title: B Cell Homeostasis and Functional Properties Are Altered in an Hypochlorous Acid-Induced Murine Model of Systemic Sclerosis.
abstract: BACKGROUND
  During systemic sclerosis (SSc), peripheral B cells display alterations in subset homeostasis and functional properties and are a promising therapeutic target. However, there is only few data regarding whether these anomalies are accurately reproduced in animal models of SSc.
  
  
  OBJECTIVE
  In this work, we assessed the B cell homeostasis modifications in an experimental model of SSc [hypochlorous acid (HOCl)-induced mouse], both at a phenotypic and functional level, during the course of the disease.
  
  
  METHODS
  Balb/c mice underwent daily intradermal injections of HOCl (or phosphate-buffered saline) and were then sacrificed at day 21 (early inflammatory stage) or day 42 (late fibrotic stage). For phenotypic studies, the distribution of the main spleen cell subsets (B cells, T CD4 and CD8 cells, NK cells, macrophages) and splenic B cell subsets (immature, mature naïve, germinal center, antibody-secreting, memory, B1) was assessed by flow cytometry. For functional studies, splenic B cells were immediately MACS-sorted. Production of interleukin (IL)-6, CCL3, IL-10, and transforming growth factor (TGF)-β was assessedex vivoby RT-PCR and after 48 h of culture by ELISA. Regulatory B cell (Breg) counts were quantified by flow cytometry.
  
  
  RESULTS
  Phenotypic analyses showed an early expansion of transitional B cells, followed by a late expansion of the mature naive subset and decrease in plasmablasts and memory B cells. These anomalies are similar to those encountered in SSc patients. Functional analyses revealed a B-cell overproduction of pro-inflammatory cytokines (IL-6 and CCL3) and an impairment of their anti-inflammatory capacities (decreased production of IL-10 and TGF-β, reduced levels of Bregs) at the early inflammatory stage; and an overproduction of pro-fibrotic cytokines (TGF-β and IL-6) at the late fibrotic stage. These results approximate the anomalies observed in human SSc.
  
  
  CONCLUSIONS
  This work reports the existence of anomalies in B cell homeostasis and functional properties in an animal model of SSc that approximate those displayed by SSc patients. These anomalies vary over the course of the disease, which pleads for their participation in inflammatory and fibrotic events. This makes the HOCl mouse a relevant experimental model for the study of B cells, and therefore, B-cell-targeted therapies in SSc.
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Sanges
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France.
authors.forename: Manel
authors.initials: M
authors.lastname: Jendoubi
authors.affiliation: Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'immunologie biologique, AP-HP Hôpital Cochin, Université Paris Descartes, Sorbonne Paris-Cité , Paris , France.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Institut d'Immunologie, CHU Lille, Lille, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Hauspie
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Speca
authors.affiliation: Octapharma France SAS, Medical Department , Boulogne-Billancourt , France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Crave
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Guerrier
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), Lille, France; Institut d'Immunologie, CHU Lille, Lille, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lefèvre
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), Lille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sobanski
authors.affiliation: Institut Roche , Boulogne-Billancourt , France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), Lille, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Hatron
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Institut d'Immunologie, CHU Lille, Lille, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Labalette
authors.affiliation: Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'immunologie biologique, AP-HP Hôpital Cochin, Université Paris Descartes, Sorbonne Paris-Cité , Paris , France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Institut d'Immunologie, CHU Lille, Lille, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Dubucquoi
authors.affiliation: U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Launay
keywords: B cell; animal model; interleukin-10; interleukin-6; regulatory B cells; systemic sclerosis