The immune cell landscape in kidneys of patients with lupus
nephritis

Arazi, Arnon; Rao, Deepak A; Berthier, Celine C; Davidson, Anne; Liu, Yanyan; Hoover, Paul J; Chicoine, Adam T.; Eisenhaure, Thomas M; Jonsson, A Helena; Li, Shuqiang; Lieb, David J.; Zhang, Fan; Slowikowski, Kamil; Browne, Edward P.; Noma, Akiko; Sutherby, Danielle; Steelman, Scott; Smilek, Dawn E.; Tosta, Patti; Apruzzese, William; Massarotti, Elena M; Dall’Era, Maria; Park, Meyeon; Kamen, Diane L.; Furie, Richard A; Payan-Schober, Fernanda; Pendergraft, William F; McInnis, Elizabeth A.; Buyon, Jill P; Petri, Michelle A.; Putterman, Chaim; Kalunian, Kenneth C; Woodle, E Steve; Lederer, James A.; Hildeman, David A.; Nusbaum, Chad; Raychaudhuri, Soumya; Kretzler, Matthias; Anolik, Jennifer H.; Brenner, Michael B; Wofsy, David; Hacohen, Nir; Diamond, Betty

doi:10.1038/s41590-019-0398-x

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The immune cell landscape in kidneys of patients with lupus nephritis

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Author(s): Arnon Arazi ¹ , Deepak A. Rao ² , Celine C. Berthier ³ , Anne Davidson ⁴ , Yanyan Liu ² , Paul J. Hoover ¹ , Adam Chicoine ² , Thomas M. Eisenhaure ¹ , A. Helena Jonsson ² , Shuqiang Li ¹ , David J. Lieb ¹ , Fan Zhang ² , Kamil Slowikowski ² , Edward P. Browne ⁵ , Akiko Noma ¹ , Danielle Sutherby ⁶ , Scott Steelman ⁷ , Dawn E. Smilek ⁸ ^, ⁹ , Patti Tosta ⁸ ^, ⁹ , William Apruzzese ² , Elena Massarotti ² , Maria Dall’Era ¹⁰ , Meyeon Park ¹¹ , Diane L. Kamen ¹² , Richard A. Furie ¹³ , Fernanda Payan-Schober ¹⁴ , William F. Pendergraft III ¹⁵ , Elizabeth A. McInnis ¹⁶ , Jill P. Buyon ¹⁷ , Michelle A. Petri ¹⁸ , Chaim Putterman ¹⁹ , Kenneth C. Kalunian ²⁰ , E. Steve Woodle ²¹ , James A. Lederer ²² , David A. Hildeman ²³ ^, ²⁴ , Chad Nusbaum ⁷ , Soumya Raychaudhuri ² , Matthias Kretzler ³ , Jennifer H. Anolik ²⁵ , Michael B. Brenner ² , David Wofsy ¹⁰ , Nir Hacohen ¹ ^, ^** , Betty Diamond ⁴ ^, ^** , Accelerating Medicines Partnership in SLE network ²⁶

Publication date (Electronic): 17 June 2019

Journal: Nature immunology

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Abstract

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

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Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Yoav Benjamini, Yosef Hochberg (1995)

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Immune interferon in the circulation of patients with autoimmune disease.

H Moutsopoulos, S. Geis, N Ståhl … (1979)

The observation that type II, or immune, interferon could be produced by peripheral-blood leukocytes in vitro on an immune-specific basis suggested that it also might be produced in vivo in various autoimmune disorders. We found immune interferon in the serums of patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma and Sjögren's syndrome. Among 28 patients with systemic lupus erythematosus, 71 per cent of those with active and 21 per cent of those with inactive disease showed interferon in their serums. Serial serum samples showed a good correlation between interferon titers and disease activity. Moreover, interferon titers correlated positively with antibodies to DNA and negatively with serum levels of the third component of complement. It is possible that the production of interferon may contribute to immunologic aberrations in auto-immune diseases and also protect the already compromised host from viral infections.

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Is Open Access

Data exploration, quality control and testing in single-cell qPCR-based gene expression experiments

Andrew McDavid, Greg Finak, Pratip Chattopadyay … (2012)

