Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients

Romain Banchereau; Seunghee Hong; Brandi Cantarel; Nicole Baldwin; Jeanine Baisch; Michelle Edens; Alma Martina Cepika; Peter Acs; Jacob Turner; Esperanza Anguiano; Parvathi Vinod; Shaheen Kahn; Gerlinde Obermoser; Derek Blankenship; Edward Wakeland; Lorien Nassi; Alisa Gotte; Marilynn Punaro; Yong Jun Liu; Jacques Banchereau; Jose Rossello-Urgell; Tracey Wright; Virginia Pascual

doi:10.1016/j.cell.2016.03.008

Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients

Romain Banchereau, Seunghee Hong, Brandi Cantarel, Nicole Baldwin, Jeanine Baisch, Michelle Edens, Alma Martina Cepika, Peter Acs, Jacob Turner, Esperanza Anguiano, Parvathi Vinod, Shaheen Kahn, Gerlinde Obermoser, Derek Blankenship, Edward Wakeland, Lorien Nassi, Alisa Gotte, Marilynn Punaro, Yong Jun Liu, Jacques BanchereauJose Rossello-Urgell, Tracey Wright, Virginia Pascual

Department of Biotechnology

Research output: Contribution to journal › Article › peer-review

377 Citations (Scopus)

Abstract

Summary Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA. We detected gradual enrichment of neutrophil transcripts during progression to active nephritis and distinct signatures in response to treatment in different nephritis subclasses. Importantly, personalized immunomonitoring uncovered individual correlates of disease activity that enabled patient stratification into seven groups, supported by patient genotypes. Our study uncovers the molecular heterogeneity of SLE and provides an explanation for the failure of clinical trials. This approach may improve trial design and implementation of tailored therapies in genetically and clinically complex autoimmune diseases.

Original language	English
Pages (from-to)	551-565
Number of pages	15
Journal	Cell
Volume	165
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2016.03.008
Publication status	Published - 2016 Apr 21

Bibliographical note

Funding Information:
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50 AR054083-01), the National Institute of Allergy and Infectious Diseases (U19 AI082715), the Alliance for Lupus Research, and the Baylor-Scott & White Health Care Research Foundation and is dedicated to the memory of Dr. J. Donald Capra. We thank members of the sample, genomics, and flow cytometry cores at BIIR for research support. We thank Dr. Anna Lisa Lucido for her critical review of the manuscript and Drs. Katie Stewart, Julie Fuller, and Ashley Cooper for their clinical expertise. Jacques Banchereau is a member of the Board of Directors and the chairman of the Scientific Advisory Board of Neovacs, a French biotechnology company focused on the development of Kinoids, therapeutic vaccines for the treatment of autoimmune and inflammatory diseases (in particular SLE) and cancer. Yong-Jun Liu is an employee of Medimmune, which is involved in the development of drugs to treat SLE.

Publisher Copyright:
© 2016 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2016.03.008

Cite this

Banchereau, R., Hong, S., Cantarel, B., Baldwin, N., Baisch, J., Edens, M., Cepika, A. M., Acs, P., Turner, J., Anguiano, E., Vinod, P., Kahn, S., Obermoser, G., Blankenship, D., Wakeland, E., Nassi, L., Gotte, A., Punaro, M., Liu, Y. J., ... Pascual, V. (2016). Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell, 165(3), 551-565. https://doi.org/10.1016/j.cell.2016.03.008

@article{75801541f1a8442695de24664afd9653,

title = "Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients",

abstract = "Summary Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA. We detected gradual enrichment of neutrophil transcripts during progression to active nephritis and distinct signatures in response to treatment in different nephritis subclasses. Importantly, personalized immunomonitoring uncovered individual correlates of disease activity that enabled patient stratification into seven groups, supported by patient genotypes. Our study uncovers the molecular heterogeneity of SLE and provides an explanation for the failure of clinical trials. This approach may improve trial design and implementation of tailored therapies in genetically and clinically complex autoimmune diseases.",

author = "Romain Banchereau and Seunghee Hong and Brandi Cantarel and Nicole Baldwin and Jeanine Baisch and Michelle Edens and Cepika, {Alma Martina} and Peter Acs and Jacob Turner and Esperanza Anguiano and Parvathi Vinod and Shaheen Kahn and Gerlinde Obermoser and Derek Blankenship and Edward Wakeland and Lorien Nassi and Alisa Gotte and Marilynn Punaro and Liu, {Yong Jun} and Jacques Banchereau and Jose Rossello-Urgell and Tracey Wright and Virginia Pascual",

