Mapping systemic lupus erythematosus heterogeneity at the single-cell level

Djamel Nehar-Belaid; Seunghee Hong; Radu Marches; Guo Chen; Mohan Bolisetty; Jeanine Baisch; Lynnette Walters; Marilynn Punaro; Robert J. Rossi; Cheng Han Chung; Richie P. Huynh; Prashant Singh; William F. Flynn; Joy Ann Tabanor-Gayle; Navya Kuchipudi; Asuncion Mejias; Magalie A. Collet; Anna Lisa Lucido; Karolina Palucka; Paul Robson; Santhanam Lakshminarayanan; Octavio Ramilo; Tracey Wright; Virginia Pascual; Jacques F. Banchereau

doi:10.1038/s41590-020-0743-0

Mapping systemic lupus erythematosus heterogeneity at the single-cell level

Djamel Nehar-Belaid, Seunghee Hong, Radu Marches, Guo Chen, Mohan Bolisetty, Jeanine Baisch, Lynnette Walters, Marilynn Punaro, Robert J. Rossi, Cheng Han Chung, Richie P. Huynh, Prashant Singh, William F. Flynn, Joy Ann Tabanor-Gayle, Navya Kuchipudi, Asuncion Mejias, Magalie A. Collet, Anna Lisa Lucido, Karolina Palucka, Paul RobsonSanthanam Lakshminarayanan, Octavio Ramilo, Tracey Wright, Virginia Pascual, Jacques F. Banchereau

Department of Biotechnology

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114 Citations (Scopus)

Abstract

Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISG^hi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4⁺ and CD8⁺ T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.

Original language	English
Pages (from-to)	1094-1106
Number of pages	13
Journal	Nature Immunology
Volume	21
Issue number	9
DOIs	https://doi.org/10.1038/s41590-020-0743-0
Publication status	Published - 2020 Sept 1

Bibliographical note

Funding Information:
We are grateful to the patients with SLE, their families, the healthy individuals who participated in our study and the members of the Pediatric Rheumatology Clinics at Texas Scottish Rite Hospital for Children and the Children’s Medical Center in Dallas, TX and M. Sansone, T. Jackson and F. Jawed for help with recruiting adults with SLE. We gratefully acknowledge the contribution of Flow Cytometry, Single Cell Biology and Genome Technologies Scientific Services at The Jackson Laboratory, which are partially supported by NCI P30CA034196, and thank them for expert assistance with the work described in this publication. In addition, we thank JAX Research IT (particularly Sandeep Namburi) for the support with maintaining the R Shiny application. This work was supported by grants NIAMS CORT P50AR070594 Center for Lupus Research (to V.P. and J.F.B.), NIAID NIH U19 AI082715 (to V.P.) and U01 AI131386 (to O.R. and J.F.B.) and start-up funds from the Jackson Laboratory and the Drukier Institute for Children’s Health at Weill Cornell Medicine.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

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10.1038/s41590-020-0743-0

Cite this

Nehar-Belaid, D., Hong, S., Marches, R., Chen, G., Bolisetty, M., Baisch, J., Walters, L., Punaro, M., Rossi, R. J., Chung, C. H., Huynh, R. P., Singh, P., Flynn, W. F., Tabanor-Gayle, J. A., Kuchipudi, N., Mejias, A., Collet, M. A., Lucido, A. L., Palucka, K., ... Banchereau, J. F. (2020). Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nature Immunology, 21(9), 1094-1106. https://doi.org/10.1038/s41590-020-0743-0

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title = "Mapping systemic lupus erythematosus heterogeneity at the single-cell level",

abstract = "Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.",

author = "Djamel Nehar-Belaid and Seunghee Hong and Radu Marches and Guo Chen and Mohan Bolisetty and Jeanine Baisch and Lynnette Walters and Marilynn Punaro and Rossi, {Robert J.} and Chung, {Cheng Han} and Huynh, {Richie P.} and Prashant Singh and Flynn, {William F.} and Tabanor-Gayle, {Joy Ann} and Navya Kuchipudi and Asuncion Mejias and Collet, {Magalie A.} and Lucido, {Anna Lisa} and Karolina Palucka and Paul Robson and Santhanam Lakshminarayanan and Octavio Ramilo and Tracey Wright and Virginia Pascual and Banchereau, {Jacques F.}",

