Aurélie De Groof1, Julie Ducreux1, Floor Aleva2, Andrew J Long3, Alina Ferster4, Andre van der Ven2, Frank van de Veerdonk2, Frédéric A Houssiau1,5, Bernard R Lauwerys1,5. 1. Pôle de pathologies rhumatismales inflammatoires et systémiques, Institut de Recherche Expérimentale et Cliniques, Université catholique de Louvain, Brussels, Belgium. 2. Department of General Internal Medicine, Radboud University, Nijmegen, The Netherlands. 3. Department of Pharmacology, Abbvie Bioresearch Center, Worcester, MA, USA. 4. Service d'Onco-Hématologie, Hôpital Reine Fabiola, Brussels, Belgium. 5. Service de Rhumatologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Abstract
OBJECTIVE: Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. METHODS: Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. RESULTS: Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. CONCLUSION: IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.
OBJECTIVE: Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. METHODS: Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLEpatients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. RESULTS: Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLEpatients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. CONCLUSION: IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.
Authors: Katharina Robichon; Tim Maiwald; Marcel Schilling; Annette Schneider; Joschka Willemsen; Florian Salopiata; Melissa Teusel; Clemens Kreutz; Christian Ehlting; Jun Huang; Sajib Chakraborty; Xiaoyun Huang; Georg Damm; Daniel Seehofer; Philipp A Lang; Johannes G Bode; Marco Binder; Ralf Bartenschlager; Jens Timmer; Ursula Klingmüller Journal: PLoS Pathog Date: 2020-10-01 Impact factor: 6.823