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Abstract Number: 2741

Integration of Single Cells from Inflammatory Disease Tissues Reveals Common and Unique Pathogenic Cell States

Fan Zhang1, Joseph Mears 1, ilya Korsunsky 1, Kevin Wei 2, Anna Helena Jonsson 2, Deepak Rao 1, Edy Kim 3, Laura Donlin 4, Jill Buyon 5, Michelle Petri 6, Chaim Putterman 7, Thomas Tuschl 8, Nir Hacohen 9, Betty Diamond 10, Michael Brenner 11 and Soumya Raychaudhuri 1, 1Brigham and Women's Hospital, Boston, MA, 2Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 3Brigham and Women's Hospital, Boton, MA, 4Hospital For Special Surgery, New York, NY, 5New York University School of Medicine, New York, NY, 6Johns Hopkins University School of Medicine, Baltimore, MD, 7Albert Einstein College of Medicine, New York, NY, 8Rockefeller Research Laboratories, New York, 9Broad Institute, Cambridge, 10Feinstein Institutes for Medical Research, Manhasset, 11Brigham and Women’s Hospital:, Boston

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: autoimmune diseases, Immunogenetics and Gene Expression, Lupus nephritis, rheumatoid arthritis, synovium

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Session Information

Date: Tuesday, November 12, 2019

Session Title: 5T088: Genetics, Genomics & Proteomics (2738–2743)

Session Type: ACR Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Different autoimmune diseases can co-exist in an individual and share similar genetic associations, autoimmune signaling pathways, and clinical manifestations. However, autoimmune diseases present varied cellular heterogeneities and may be distinguished by their primary target organs or tissues. The immune mechanisms that are shared between similar autoimmune diseases remain poorly understood due to limited access to affected human tissues and computational scalability. Recently, high resolution single-cell RNA-seq profiles have provided the opportunity for study of the contribution of diverse cell populations to disease pathogenesis. This advance has enabled unbiased comparison of disease across affected tissues with the goal of understanding autoimmune similarities.

Methods: We have analyzed and integrated ~80,000 cells from 176 donors from publicly available single-cell RNA-seq datasets generated from rheumatoid arthritis (RA) and osteoarthritis (OA) synovium1, pulmonary fibrosis and healthy lung, systemic lupus erythematosus (SLE) and healthy kidney and skin2,3, inflammatory bowel disease (IBD) and healthy colon, and Crohn intestinal mucosal biopsies. We use a robust integrative strategy4 to cluster and project all the cells into two dimensional-space by correcting technical batch effect across tissue, donor, and single-cell platform (10X Genomics, Celseq2, Dropseq, Fluidigm, and Smartseq).

Results: We identify 21 diverse cell type populations across multiple tissue sources (Figure 1A). In the myeloid cell population, we observed four distinct subsets including VSIG4+ M2-like macrophages, S100A8+ macrophages, SPP1+ MMP9+ inflammatory macrophages, and dendritic cells (DC). The SPP1+ MMP9+ inflammatory macrophage population with high expression of matrix metalloproteinases genes is co-localized between macrophages in RA synovium, SLE kidney, and alveolar from pulmonary fibrosis lung, and is absent in healthy lung tissue (Figure 1B). For CD8 T cells and nature killer cells, we identified a shared transcriptional gradient of granzyme-expressing cytotoxic effectors between RA synovium, SLE kidney, and fibrotic lung. Interestingly, the GzmK+ CD8 T cell population is absent in the healthy lung (Figure 1C). The patterns of cytotoxic effector states may suggest similarities between the primary sites of inflamed RA and inflamed fibrotic lung, including potential common active pathways. In the stromal cell compartment, we observed distinct populations across different diseases and tissues, including fibroblasts, pericytes, mesangial, and tubular cells.

Conclusion: We demonstrate that integrative analyses between disease tissues by single-cell transcriptomics is capable to discovering shared and unique disease-specific gene expression modules and cell states, and may help predict potential therapeutic targets for inflammatory and fibrotic diseases.

Reference

  1. Zhang, F. et al. Nat Immunol (2019)
  2. Der, E., et al. Nat Immunol (2019)
  3. Arazi, A., et al. Nat Immunol, In press
  4. Korsunsky, I., et al. bioRxiv (2018)


ACR_Figure1

Figure 1. Integration of ~80,000 cells from 176 donors reveal common and unique cell populations from RA and OA synovium, pulmonary fibrosis and healthy lung, SLE and healthy kidney and skin, IBD and healthy colon, and Crohn. A. Shared and unique cell states across multiple tissues. B. SPP1 expression pattern for each disease and tissue source in inflammatory macrophages. C. GZMK expression pattern for each disease and tissue source in CD8 T cells.


Disclosure: F. Zhang, None; J. Mears, None; i. Korsunsky, None; K. Wei, None; A. Jonsson, Amgen, 2; D. Rao, Janssen, 5, Merck, 2, Pfizer, 5; E. Kim, None; L. Donlin, Karius Inc, 9, Karius, Inc, 2, Stryker, 5; J. Buyon, Bristol Myers Squibb, 5, Exagen Diagnostics, 2; M. Petri, Eli Lilly and Company, 5, Exagen, 2, 5; C. Putterman, Equillium, 5, Equillium, Inc, 2, 5, Exagen, 2; T. Tuschl, None; N. Hacohen, Neon Therapeutics, 1, 8; B. Diamond, GSK, 5, Jansen, 5, Lilly, 5; M. Brenner, None; S. Raychaudhuri, None.

To cite this abstract in AMA style:

Zhang F, Mears J, Korsunsky i, Wei K, Jonsson A, Rao D, Kim E, Donlin L, Buyon J, Petri M, Putterman C, Tuschl T, Hacohen N, Diamond B, Brenner M, Raychaudhuri S. Integration of Single Cells from Inflammatory Disease Tissues Reveals Common and Unique Pathogenic Cell States [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/integration-of-single-cells-from-inflammatory-disease-tissues-reveals-common-and-unique-pathogenic-cell-states/. Accessed January 31, 2023.
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