Single-cell transcriptome landscape of circulating CD4+ T cell populations in autoimmune diseases

Yasumizu, Yoshiaki; Takeuchi, Daiki; Morimoto, Reo; Takeshima, Yusuke; Okuno, Tatsusada; Kinoshita, Makoto; Morita, Takayoshi; Kato, Yasuhiro; Wang, Min; Motooka, Daisuke; Okuzaki, Daisuke; Nakamura, Yamami; Mikami, Norihisa; Arai, Masaya; Zhang, Xuan; Kumanogoh, Atsushi; Mochizuki, Hideki; Ohkura, Naganari; Sakaguchi, Shimon

doi:10.1016/j.xgen.2023.100473

Cited by 13 publications

(7 citation statements)

References 108 publications

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“…However, CXCR5 -PDCD1 + T peripheral helper (Tph) cells, observed at inflammatory sites in rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome [31][32][33] , were not clearly identified as distinct cell populations in our single-cell analysis. While our study and others have reported an increase in circulating Tph cells in MG, these results were contrary to our expectation 2,34 . Additionally, effector Tregs were also observed to be abundant in the medulla of MG thymoma.…”

Section: Discussioncontrasting

confidence: 99%

“…Myasthenia gravis (MG) is an autoimmune disease that causes systemic muscle weakness due to the production of autoantibodies that target the neuromuscular junction. Similar to other autoimmune diseases, genome-wide association studies (GWAS) have identified MG as a polygenic disease, with variants associated with T cell and B cell functions 1,2 . MG is also associated with thymoma and thymic hyperplasia.…”

Section: Introductionmentioning

confidence: 99%

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Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

Yasumizu,

Kinoshita,

Zhang

et al. 2024

Preprint

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Myasthenia gravis (MG) is known to be epidemiologically associated with abnormalities of the thymus, an organ that maintains central tolerance. However, due to the complexity of the thymus, specific characteristics related to the pathogenesis of MG remain elusive. In our study, we attempted to narrow down the features associated with MG using spatial transcriptome analysis of thymoma and thymic hyperplasia samples. We found that the majority of thymomas were constituted by the cortical region, whereas the medullary region was localized in comparatively restricted areas. Moreover, the medullary region contained polygenic enrichment, MG-specific germinal center structures, and a supporting immune microenvironment. Additionally, neuromuscular medullary thymic epithelial cells (nmTECs), previously identified as MG-specific autoantigen-producing cells, were situated at the cortico-medullary junction. The immune microenvironment in the medulla was characterized by a specific chemokine pattern and specific immune cells, such as CCR7+ migratory dendritic cells (migDCs) and effector regulatory T (Treg) cells. Furthermore, similar germinal center structures and immune microenvironments were observed in the medulla during thymic hyperplasia. This study indicates that the medulla and junction areas are related to the pathology of MG, suggesting that these areas should be the focus of future studies on MG pathogenesis and drug targeting.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

Yasumizu,

Kinoshita,

Zhang

et al. 2024

Preprint

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“…Though CD4 + T cells are thought to play a central role in MS pathophysiology, limited changes were observed in the CD4 + T cell compartment using singleR, MonacoImmune, and manual cellular annotation methods. Therefore, we applied a recently developed framework that captures a more granular classification and qualitative assessment of CD4 + T cells based on scRNAseq data (Fig 6a) 31 . This novel framework assigned CD4 T cells into five major clusters (cluster Layer 1 or L1) and 18 minor clusters (cluster L2) by Symphony reference mapping (Fig 6b, Supplementary Fig 7a and 8a), and measured the activities of 12 pre-defined transcriptomic gene programs of CD4 + T cells using non-negative matrix factorization projection (NMFproj).…”

Section: Resultsmentioning

confidence: 99%

“…The PBMC and CSF data were processed using the pipeline developed in the previous study 31 to assign CD4 + T cell clusters. This pipeline employs Azimuth 37 for the extraction of CD4 + T cells and uses Symphony 66 for predicting CD4 + T cell clusters.…”

Section: Methodsmentioning

confidence: 99%

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Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis

Wei,

Moon,

Yasumizu

et al. 2024

Preprint

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Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven "in vivo perturbation" modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16+ monocytes increased in frequency post-B cell depletion. In addition, we observed increases in TNFa messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFa treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion also induced changes in peripheral CD4+ T cell populations, including increases in the frequency of TIGIT+ regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4+ T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.

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Single-cell analysis in rheumatic and allergic diseases: insights for clinical practice

Nishide,

Shimagami,

Kumanogoh

2024

Nat Rev Immunol

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Single-cell transcriptome landscape of circulating CD4+ T cell populations in autoimmune diseases

Cited by 13 publications

References 108 publications

Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis

Single-cell analysis in rheumatic and allergic diseases: insights for clinical practice

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