Modulation of interferon-[alpha] secretion by activated platelets in systemic lupus erythematosus.

Pierre Duffau,Jean-François Moreau,Jean-Luc Pellegrin,Frédéric Batteux,Bernard Weill,Patrick Blanco,Julien Seneschal,Jean-François Viallard,Carole Nicco

doi:10.1038/npre.2008.1528.1

Abstract

AbstractType I interferons play a key role in systemic lupus erythematosus (SLE) pathogenesis as an "IFN signature" is found in the majority of patients with active SLE. Immune complexes are internalized by plasmacytoid dendritic cells (DC) via Fc-[gamma] ReceptorIIA, reach the endosomal compartment and activate IFN-[alpha] secretion through TLR7/9-dependent pathways. Naturally occurring differences in expression of the TLR7/9 gene as well as factors that modulate TLR7/9 expression, including CD154 could therefore contribute to SLE pathogenesis. Although its origin is not elucidated CD154 is hyperexpressed in SLE patients, and is important for the differentiation of autoantibody-secreting cells. We hypothesized that platelets which are an abundant source of CD154, and which can mediate proinflammatory effects could be an actor involved in SLE pathogenesis. Platelets from SLE patients are activated in vivo by circulating immune complexes which are abundant in SLE sera, via a CD32-dependent mechanism. Activated platelets formed aggregates with antigen-presenting cells in SLE patients and enhanced interferon-[alpha] secretion induced by immune-complexes stimulated plasmacytoid DCs. Finally, in vivo depletion of platelets and megakaryocytes in NZBxNZW(F1) lupus prone mice improved all parameters assessing disease activity, whereas transfusion of activated platelets worsened the disease course. Altogether, these data identify platelets as a mediator of SLE pathogenesis and a new therapeutical target.

Highlights

INTRODUCTORY PARAGRAPH Type I interferons play a key role in systemic lupus erythematosus (SLE) pathogenesis[1,2] as an “IFN signature” is found in the majority of patients with active SLE3,4
Platelets from SLE patients are activated in vivo by circulating immune complexes which are abundant in SLE sera, via a CD32-dependent mechanism
Platelets isolated from SLE patients with a wide range of disease activity (Supplementary Table 1) but not from normal individuals, spontaneously expressed CD154 (CD40 ligand) and CD62P (P-Selectin) at their membrane surface, two markers which are a hallmark of platelet activation [9, 11]

Summary

AUTHORS CONTRIBUTIONS

P.D., J.S., did the experiments on human SLE. N.C., F.B. and B.W. did the experiment in mice. J.F.V. and J.L.P. conducted the sampling and clinical study of SLE patients. P.D., J.S. and F.B. participated in the interpretation of the results and the editing of the manuscript

Platelets activation

Findings

Platelet transfusion