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Single-cell technologies — studying rheumatic diseases one cell at a time

Abstract

Cells, the basic units of life, have striking differences at transcriptomic, proteomic and epigenomic levels across tissues, organs, organ systems and organisms. The coordination of individual immune cells is essential for the generation of effective immune responses to pathogens while immune tolerance is maintained to protect the host. In rheumatic diseases, when immune responses are dysregulated, pathologically important cells might represent only a small fraction of the immune system. Interrogation of the contributions of individual immune cells to pathogenesis and disease progression should therefore reveal important insights into the complicated aetiology of rheumatic diseases. Technological advances are enabling the high-dimensional dissection of single cells at multiple omics levels, which could facilitate the identification of dysregulated molecular mechanisms in patients with rheumatic diseases and the discovery of new therapeutic targets and biomarkers. The single-cell technologies that have been developed over the past decade and the experimental platforms that enable multi-omics integrative analyses have already made inroads into immunology-related fields of study and have potential for use in rheumatology. Layers of omics data derived from single cells are likely to fundamentally change our understanding of the molecular pathways that underpin the pathogenesis of rheumatic diseases.

Key points

  • Many analytical platforms are available for the quantitative analyses of the genome, epigenome, transcriptome and proteome of single cells, although these technologies have not been fully exploited in rheumatology research.

  • Single-cell RNA sequencing facilitates the simultaneous interrogation of the transcriptome of thousands of cells and transcript-based analyses of paired antigen receptor sequences.

  • Mass cytometry enables the deep immunophenotyping and functional characterization of protein markers that, when coupled with mass spectrometry imaging, provide information on the spatial relationships between molecules.

  • Many analytical platforms have been developed to investigate different layers of epigenomic regulation in single cells, including DNA methylation, histone modifications, chromatin accessibility and chromatin conformation.

  • High-dimensional multi-omics analyses enable the direct comparison of DNA, RNA and proteins and/or the epigenome in individual cells and offer great potential for understanding rheumatic diseases.

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Fig. 1: Single-cell experimental platforms for omics analysis.
Fig. 2: Methods to simultaneously perform genomic, transcriptomic and epigenomic analysis.
Fig. 3: Methods to simultaneously perform nucleic acid and protein marker analysis.

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Acknowledgements

The authors thank the Autoimmunity Centers of Excellence (5U19AI110491-04 and 5UM1A110498-04), a research consortium supported by grants from the US National Institute of Allergy and Infectious Diseases (to P.J.U.), the Donald E. and Delia B. Baxter Foundation (to P.J.U.), E. F. Adler (to P.J.U.), the Henry Gustav Floren Trust (to P.J.U.) and the US NIH (5R01AI125197-02 to P.J.U. and P.K.).

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Nature Reviews Rheumatology thanks F. Mizoguchi, V. Malmström and K. Wei for their contribution to the peer review of this work.

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A.J.K. and P.C. researched data for the article and provided a substantial contribution to discussion of content. All authors wrote and reviewed or edited the article before submission.

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Cheung, P., Khatri, P., Utz, P.J. et al. Single-cell technologies — studying rheumatic diseases one cell at a time. Nat Rev Rheumatol 15, 340–354 (2019). https://doi.org/10.1038/s41584-019-0220-z

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