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
C2 - 27040498
AN - SCOPUS:84962128086
SN - 0092-8674
VL - 165
SP - 551
EP - 565
JO - Cell
JF - Cell
IS - 3
ER -