G. Lefevre

Role of B cells in the pathogenesis of systemic sclerosis

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-β (TGF-β) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

Proinflammatory B-cell profile in the early phases of MS predicts an active disease

Objective: To assess whether any alteration of B-cell subset distribution and/or the cytokine production capacities of B cells could be associated with any stage of MS and could be predictive of MS evolution. Methods: We prospectively enrolled radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), naive patients with relapsing remitting MS (RRMS) of any disease modifying drug, and healthy controls (HCs). Peripheral blood B-cell subset distributions and the interleukin (IL)-6/IL-10–producing B-cell ratio were assessed by flow cytometry to evaluate their proinflammatory and anti-inflammatory functional properties. Results: Twelve RIS, 46 CIS, 31 RRMS patients, and 36 HCs were enrolled. We observed that a high IL-6/IL-10–producing B-cell ratio in patients with RIS/CIS was associated with the evolution of the disease in the short term (6 months). This imbalance in cytokine production was mainly explained by an alteration of the production of IL-10 by B cells, especially for the transitional B-cell subset. In addition, a significant increase in IgD−/CD27− B cells was detected in patients with CIS and RRMS compared with HCs (p = 0.01). Apart from this increase in exhausted B cells, no other variation in B-cell subsets was observed. Conclusions: The association between a high IL-6/IL-10–producing B-cell ratio and the evolution of patients with RIS/CIS suggest a skew of B cells toward proinflammatory properties that might be implicated in the early phases of MS disease.

Histoire naturelle de l’hypertension artérielle pulmonaire au cours de la sclérodermie systémique : complication tardive ou précoce ?

David Launay, Marc Humbert, Luc Mouthon, Guillaume Lefebvre, Alice Berezné, PierreYves Hatron Pierre Clerson, Gérald Simonneau, Eric Hachulla. Service de Médecine Interne, Centre National de Référence de la Sclérodermie, Hôpital ClaudeHuriez, Université Lille 2; CHRU Lille; 1, Place de Verdun, 59037 Lille Cedex, France ; Service de Pneumologie et Réanimation Respiratoire, Centre National de Référence de l’Hypertension Artérielle Pulmonaire, Hôpital Antoine-Béclère, Assistance Publique-Hôpitaux de Paris, université Paris Sud-11, 92141 Clamart cedex, France ; 3 Service de Médecine Interne, Centre National de Référence de la Sclérodermie et des Vascularites ; Hôpital Cochin, Assistance Publique-Hôpitaux de Paris ; Université Paris Descartes, UPRES EA 4058, , Paris, France ; Orgamétrie Biostatistiques, Roubaix, France