BACKGROUND: The mechanisms underlying the loss of self-tolerance in systemic lupus erythematosus (SLE) are incompletely deciphered. TGF-β plays a key role in self-tolerance demonstrated by the onset of a fatal autoimmune syndrome associated with lupus autoantibodies in mice lacking a functional TGF-β receptor. The present work aims to define whether resistance to TGF-β might contribute to the pathogenesis of SLE. METHODS: Twenty-two patients with active SLE, 16 with other connective tissue diseases, and 10 healthy controls were prospectively included in this study. The effects of exogenous TGF-β1 on IL-2-dependent T-cell proliferation, IFN-γ secretion, and target gene transcription were analyzed on peripheral blood mononuclear cells. RESULTS: Our results showed that 75% of patients with SLE or other connective tissue diseases were totally or partially resistant to the effects of TGF-β1. The responses to the anti-proliferative and transcriptional effects of TGF-β were, however, discordant in a high proportion of our patients. Hence, we distinguish three distinct profiles of resistance to TGF-β1 and suggest that patients may exhibit different defects affecting distinct points of TGF-β1 signaling pathways. CONCLUSION: Our data demonstrate the presence of an impaired response of peripheral cells to TGF-β1 in patients with active SLE that may participate to the pathogenesis of the disease. Further studies will be necessary to delineate the mechanisms underlying the lymphocyte resistance to TGF-β1 in SLE.
BACKGROUND: The mechanisms underlying the loss of self-tolerance in systemic lupus erythematosus (SLE) are incompletely deciphered. TGF-β plays a key role in self-tolerance demonstrated by the onset of a fatal autoimmune syndrome associated with lupus autoantibodies in mice lacking a functional TGF-β receptor. The present work aims to define whether resistance to TGF-β might contribute to the pathogenesis of SLE. METHODS: Twenty-two patients with active SLE, 16 with other connective tissue diseases, and 10 healthy controls were prospectively included in this study. The effects of exogenous TGF-β1 on IL-2-dependent T-cell proliferation, IFN-γ secretion, and target gene transcription were analyzed on peripheral blood mononuclear cells. RESULTS: Our results showed that 75% of patients with SLE or other connective tissue diseases were totally or partially resistant to the effects of TGF-β1. The responses to the anti-proliferative and transcriptional effects of TGF-β were, however, discordant in a high proportion of our patients. Hence, we distinguish three distinct profiles of resistance to TGF-β1 and suggest that patients may exhibit different defects affecting distinct points of TGF-β1 signaling pathways. CONCLUSION: Our data demonstrate the presence of an impaired response of peripheral cells to TGF-β1 in patients with active SLE that may participate to the pathogenesis of the disease. Further studies will be necessary to delineate the mechanisms underlying the lymphocyte resistance to TGF-β1 in SLE.
Authors: Christopher A Aoki; Andrea T Borchers; Ming Li; Richard A Flavell; Christopher L Bowlus; Aftab A Ansari; M Eric Gershwin Journal: Autoimmun Rev Date: 2005-09 Impact factor: 9.754
Authors: M Aringer; G H Stummvoll; G Steiner; M Köller; C W Steiner; E Höfler; H Hiesberger; J S Smolen; W B Graninger Journal: Rheumatology (Oxford) Date: 2001-08 Impact factor: 7.580
Authors: Ming O Li; Yisong Y Wan; Shomyseh Sanjabi; Anna-Karin L Robertson; Richard A Flavell Journal: Annu Rev Immunol Date: 2006 Impact factor: 28.527
Authors: Eszter Kohut; Melinda Hajdu; Péter Gergely; László Gopcsa; Katalin Kilián; Katalin Pálóczi; László Kopper; Anna Sebestyén Journal: Pathol Oncol Res Date: 2008-11-20 Impact factor: 3.201