BLyS and APRIL in rheumatoid arthritis
Thorsten M. Seyler, … , Jörg J. Goronzy, Cornelia M. Weyand
Thorsten M. Seyler, … , Jörg J. Goronzy, Cornelia M. Weyand
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3083-3092. https://doi.org/10.1172/JCI25265.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 3

BLyS and APRIL in rheumatoid arthritis

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.

Authors

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

×

Figure 7

Options: View larger image (or click on image) Download as PowerPoint
APRIL/BLyS blockade results in collapse of ectopic GCs. GC+ synovium was...
APRIL/BLyS blockade results in collapse of ectopic GCs. GC+ synovium was implanted into SCID mice, and the chimeras were treated with TACI:Fc or control Fc as described in Figure 6. Explanted synovial grafts were embedded, and frozen tissue sections were stained for CD3 and CD20. Tissue extracts were assayed by PCR for the presence of CD21L transcripts, a marker for FDCs exclusively expressed in synovitis with intact GCs. (A) Treatment of GC+ synovitis with TACI:Fc resulted in the destruction of ectopic GCs. Scale bars: 50 μm. (B) In synovial grafts treated with TACI:Fc, few CD20+ B cells remained, and CD3+ T cells were markedly reduced. HPF, high-powered field. (C) TACI:Fc injection caused loss of CD21L, confirming that FDC networks were no longer sustained. First lane, size markers. +, positive control; –, negative control.