Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity

Abstract

Recent studies have renewed the interest on the potential role that neutrophils play in the development of systemic lupus erythematosus (SLE) and other autoimmune conditions. A distinct subset of proinflammatory, low-density granulocytes (LDGs) isolated from the peripheral blood mononuclear cell fractions of patients with SLE has been described. While the origin and role of LDGs needs to be fully characterized, there is evidence that these cells may contribute to lupus pathogenesis and to the development of end-organ damage through heightened proinflammatory responses, altered phagocytic capacity, enhanced ability to synthesize type I Interferons and to kill endothelial cells. Furthermore, these cells readily form neutrophil extracellular traps (NETs), a phenomenon that may promote autoantigen externalization and organ damage. This review examines the biology and potential origin of LDGs, describes the ultrastructural characteristics of these cells, and discusses their putative pathogenic role in systemic autoimmune diseases.

Neutrophil extracellular traps — the dark side of neutrophils

“…Accordingly, PAD4-deficient mice are incapable of generating NETs; however, these animals do not phils that have been activated and partially degranulated (36,37). Whether such phenotypic differences are relevant to the ability of these cells to undergo NETosis is not known, but circumstantial evidence points in this direction, as discussed below.…”

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

“…Neutrophils exposed to ribonucleoprotein immune complexes are liable to undergo NETosis through the induction of mitochondrial reactive oxygen species (ROS) [34]. Moreover, SLE patients have a distinct subset of proinflammatory neutrophils, lowdensity granulocytes (LDGs) [35], which have an enhanced capacity of forming NETs [20] and synthesizing mitochondrial ROS [34]. Taken together, all these studies provide convincing evidence that NETosis is one of the major sources of self-dsDNA, and a defect in NETs clearance plays an important role in SLE pathogenesis.…”

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

“…Villanueva et al (46) showed that low-density granulocytes spontaneously can form NETs. Low-density granulocytes are a neutrophil subset that can be found in the mononuclear cell fraction, and they have been reported to be present in all SLE patients (48). Comparing gene array profiles of low-density granulocytes to normal density neutrophils showed that low-density granulocytes significantly overexpressed mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus neutrophils and control neutrophils.…”