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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Animals
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Arthritis, Rheumatoid / immunology*
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Arthritis, Rheumatoid / metabolism
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Arthritis, Rheumatoid / pathology
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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B-Lymphocyte Subsets / metabolism
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Female
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Humans
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Inflammation Mediators / physiology
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Interferon-gamma / biosynthesis
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Male
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Mice
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Mice, SCID
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Middle Aged
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / physiology
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Signal Transduction / immunology
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Synovitis / immunology
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Synovitis / metabolism
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Synovitis / pathology
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T-Lymphocyte Subsets / metabolism
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Transmembrane Activator and CAML Interactor Protein
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Tumor Necrosis Factor Ligand Superfamily Member 13
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / physiology*
Substances
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B-Cell Activating Factor
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B-Cell Activation Factor Receptor
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BLyS receptor
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Inflammation Mediators
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Membrane Proteins
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Receptors, Tumor Necrosis Factor
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TNFRSF13B protein, human
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TNFRSF13C protein, human
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TNFSF13 protein, human
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TNFSF13B protein, human
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Tnfsf13b protein, mouse
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Transmembrane Activator and CAML Interactor Protein
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Tumor Necrosis Factor Ligand Superfamily Member 13
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Tumor Necrosis Factor-alpha
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Interferon-gamma