note = "Funding Information: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50 AR054083-01), the National Institute of Allergy and Infectious Diseases (U19 AI082715), the Alliance for Lupus Research, and the Baylor-Scott & White Health Care Research Foundation and is dedicated to the memory of Dr. J. Donald Capra. We thank members of the sample, genomics, and flow cytometry cores at BIIR for research support. We thank Dr. Anna Lisa Lucido for her critical review of the manuscript and Drs. Katie Stewart, Julie Fuller, and Ashley Cooper for their clinical expertise. Jacques Banchereau is a member of the Board of Directors and the chairman of the Scientific Advisory Board of Neovacs, a French biotechnology company focused on the development of Kinoids, therapeutic vaccines for the treatment of autoimmune and inflammatory diseases (in particular SLE) and cancer. Yong-Jun Liu is an employee of Medimmune, which is involved in the development of drugs to treat SLE. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = apr,

day = "21",

doi = "10.1016/j.cell.2016.03.008",

language = "English",

volume = "165",

pages = "551--565",

journal = "Cell",

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Banchereau, R, Hong, S, Cantarel, B, Baldwin, N, Baisch, J, Edens, M, Cepika, AM, Acs, P, Turner, J, Anguiano, E, Vinod, P, Kahn, S, Obermoser, G, Blankenship, D, Wakeland, E, Nassi, L, Gotte, A, Punaro, M, Liu, YJ, Banchereau, J, Rossello-Urgell, J, Wright, T & Pascual, V 2016, 'Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients', Cell, vol. 165, no. 3, pp. 551-565. https://doi.org/10.1016/j.cell.2016.03.008

TY - JOUR

T1 - Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients

AU - Banchereau, Romain

AU - Hong, Seunghee

AU - Cantarel, Brandi

AU - Baldwin, Nicole

AU - Baisch, Jeanine

AU - Edens, Michelle

AU - Cepika, Alma Martina

AU - Acs, Peter

AU - Turner, Jacob

AU - Anguiano, Esperanza

AU - Vinod, Parvathi

AU - Kahn, Shaheen

AU - Obermoser, Gerlinde

AU - Blankenship, Derek

AU - Wakeland, Edward

AU - Nassi, Lorien

AU - Gotte, Alisa

AU - Punaro, Marilynn

AU - Liu, Yong Jun

AU - Banchereau, Jacques

AU - Rossello-Urgell, Jose

AU - Wright, Tracey

AU - Pascual, Virginia

N1 - Funding Information: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (P50 AR054083-01), the National Institute of Allergy and Infectious Diseases (U19 AI082715), the Alliance for Lupus Research, and the Baylor-Scott & White Health Care Research Foundation and is dedicated to the memory of Dr. J. Donald Capra. We thank members of the sample, genomics, and flow cytometry cores at BIIR for research support. We thank Dr. Anna Lisa Lucido for her critical review of the manuscript and Drs. Katie Stewart, Julie Fuller, and Ashley Cooper for their clinical expertise. Jacques Banchereau is a member of the Board of Directors and the chairman of the Scientific Advisory Board of Neovacs, a French biotechnology company focused on the development of Kinoids, therapeutic vaccines for the treatment of autoimmune and inflammatory diseases (in particular SLE) and cancer. Yong-Jun Liu is an employee of Medimmune, which is involved in the development of drugs to treat SLE. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/4/21

Y1 - 2016/4/21

N2 - Summary Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA. We detected gradual enrichment of neutrophil transcripts during progression to active nephritis and distinct signatures in response to treatment in different nephritis subclasses. Importantly, personalized immunomonitoring uncovered individual correlates of disease activity that enabled patient stratification into seven groups, supported by patient genotypes. Our study uncovers the molecular heterogeneity of SLE and provides an explanation for the failure of clinical trials. This approach may improve trial design and implementation of tailored therapies in genetically and clinically complex autoimmune diseases.

AB - Summary Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA. We detected gradual enrichment of neutrophil transcripts during progression to active nephritis and distinct signatures in response to treatment in different nephritis subclasses. Importantly, personalized immunomonitoring uncovered individual correlates of disease activity that enabled patient stratification into seven groups, supported by patient genotypes. Our study uncovers the molecular heterogeneity of SLE and provides an explanation for the failure of clinical trials. This approach may improve trial design and implementation of tailored therapies in genetically and clinically complex autoimmune diseases.

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U2 - 10.1016/j.cell.2016.03.008

DO - 10.1016/j.cell.2016.03.008

M3 - Article

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AN - SCOPUS:84962128086

SN - 0092-8674

VL - 165

SP - 551

EP - 565

JO - Cell

JF - Cell

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ER -

Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients

Abstract

Bibliographical note

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