Consecutive mRNA vaccinations against SARS-CoV-2 reinforced both innate and adaptive immune responses. However, it remains unclear whether the enhanced innate immune responses are mediated by ...epigenetic regulation and, if so, whether these effects persist. Using mass cytometry, RNA-Seq, and ATAC-Seq, we show that BNT162b2 mRNA vaccination upregulated antiviral and IFN-stimulated gene expression in monocytes with greater effects after the second vaccination than those after the first vaccination. Transcription factor-binding motif analysis also revealed enriched IFN regulatory factors and PU.1 motifs in accessible chromatin regions. Importantly, although consecutive BNT162b2 mRNA vaccinations boosted innate immune responses and caused epigenetic changes in isolated monocytes, we show that these effects occurred only transiently and disappeared 4 weeks after the second vaccination. Furthermore, single-cell RNA-Seq analysis revealed that a similar gene signature was impaired in the monocytes of unvaccinated patients with COVID-19 with acute respiratory distress syndrome. These results reinforce the importance of the innate immune response in the determination of COVID-19 severity but indicate that, unlike adaptive immunity, innate immunity is not unexpectedly sustained even after consecutive vaccination. This study, which focuses on innate immune memory, may provide novel insights into the vaccine development against infectious diseases.
Objective
Idiopathic inflammatory myopathies (IIM) demonstrate characteristic clinical phenotypes depending on the myositis‐specific antibody (MSAs) present. We aimed to identify common or ...MSA‐specific immunological pathways in different immune cell types from peripheral blood by transcriptome analysis.
Methods
We recruited 33 patients with IIM who were separated into the following groups: 15 patients with active disease at onset and 18 with inactive disease under treatment. All patients were positive for MSAs: anti–melanoma differentiation‐associated gene 5 (MDA5) antibody (Ab) in 10 patients, anti‐Mi‐2 Ab in 7, and anti‐aminoacyl‐transfer RNA synthetase (ARS) Ab in 16. The patients were compared with 33 healthy controls. Twenty‐four immune cell types sorted from peripheral blood were analyzed by flow cytometry, RNA sequencing, and differentially expressed gene analysis combined with pathway analysis.
Results
The frequencies of memory B cell types were significantly decreased in active patients, and the frequency of plasmablasts was prominently increased in active patients with anti‐MDA5 Ab in comparison with healthy controls. The expression of type I interferon (IFN)‐stimulated genes of all immune cell types was increased in the active, but not inactive, patients. Endoplasmic reticulum stress‐related genes in all IIM memory B cells and oxidative phosphorylation‐related genes in inactive IIM double negative B cells were also increased, suggesting prominent B cell activation in IIM. Furthermore, active patients with anti‐MDA5 Ab, anti‐Mi‐2 Ab, or anti‐ARS Ab were distinguished by IFN‐stimulated and oxidative phosphorylation‐related gene expression in plasmablasts.
Conclusion
Unique gene expression patterns in patients with IIM with different disease activity levels and MSA types suggest different pathophysiologies. Especially, B cells may contribute to common and MSA‐specific immunological pathways in IIM.
The acute onset of idiopathic nephrotic syndrome (NS) is often accompanied by acute kidney injury, which can lead to congestive heart failure and lung edema. In this report, we present two cases of ...NS-induced acute kidney injury successfully treated with a low dose of carperitide, a human atrial natriuretic peptide. In combination with standard diuretic therapy and immunotherapy, carperitide retained the renal function and spared the need for renal replacement therapy, including hemodialysis. Although further investigation in clinical trials is required to validate these findings, carperitide may be useful for maintaining the renal function in cases of NS-induced acute kidney injury.
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.
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•Gene-regulation atlas of 28 immune cell types under immune-mediated diseases (IMDs)•Expression QTLs show immune cell-type and disease context specificity•Cellular pathways diversify eQTL effects under in vivo disease conditions•This atlas links IMD GWAS variants to susceptible genes, cell types, and environment
The gene-regulation atlas of 28 immune cell types was constructed with immune-mediated disease patient samples and shows the dynamics of gene regulation depending on cell types and immunological conditions.
Immunological disturbances have been reported in systemic sclerosis (SSc). This study assessed the transcriptome disturbances in immune cell subsets in SSc and characterized a disease-related gene ...network module and immune cell cluster at single cell resolution.
Twenty-one Japanese SSc patients were enrolled and compared with 13 age- and sex-matched healthy controls (HC). Nineteen peripheral blood immune cell subsets were sorted by flow cytometry and bulk RNA-seq analysis was performed for each. Differential expression and pathway analyses were conducted. Iterative weighted gene correlation network analysis (iWGCNA) of each subset revealed clustered co-expressed gene network modules. Random forest analysis prioritized a disease-related gene module. Single cell RNA-seq analysis of 878 monocytes was integrated with bulk RNA-seq analysis and with a public database for single cell RNA-seq analysis of SSc patients.
Inflammatory pathway genes were differentially expressed in widespread immune cell subsets of SSc. An inflammatory gene module from CD16+ monocytes, which included KLF10, PLAUR, JUNB and JUND, showed the greatest discrimination between SSc and HC. One of the clusters of SSc monocytes identified by single-cell RNA-seq analysis characteristically expressed these inflammatory co-expressed genes and was similar to lung infiltrating FCN1hi monocytes expressing IL1B.
