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 H 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.
Bibliographical noteFunding Information:
ASCs in our study would favor the former possibility. Nevertheless, these mechanisms are not mutually exclusive, since multiple cytokines and stimulation via Toll-like receptors19,32 could induce activation of bystander cells while promoting clonal expansion of autoreactive cells receiving BCR-transduced signal 1 (refs. 33,34). Indeed, that last component is supported by the clonal expansion of VH4-34+ ASCs with disease-associated autoreactivity.
© 2015 Nature America, Inc. All rights reserved.