note = "Funding Information: We are grateful to the patients with SLE, their families, the healthy individuals who participated in our study and the members of the Pediatric Rheumatology Clinics at Texas Scottish Rite Hospital for Children and the Children{\textquoteright}s Medical Center in Dallas, TX and M. Sansone, T. Jackson and F. Jawed for help with recruiting adults with SLE. We gratefully acknowledge the contribution of Flow Cytometry, Single Cell Biology and Genome Technologies Scientific Services at The Jackson Laboratory, which are partially supported by NCI P30CA034196, and thank them for expert assistance with the work described in this publication. In addition, we thank JAX Research IT (particularly Sandeep Namburi) for the support with maintaining the R Shiny application. This work was supported by grants NIAMS CORT P50AR070594 Center for Lupus Research (to V.P. and J.F.B.), NIAID NIH U19 AI082715 (to V.P.) and U01 AI131386 (to O.R. and J.F.B.) and start-up funds from the Jackson Laboratory and the Drukier Institute for Children{\textquoteright}s Health at Weill Cornell Medicine. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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Nehar-Belaid, D, Hong, S, Marches, R, Chen, G, Bolisetty, M, Baisch, J, Walters, L, Punaro, M, Rossi, RJ, Chung, CH, Huynh, RP, Singh, P, Flynn, WF, Tabanor-Gayle, JA, Kuchipudi, N, Mejias, A, Collet, MA, Lucido, AL, Palucka, K, Robson, P, Lakshminarayanan, S, Ramilo, O, Wright, T, Pascual, V & Banchereau, JF 2020, 'Mapping systemic lupus erythematosus heterogeneity at the single-cell level', Nature Immunology, vol. 21, no. 9, pp. 1094-1106. https://doi.org/10.1038/s41590-020-0743-0

TY - JOUR

T1 - Mapping systemic lupus erythematosus heterogeneity at the single-cell level

AU - Nehar-Belaid, Djamel

AU - Hong, Seunghee

AU - Marches, Radu

AU - Chen, Guo

AU - Bolisetty, Mohan

AU - Baisch, Jeanine

AU - Walters, Lynnette

AU - Punaro, Marilynn

AU - Rossi, Robert J.

AU - Chung, Cheng Han

AU - Huynh, Richie P.

AU - Singh, Prashant

AU - Flynn, William F.

AU - Tabanor-Gayle, Joy Ann

AU - Kuchipudi, Navya

AU - Mejias, Asuncion

AU - Collet, Magalie A.

AU - Lucido, Anna Lisa

AU - Palucka, Karolina

AU - Robson, Paul

AU - Lakshminarayanan, Santhanam

AU - Ramilo, Octavio

AU - Wright, Tracey

AU - Pascual, Virginia

AU - Banchereau, Jacques F.

N1 - Funding Information: We are grateful to the patients with SLE, their families, the healthy individuals who participated in our study and the members of the Pediatric Rheumatology Clinics at Texas Scottish Rite Hospital for Children and the Children’s Medical Center in Dallas, TX and M. Sansone, T. Jackson and F. Jawed for help with recruiting adults with SLE. We gratefully acknowledge the contribution of Flow Cytometry, Single Cell Biology and Genome Technologies Scientific Services at The Jackson Laboratory, which are partially supported by NCI P30CA034196, and thank them for expert assistance with the work described in this publication. In addition, we thank JAX Research IT (particularly Sandeep Namburi) for the support with maintaining the R Shiny application. This work was supported by grants NIAMS CORT P50AR070594 Center for Lupus Research (to V.P. and J.F.B.), NIAID NIH U19 AI082715 (to V.P.) and U01 AI131386 (to O.R. and J.F.B.) and start-up funds from the Jackson Laboratory and the Drukier Institute for Children’s Health at Weill Cornell Medicine. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.

AB - Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.

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JO - Nature Immunology

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ER -

Mapping systemic lupus erythematosus heterogeneity at the single-cell level

Abstract

Bibliographical note

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