Genomic Identification of Low-Density Granulocytes and Analysis of Their Role in the Pathogenesis of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of low-density granulocytes (LDGs) with a heightened capacity for spontaneous NETosis, but the contribution of LDGs to SLE pathogenesis remains unclear. To characterize LDGs in human SLE, gene expression profiles derived from isolated LDGs were characterized by weighted gene coexpression network analysis, and a 92-gene module was identified. The LDG gene signature was enriched in genes related to neutrophil degranulation and cell cycle regulation. This signature was assessed in gene expression datasets from two large-scale SLE clinical trials to study associations between LDG enrichment, SLE manifestations, and treatment regimens. LDG enrichment in the blood was associated with corticosteroid treatment as well as anti-dsDNA, low serum complement, renal manifestations, and vasculitis, but the latter two of these associations were dependent on concomitant corticosteroid treatment. In addition, LDG enrichment was associated with enrichment of gene signatures induced by type I IFN and TNF irrespective of corticosteroid treatment. Notably, LDG enrichment was not found in numerous tissues affected by SLE. Comparison with relevant reference datasets indicated that LDG enrichment is likely reflective of increased granulopoiesis in the bone marrow and not peripheral neutrophil activation. The results have uncovered important determinants of the appearance of LDGs in SLE and have emphasized the likely role of LDGs in specific aspects of lupus pathogenesis.