A prototypical phenotype for neutrophils in lupus: the potential contribution of immune complexes

Abstract

PurposeSystemic lupus erythematosus is an autoimmune disease hallmarked by a plethora of autoantibodies, interferon-signature, auto-immune complexes, dysregulation of soluble factors in circulation, and abnormal neutrophils. We characterized the neutrophil phenotype in a cohort of lupus patients and assessed the implication of the cells environment. MethodsBlood samples were analyzed for neutrophil expression of surface markers and viability, by flow cytometry. Neutrophils from healthy volunteers were stimulated with serum samples from lupus patients. Plasma samples were subjected to multiplex analysis. Whole blood and isolated neutrophils were stimulated with lupus-relevant soluble factors or with heat-aggregated IgGs that mimic the engagement of Fc gamma (Fc{gamma}) receptors by immune complexes, for viability and activation analysis. ResultsLupus neutrophils displayed significant alterations in the expression of surface markers of adhesion, complement regulation, degranulation, and immune complex response. They also had reduced viability and increased apoptosis. Stimulation of healthy neutrophils with lupus serum increased apoptosis. Lupus-relevant soluble factors accelerated neutrophil apoptosis. Heat-aggregated IgGs mirrored most of the key alterations in viability and surface marker expression observed in lupus neutrophils. ConclusionThis study offers a prototypical phenotype for neutrophils in lupus, characterized by shortened viability, partial degranulation, heightened adhesion capacity, and responsiveness to complement activation. It also points to Fc{gamma} receptors engagement as a major driver of the phenotype observed herein. Finally, results emphasize the therapeutic potential of targeting neutrophil-immune complex interactions and the inflammatory plasma milieu in lupus, from which neutrophil dysfunction is largely acquired. HIGHLIGHTSO_LINeutrophils from patients with lupus exhibit abnormal phenotype and viability. C_LIO_LIAnalysis of plasmas in lupus reveals altered levels of analytes. C_LIO_LIStimulation of healthy whole blood with a model of immune complexes reproduces most of the neutrophil phenotypic abnormalities observed in lupus. C_LIO_LINeutrophil abnormalities in lupus are largely acquired, rather than representing subsets. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/653336v2_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@18547c1org.highwire.dtl.DTLVardef@129f495org.highwire.dtl.DTLVardef@178a36corg.highwire.dtl.DTLVardef@131158b_HPS_FORMAT_FIGEXP M_FIG C_FIG