefore we tried to dissect this further. The type I ISG signature has been previously found to correlate with measures of global and muscle DA and is thought to drive pathology (8,39).…”

Section: Discussionmentioning

confidence: 99%

“…Inflammatory infiltrates in affected muscle tissue from juvenile DM patients include B cells, CD4+ and CD8+ T cells, and dendritic cells (DCs) (7). Gene expression profiling of juvenile DM blood and muscle tissue highlights the prevalent expression of interferon (IFN)-stimulated genes (ISGs) associated with muscle DA (8,9). Yet, detailed understanding of the interaction between the IFN signal and immune cell types remains limited.…”

Section: Introductionmentioning

confidence: 99%

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Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers

Gofshteyn

Mansfield

Spitznagle

et al. 2023

Arthritis & Rheumatology

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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 (CXCR5 low/-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 CXCR5 low/-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 CXCR5 low/-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.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers

Gofshteyn

Mansfield

Spitznagle

et al. 2023

Arthritis & Rheumatology

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“…This is the first study to utilize RNAseq on multiple sorted immune cell subsets to compare differential upregulated and downregulated gene expression in NK, B, and T cells from new-onset JDM patients and healthy pediatric controls. The only four prior published RNAseq studies in JDM that we are aware of include a study of total PBMCs from JDM patients ( 55 ), plasma exomes from JDM patients ( 56 ), study of B cells of JDM patients ( 8 ), and a comparison of JDM treatment responders vs non-responders ( 57 ). While these studies have mainly explored JDM PBMC transcription as a whole (with the exception of the study focused on B cells), we chose to compare highly enriched sorted lymphocyte subsets to gain further insight into JDM pathogenesis by delineating the role of each of these subsets at the transcript level.…”

Section: Discussionmentioning

confidence: 99%

Expansion of a novel population of NK cells with low ribosome expression in juvenile dermatomyositis

Hilliard

Throm²,

Pingel³

et al. 2022

Front. Immunol.

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Juvenile dermatomyositis (JDM) is a pediatric autoimmune disease associated with characteristic rash and proximal muscle weakness. To gain insight into differential lymphocyte gene expression in JDM, peripheral blood mononuclear cells from 4 new-onset JDM patients and 4 healthy controls were sorted into highly enriched lymphocyte populations for RNAseq analysis. NK cells from JDM patients had substantially greater differentially expressed genes (273) than T (57) and B (33) cells. Upregulated genes were associated with the innate immune response and cell cycle, while downregulated genes were associated with decreased ribosomal RNA. Suppressed ribosomal RNA in JDM NK cells was validated by measuring transcription and phosphorylation levels. We confirmed a population of low ribosome expressing NK cells in healthy adults and children. This population of low ribosome NK cells was substantially expanded in 6 treatment-naïve JDM patients and was associated with decreased NK cell degranulation. The enrichment of this NK low ribosome population was completely abrogated in JDM patients with quiescent disease. Together, these data suggest NK cells are highly activated in new-onset JDM patients with an increased population of low ribosome expressing NK cells, which correlates with decreased NK cell function and resolved with control of active disease.

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“…We found that some of the significantly enriched GO terms have been mentioned in the context of other infectious diseases. In the microarray example, we selected the biological process GO:0002483 which was also found enriched in a study on juvenile dermatomyositis [ 34 ], which is supposed to be caused by viruses and can involve inflammation of the lung. The cellular component of phagocytic vesicles (GO:0045335) was also mentioned in the context of SARS-CoV-2 infection and pulmonary fibrosis [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Augmentation of Transcriptomic Data for Improved Classification of Patients with Respiratory Diseases of Viral Origin

Kircher¹,

Chludzinski²,

Krepel³

et al. 2022

IJMS

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To better understand the molecular basis of respiratory diseases of viral origin, high-throughput gene-expression data are frequently taken by means of DNA microarray or RNA-seq technology. Such data can also be useful to classify infected individuals by molecular signatures in the form of machine-learning models with genes as predictor variables. Early diagnosis of patients by molecular signatures could also contribute to better treatments. An approach that has rarely been considered for machine-learning models in the context of transcriptomics is data augmentation. For other data types it has been shown that augmentation can improve classification accuracy and prevent overfitting. Here, we compare three strategies for data augmentation of DNA microarray and RNA-seq data from two selected studies on respiratory diseases of viral origin. The first study involves samples of patients with either viral or bacterial origin of the respiratory disease, the second study involves patients with either SARS-CoV-2 or another respiratory virus as disease origin. Specifically, we reanalyze these public datasets to study whether patient classification by transcriptomic signatures can be improved when adding artificial data for training of the machine-learning models. Our comparison reveals that augmentation of transcriptomic data can improve the classification accuracy and that fewer genes are necessary as explanatory variables in the final models. We also report genes from our signatures that overlap with signatures presented in the original publications of our example data. Due to strict selection criteria, the molecular role of these genes in the context of respiratory infectious diseases is underlined.

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Transcriptomes of peripheral blood mononuclear cells from juvenile dermatomyositis patients show elevated inflammation even when clinically inactive

Cited by 16 publications

References 63 publications

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers

Expansion of a novel population of NK cells with low ribosome expression in juvenile dermatomyositis

Augmentation of Transcriptomic Data for Improved Classification of Patients with Respiratory Diseases of Viral Origin

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