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

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

Author information

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.

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.

PMID:
26006014
PMCID:
PMC4512288
DOI:
10.1038/ni.3175
[Indexed for MEDLINE]
Free PMC Article

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