Biological roles and clinical translation of low-density neutrophils in rheumatic, autoimmune and inflammatory diseases: paradigm reconstruction and unresolved questions

Neutrophils are increasingly recognized as a heterogeneous lineage rather than a uniform population of short-lived innate effector cells. Low-density neutrophils (LDNs; often termed low-density granulocytes, LDGs) are operationally defined by their co-sedimentation with peripheral blood mononuclear cells after density-gradient centrifugation, but this physical definition encompasses cells with different maturation states, origins and functions. In rheumatic and autoimmune diseases, expansion of the low-density compartment is associated with disease activity, autoantibody titers, interferon signatures and organ involvement. Mechanistic studies implicate enhanced neutrophil extracellular trap (NET) formation, oxidized mitochondrial DNA, platelet-neutrophil interactions, inflammasome activation and endothelial injury in disease amplification. However, LDNs can also be detected in healthy individuals, and immunoregulatory low-density neutrophil states occur in other biological contexts, underscoring that low density is not synonymous with pathogenicity. This Review critically integrates current evidence on LDN origin, heterogeneity, disease associations and clinical translation. Particular emphasis is placed on the unresolved distinction between correlation and causation, the limitations of density-based nomenclature, and the evidentiary gap between mechanistic observations and therapeutic claims. We distinguish findings demonstrated in rheumatic disease from strategies extrapolated from general neutrophil biology or tumor-associated PMN-MDSCs, and outline the methodological and experimental steps required for molecularly defined biomarkers and subset-specific interventions.