Characterization of low-density granulocytes in autoinflammatory disorders

Authors

• PD Mistry
• M Purmalek
• A Jones
• AK Ombrello
• I Aksentijevich
• DL Kastner
• MJ Kaplan

Abstract

Autoinflammatory disorders (AD) are characterized by recurrent fevers associated with systemic symptoms in the absence of adaptive immune responses. Profound dysregulations in various innate immune pathways including the inflammasome-mediated IL-1 signaling are characteristic of these syndromes. While previous studies have revealed that neutrophils may play critical roles in promoting inflammation in AD, whether specific neutrophil subsets and neutrophil processes play pathogenic roles in these diseases remains to be characterized. We examined the presence of distinct proinflammatory neutrophil subsets in AD and assessed their pathogenic potential. Blood was obtained from healthy controls and from patients with Familial Mediterranean Fever (FMF), Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cryopyrin Associated Periodic Syndromes (CAPS), Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (APLAID), and mutation negative AD. Normal density granulocytes (NDGs) were isolated by dextran sedimentation and PBMCs were isolated by Ficoll gradient. Presence of low-density granulocytes (LDGs) was assessed by a negative selection magnetic bead procedure from the PBMC fraction. LDGs were detected in all AD samples tested. Compared to healthy control NDGs and autologous NDGs, LDGs from AD patients displayed an enhanced ability to spontaneously form NETs. The proinflammatory cytokine IL-1β was externalized in NETs from NDGs and LDGs from AD patients. NDGs and LDGs from AD patients displayed distinct mRNA expression profile for inflammasome-related proteins and nucleic acid-sensing TLRs. Collectively, these preliminary results suggest that LDGs are present in AD, may represent a potential source for IL-1β production and contribute to tissue damage and disease manifestations.

Scientific Focus Area: Immunology

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