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
Thorsten M. Seyler, Yong W. Park, Seisuke Takemura, Richard J. Bram, Paul J. Kurtin, Jörg J. Goronzy, Cornelia M. Weyand
View: Text | PDF
Research Article Immunology

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 1

Options: View larger image (or click on image) Download as PowerPoint
B cell function and tissue expression of APRIL/BLyS in RA synovium. Syno...
B cell function and tissue expression of APRIL/BLyS in RA synovium. Synovial biopsies from 72 patients were classified according to the lymphoid microarchitectures. Sixteen patients had GC+ synovitis, 30 patients had aggregate synovitis, and 26 patients had diffuse synovitis. cDNA from tissue extracts was adjusted relative to 2 × 106 β-actin copies, and specific transcripts were determined by real-time PCR. (A) H&E staining of representative tissues displayed classical GC (left), lymphoid aggregates (Agg) without GC formation (middle), and diffuse (Diff) mononuclear infiltrates without topographical clustering (right). Original magnification, ×100. (B) IgG transcription was highest in GC+ synovitis, intermediate in aggregate synovitis, and low in diffuse synovitis. LT-β and CCL19 production correlated closely with the pattern of lymphoid organogenesis in the synovium. (C) Tissue transcripts for APRIL followed the same hierarchy as LT-β and CCL19. BLyS-specific sequences were abundantly found in all tissues with no correlation to synovial lymphoid microstructures. Results are shown as box plots with medians, twenty-fifth and seventy-fifth percentiles as boxes and tenth and nintieth percentiles as whiskers. P values are indicated where statistically significant.