Motivation: Cell populations are never truly homogeneous; individual cells exist in biochemical states that define functional differences between them. New technology based on microfluidic arrays combined with multiplexed quantitative polymerase chain reactions now enables high-throughput single-cell gene expression measurement, allowing assessment of cellular heterogeneity. However, few analytic tools have been developed specifically for the statistical and analytical challenges of single-cell quantitative polymerase chain reactions data. Results: We present a statistical framework for the exploration, quality control and analysis of single-cell gene expression data from microfluidic arrays. We assess accuracy and within-sample heterogeneity of single-cell expression and develop quality control criteria to filter unreliable cell measurements. We propose a statistical model accounting for the fact that genes at the single-cell level can be on (and a continuous expression measure is recorded) or dichotomously off (and the recorded expression is zero). Based on this model, we derive a combined likelihood ratio test for differential expression that incorporates both the discrete and continuous components. Using an experiment that examines treatment-specific changes in expression, we show that this combined test is more powerful than either the continuous or dichotomous component in isolation, or a t-test on the zero-inflated data. Although developed for measurements from a specific platform (Fluidigm), these tools are generalizable to other multi-parametric measures over large numbers of events. Availability: All results presented here were obtained using the SingleCellAssay R package available on GitHub (http://github.com/RGLab/SingleCellAssay). Contact: rgottard@fhcrc.org Supplementary information: Supplementary data are available at Bioinformatics online.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Journal ID (iso-abbrev): Nat. Immunol.

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 10 June 2019

Publication date (Electronic): 17 June 2019

Publication date (Print): July 2019

Publication date PMC-release: 17 December 2019

Volume: 20

Issue: 7

Pages: 902-914

Affiliations

[1 ]Broad Institute of MIT and Harvard, Cambridge Massachusetts, USA

[2 ]Division of Rheumatology, Immunology, Allergy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston Massachusetts, USA

[3 ]Internal Medicine, Department of Nephrology, University of Michigan, Ann Arbor, Michigan, USA

[4 ]Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA

[5 ]UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

[6 ]Celsius Therapeutics, Cambridge, Massachusetts, USA

[7 ]Cellarity, Inc., Cambridge, Massachusetts, USA

[8 ]Lupus Nephritis Trials Network, University of California San Francisco, San Francisco, California, USA

[9 ]Immune Tolerance Network, University of California San Francisco, San Francisco, California, USA

[10 ]Rheumatology Division, University of California San Francisco, San Francisco, California, USA

[11 ]Division of Nephrology, University of California San Francisco, San Francisco, California, USA

[12 ]Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA

[13 ]Division of Rheumatology, Northwell Health, Great Neck, New York, USA

[14 ]Department of Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.

[15 ]The Integrative Medical Clinic of North Carolina, PLLC, Chapel Hill, North Carolina, USA

[16 ]University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, UNC School of Medicine, Chapel Hill, North Carolina, USA

[17 ]Department of Medicine, Division of Rheumatology, New York University School of Medicine, New York, New-York, USA

[18 ]Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA

[19 ]Division of Rheumatology and Department of Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA

[20 ]University of California San Diego School of Medicine, La Jolla, California, USA

[21 ]Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

[22 ]Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

[23 ]Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA

[24 ]Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

[25 ]Department of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA

[26 ]A list of members and affiliations appears at the end of the paper.

Author notes

[** ] nhacohen@ 123456mgh.harvard.edu ; BDiamond@ 123456northwell.edu .

[*]

These authors contributed equally: Arnon Arazi, Deepak A. Rao and Celine C. Berthier.

AUTHORS CONTRIBUTIONS

A.A., D.A.R, A.D., P.J.H., A.H.J. and D.J.L. analyzed the data; D.A.R., C.C.B., T.M.E., E.P.B., J.A.L. and D.A.H. developed the sample collection and processing protocols; D.A.R., Y.L., P.J.H., A.C., A.N., D.S. and S.S. processed the samples; S.L., D.J.L., A.N., D.S. and S.S. developed the scRNA-seq library preparation protocol; F.Z. and K.S. developed the web-based browser of the data; D.E.S., P.T., E.M., M.D.E., M.P., D.L.K., R.A.F., F.P.S., W.F.P., E.A.M., J.P.B., M.A.P., C.P., K.C.K., E.S.W., D.A.H., D.W. and J.H.A. acquired samples; A.A., D.A.R., C.C.B., A.D., W.A., J.A.L., D.A.H., C.N., D.W., M.K., J.H.A., M.B.B., N.H. and B.D. designed the study; A.D., W.A., D.A.H., C.N., S.R., D.W., M.K., J.H.A., M.B.B., N.H. and B.D. supervised the work; A.A., D.A.R., C.C.B., A.D., P.J.H., N.H. and B.D. wrote the manuscript.

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Manuscript ID: NIHMS1526529

DOI: 10.1038/s41590-019-0398-x

PMC ID: 6726437

PubMed ID: 31209404

SO-VID: c753f45c-ad08-4c44-a40d-c9303306b139

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The immune cell landscape in kidneys of patients with lupus nephritis

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Most cited references 40

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Immune interferon in the circulation of patients with autoimmune disease.

Data exploration, quality control and testing in single-cell qPCR-based gene expression experiments

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