Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus

Christopher M Tipton; Christopher F Fucile; Jaime Darce; Asiya Chida; Travis Ichikawa; Ivan Gregoretti; Sandra Schieferl; Jennifer Hom; Scott Jenks; Ron J Feldman; Ramit Mehr; Chungwen Wei; F Eun-Hyung Lee; Wan Cheung Cheung; Alexander F Rosenberg; Iñaki Sanz

doi:10.1038/ni.3175

Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus

Nat Immunol. 2015 Jul;16(7):755-65. doi: 10.1038/ni.3175. Epub 2015 May 25.

Authors

Christopher M Tipton¹, Christopher F Fucile², Jaime Darce³, Asiya Chida¹, Travis Ichikawa¹, Ivan Gregoretti³, Sandra Schieferl³, Jennifer Hom¹, Scott Jenks¹, Ron J Feldman⁴, Ramit Mehr⁵, Chungwen Wei¹, F Eun-Hyung Lee⁶, Wan Cheung Cheung³, Alexander F Rosenberg², Iñaki Sanz¹

Affiliations

¹ Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
² Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA.
³ Cell Signaling Technology, Danvers, Massachusetts, USA.
⁴ Department of Dermatology, Emory University, Atlanta, Georgia, USA.
⁵ Bar-Ilan University, Ramat Gan, Israel.
⁶ Department of Pulmonology, Emory University, Atlanta, Georgia, USA.

PMID: 26006014
PMCID: PMC4512288
DOI: 10.1038/ni.3175

Abstract

Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies.

Publication types

Multicenter Study

MeSH terms

Acute Disease
Amino Acid Sequence
Antibody Diversity / genetics
Antibody Diversity / immunology*
Antibody-Producing Cells / immunology*
Antibody-Producing Cells / metabolism
Autoantibodies / genetics
Autoantibodies / immunology*
Autoantibodies / metabolism
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
Base Sequence
Cell Proliferation*
Clone Cells / immunology
Clone Cells / metabolism
Flow Cytometry
Humans
Immunoglobulin G / blood
Immunoglobulin G / genetics
Immunoglobulin G / immunology
Immunoglobulin Heavy Chains / genetics
Immunoglobulin Heavy Chains / immunology
Immunoglobulin Heavy Chains / metabolism
Immunoglobulin Variable Region / genetics
Immunoglobulin Variable Region / immunology
Immunoglobulin Variable Region / metabolism
Influenza Vaccines / immunology
Lupus Erythematosus, Systemic / genetics
Lupus Erythematosus, Systemic / immunology*
Lupus Erythematosus, Systemic / metabolism
Molecular Sequence Data
Proteome / analysis
Proteome / immunology
Proteomics / methods
Sequence Homology, Amino Acid
Single-Cell Analysis / methods
Tandem Mass Spectrometry
Tetanus Toxoid / immunology

Substances

Autoantibodies
Immunoglobulin G
Immunoglobulin Heavy Chains
Immunoglobulin Variable Region
Influenza Vaccines
Proteome
Tetanus Toxoid

Abstract

Publication types

MeSH terms

Substances

Grants and funding