Our integrated analysis of bulk and single cell RNA-seq analysis identified an inflammatory gene module and a cluster of monocytes that are relevant to SSc pathophysiology. They could serve as candidate novel therapeutic targets in SSc.
•An inflammatory gene module of CD16+ monocytes discriminated systemic sclerosis.•A clusters of SSc monocytes characteristically expressed these co-expressed genes.•They were similar to lung infiltrating FCN1hi monocytes expressing IL1B.•The gene module and monocytes could serve as novel therapeutic targets.
Abstract
Objectives
We evaluated flow-cytometric and transcriptome features of peripheral blood immune cells from early-phase (disease duration <5 years) SSc in comparison with late-phase SSc.
...Methods
Fifty Japanese patients with SSc (12 early SSc cases and 38 late SSc cases) and 50 age- and sex-matched healthy controls were enrolled. A comparison of flow-cytometric subset proportions and RNA-sequencing of 24 peripheral blood immune cell subsets was performed. We evaluated differentially expressed genes (DEGs), characterized the co-expressed gene modules, and estimated the composition of subpopulations by deconvolution based on single-cell RNA-sequencing data. As a disease control, idiopathic inflammatory myositis (IIM) patients were also evaluated.
Results
Analysing the data from early and late SSc, fraction II effector regulatory T cell (Fr. II eTreg) genes showed a remarkable differential gene expression, enriched for genes related to oxidative phosphorylation. Although the flow-cytometric proportion of Fr. II eTregs was not changed in early SSc, deconvolution indicated expansion of the activated subpopulation. Co-expressed gene modules of Fr. II eTregs demonstrated enrichment of the DEGs of early SSc and correlation with the proportion of the activated subpopulation. These results suggested that DEGs in Fr. II eTregs from patients with early SSc were closely associated with the increased proportion of the activated subpopulation. Similar dysregulation of Fr. II eTregs was also observed in data from patients with early IIM.
Conclusions
RNA-seq of immune cells indicated the dysregulation of Fr. II eTregs in early SSc with increased proportion of the activated subpopulation.
Almost 160 years after the discovery of mitochondria, they are known for their production of energy and are called "the powerhouse of the cell". Recently, immune-metabolism has been revealed as a key ...factor controlling immune cell proliferation and differentiation. Resting lymphocytes generate energy through oxidative phosphorylation and fatty acid oxidation, whereas activated lymphocytes rapidly shift to glycolysis. Oxidative phosphorylation (OXPHOS) as well as mitochondrial reactive oxygen species (mtROS) generated through the electron transport chain (ETC) are involved in many immune cell functions. Moreover, mitochondria are dynamic organelles that can provide immunogenic molecules, such as mitochondrial DNA (mtDNA) resulting in innate immune system activation. Here, we describe the role of mitochondria in immune system regulation, highlighting metabolism-dependent and other immunogenic aspects.
CD4+ T cells are key mediators of various autoimmune diseases; however, their role in disease progression remains unclear due to cellular heterogeneity. Here, we evaluated CD4+ T cell subpopulations ...using decomposition-based transcriptome characterization and canonical clustering strategies. This approach identified 12 independent gene programs governing whole CD4+ T cell heterogeneity, which can explain the ambiguity of canonical clustering. In addition, we performed a meta-analysis using public single-cell datasets of over 1.8 million peripheral CD4+ T cells from 953 individuals by projecting cells onto the reference and cataloging cell frequency and qualitative alterations of the populations in 20 diseases. The analyses revealed that the 12 transcriptional programs were useful in characterizing each autoimmune disease and predicting its clinical status. Moreover, genetic variants associated with autoimmune diseases showed disease-specific enrichment within the 12 gene programs. The results collectively provide a landscape of single-cell transcriptomes of CD4+ T cell subpopulations involved in autoimmune disease.
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•Identified 18 cell types and 12 gene programs from blood CD4+ T cells•Meta-analysis enrolling 1.8M cells outlines CD4+ T alterations in autoimmune diseases•Observed disease-specific heritability enrichment within CD4+ T cell gene programs
Yasumizu, Takeuchi, Morimoto, et al. compile a comprehensive reference of circulating CD4+ T cells, encompassing 12 gene programs and 18 clusters. They reveal disease-specific cellular characteristics through the integration of genome-wide association studies and single-cell meta-analysis. This work provides insights for precision medicine.
The importance of cellular metabolism has long been known as Warburg effect; cancer cells are characterized by mitochondrial defect that shifts towards aerobic glycolysis. Recently, many reports ...have revealed that immune metabolism is a key factor for controlling immune cell proliferation and differentiation. Resting lymphocytes generate energy through oxidative phosphorylation and fatty acid oxidation, whereas activated lymphocytes rapidly shift to glycolysis. Especially in T cells, more precise mechanism of regulating metabolism have been clarified on differentiation from naïve T cells to effector T cells. Similar studies have also been carried out to characterize B cell and myeloid cell metabolism. Metabolic regulation is considered to be particularly important in autoimmune diseases. Metabolic changes in these diseases might not only reflect the chronic activated immune-status but also associated with their pathogenesis. Here, we review what is known on the altered metabolism in systemic lupus erythematosus (SLE), mainly focusing on T cells and B cells, and how they contribute to SLE pathogenesis. We also discuss how immune metabolic defects can become targets of future SLE therapy.
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