Acquired Neutrophil Dysregulation in Systemic Lupus Erythematosus: A Central Role for Fc gamma Receptor Engagement

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 hypothesized that lupus humoral "environment" could be responsible, at least in part, for these neutrophil abnormalities. We characterized the neutrophil phenotype in a cohort of lupus patients and assessed the impact of the "lupus environment". MethodsBlood samples were analyzed for neutrophil viability and expression of surface markers, by flow cytometry. Neutrophil-enriched suspensions were stimulated with serum samples from lupus patients, and apoptosis was monitored in real-time. Plasma samples were subjected to multiplex analysis. Whole blood and neutrophil-enriched suspensions were stimulated with lupus-relevant soluble factors or with heat-aggregated IgGs, which mimic the engagement of Fc gamma (Fc{gamma}) receptors by immune complexes, for viability and activation analysis. ResultsLupus neutrophils had reduced viability and increased apoptosis. They also displayed significant alterations in the expression of surface markers of adhesion, complement regulation, degranulation, and immune complex response. 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 demonstrates that Fc{gamma} receptors engagement is a major driver of the phenotype observed in lupus neutrophils, including increased apoptosis and dysregulated surface marker expression. These findings suggest that lupus neutrophils may not be inherently defective but rather educated by lupus-associated environmental cues.