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Author Notes:

Correspondence should be addressed to I.S. Ignacio.sanz@emory.edu. current address: Biotherapeutic Technologies; Pfizer, Cambridge, MA, USA

Author Contributions: C.M.T. obtained most samples, conducted sample prep and cell sorting, designed and conducted the next-gen sequencing 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 next-gen sequencing analysis, helped in data interpretation, produced visualizations 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.

T.I. conducted the ELISPOT experiments. A.C. conducted the experiments with single-cell monoclonal antibodies.

J.H. obtained the pemphigus samples, conducted some sequencing studies and helped with the analysis. S.J. helped with sequencing analysis.

R.J.F. provided the pemphigus samples. 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 vaccinated samples and aided in data analysis.

I.S. designed and supervised the project, helped in experimental design, analysis and wrote the manuscript.

We thank F. Stevenson (Tenovus Laboratories, Southampton, U.K.) for the 9G4 hybridoma and E. Meffre (Yale University) for expression vectors.

We would also like to thank the blood donors and research coordinators involved in this study.

Competing Financial Interests: I.S. is a member of Pfizer Visiting Professor Board and in the last years has consulted for Genentech on B cell-depleting agents. F.E-H.L. has grants with Genentech. The other authors have no competing financial interests to declare.

Subjects:

Research Funding:

Supported by grants U19 AI110483 (Autoimmunity Center of Excellence), 5P01AI078907, 5R37AI049660.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • MEMORY B-CELLS
  • PERIPHERAL-BLOOD
  • GERMINAL CENTER
  • MONOCLONAL-ANTIBODIES
  • AFFINITY MATURATION
  • ACTIVATION
  • AUTOIMMUNITY
  • RESPONSES
  • ANTIGEN
  • SLE

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

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Journal Title:

Nature Immunology

Volume:

Volume 16, Number 7

Publisher:

, Pages 755-+

Type of Work:

Article | Post-print: After Peer Review

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 V<inf>H</inf>4-34 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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