title: 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-gamma and Ig transcription. In contrast, inhibition of APRIL and BLyS in aggregate and diffuse synovitis left Ig levels unaffected and enhanced IFN-gamma 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.affiliation: Department of Medicine, Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Seyler
authors.forename: Yong W
authors.initials: YW
authors.lastname: Park
authors.forename: Seisuke
authors.initials: S
authors.lastname: Takemura
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bram
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kurtin
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000328:Adult; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D016175:B-Lymphocyte Subsets / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013585:Synovitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; C120197:BLyS receptor; D018836:Inflammation Mediators; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma