BLyS and APRIL in rheumatoid arthritis

Thorsten M. Seyler, Yong W. Park, Seisuke Takemura, Richard J. Bram, Paul J. Kurtin, Jörg J. Goronzy, Cornelia M. Weyand

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201 Scopus citations

Abstract

The cytokines B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) enhance autoimmune disease by sustaining B cell activation. In RA, B cells contribute to the formation of 3 functionally distinct types of lymphoid microarchitectures in the inflamed synovium: ectopic GCs; T cell-B cell aggregates lacking GC reactions; and unorganized, diffuse infiltrates. We examined 72 tissues representing the 3 types of synovitis for BLyS and APRIL production and for expression of APRIL/BLyS receptors. Biologic effects of BLyS and APRIL were explored by treating human synovium-SCID mouse chimeras with the APRIL and BLyS decoy receptor transmembrane activator and CAML interactor:Fc (TACI:Fc). GC+ synovitis had the highest levels of APRIL, produced exclusively by CD83+ DCs. BLyS was present in similar levels in all tissue types and derived exclusively from CD68+ macrophages. In GC+ synovitis, treatment with TACI:Fc resulted in GC destruction and marked inhibition of IFN-γ and Ig transcription. In contrast, inhibition of APRIL and BLyS in aggregate and diffuse synovitis left Ig levels unaffected and enhanced IFN-γ production. These differential immunomodulatory effects correlated with the presence of TACI+ T cells in aggregate and diffuse synovitis and their absence in GC+ synovitis. We propose that BLyS and APRIL regulate B cell as well as T cell function and have pro- and antiinflammatory activities in RA.

Original languageEnglish (US)
Pages (from-to)3083-3092
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number11
DOIs
StatePublished - Nov 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Seyler, T. M., Park, Y. W., Takemura, S., Bram, R. J., Kurtin, P. J., Goronzy, J. J., & Weyand, C. M. (2005). BLyS and APRIL in rheumatoid arthritis. Journal of Clinical Investigation, 115(11), 3083-3092. https://doi.org/10.1172/JCI25265