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

Nature Immunology volume 16, pages 755765 (2015) | Download Citation

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.

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Acknowledgements

We thank F. Stevenson (University of Southampton) for the 9G4 hybridoma; E. Meffre (Yale University) for expression vectors; and the blood donors and research coordinators involved in this study. Supported by the Autoimmunity Center of Excellence (U19 AI110483, 5P01AI078907 and 5R37AI049660) and the United States-Israel Binational Science Foundation (2013432).

Author information

Author notes

    • Wan Cheung Cheung

    Present address: Biotherapeutic Technologies, Pfizer, Cambridge, Massachusetts, USA.

Affiliations

  1. Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.

    • Christopher M Tipton
    • , Asiya Chida
    • , Travis Ichikawa
    • , Jennifer Hom
    • , Scott Jenks
    • , Chungwen Wei
    •  & Iñaki Sanz
  2. Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA.

    • Christopher F Fucile
    •  & Alexander F Rosenberg
  3. Cell Signaling Technology, Danvers, Massachusetts, USA.

    • Jaime Darce
    • , Ivan Gregoretti
    •  & Sandra Schieferl
  4. Department of Dermatology, Emory University, Atlanta, Georgia, USA.

    • Ron J Feldman
  5. Bar-Ilan University, Ramat Gan, Israel.

    • Ramit Mehr
  6. Department of Pulmonology, Emory University, Atlanta, Georgia, USA.

    • F Eun-Hyung Lee
  7. Cell Signaling Technology, Danvers, Massachusetts, USA.

    • Wan Cheung Cheung

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Contributions

C.M.T. obtained most samples, conducted sample preparation and cell sorting, designed and conducted the NGS studies, analyzed and interpreted the data, helped to design figures and helped to write the manuscript; C.F.F. and A.F.R. wrote the programs used for NGS analysis, helped in data interpretation, produced visualization of the data, and helped to design and produce the figures; J.D., I.G., S.S. and W.C.C. conducted and analyzed the proteomics studies; A.C. conducted the experiments with single-cell monoclonal antibodies; T.I. conducted the ELISPOT experiments; J.H. obtained samples from patients with pemphigus, conducted some sequencing studies and helped with the analysis; S.J. helped with sequencing analysis; R.J.F. provided samples from patients with pemphigus; R.M. provided the IgTree program and aided in analysis; C.W. provided flow cytometry data and helped with its analysis; F.E.-H.L. provided the samples from vaccinated subjects and aided in data analysis; and I.S. designed and supervised the project, helped in experimental design and analysis, and wrote the manuscript.

Competing interests

I.S. is a member of the Pfizer Visiting Professor Board and has consulted for Genentech on B cell--depleting agents, and F.E.-H.L. has grants from Genentech.

Corresponding author

Correspondence to Iñaki Sanz.

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    Supplementary Figures 1–6, Supplementary Table, and Supplementary Note

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DOI

https://doi.org/10.1038/ni.3175

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