ANCA autoantigen gene expression highlights neutrophil heterogeneity where expression in normal-density neutrophils correlates with ANCA-induced activation.

Abstract

ANCA vasculitis is an autoimmune disease with increased expression of the autoantigen genes, myeloperoxidase (MPO) and proteinase 3 (PRTN3), but the origin and significance of expression is less distinct. To clarify this, we measured MPO and PRTN3 messenger RNA in monocytes, normal-density neutrophils, and in enriched leukocytes from peripheral blood mononuclear cells. Increased autoantigen gene expression was detected in normal-density neutrophils and enriched leukocytes from patients during active disease compared to healthy individuals, with the largest difference in enriched leukocytes. RNA-seq of enriched leukocytes comparing active-remission pairs identified a gene signature for low-density neutrophils. Cell sorting revealed low-density neutrophils contained mature and immature neutrophils depending on the presence or absence of CD10. Both populations contributed to autoantigen expression but the frequency of immature cells in low-density neutrophils did not correlate with low-density neutrophil MPO or PRTN3 expression. Low-density neutrophils were refractory to MPO-ANCA induced oxidative burst, suggesting an alternative role for low-density neutrophils in ANCA vasculitis pathogenesis. In contrast, normal-density neutrophils were activated by MPO-ANCA and monoclonal anti-PR3 antibody. Normal-density neutrophil activation correlated with MPO and PRTN3 mRNA. Increased autoantigen gene expression originating from the mature low-density and normal-density neutrophils suggests transcriptional dysregulation is a hallmark of ANCA vasculitis. Thus, the correlation between autoantigen gene expression and antibody-mediated normal-density neutrophil activation connects autoantigen gene expression with disease pathogenesis.

• Authors: Britta E Jones, Carolina A Herrera, Christian Agosto-Burgos, Joshua Starmer, William A Bass, Caroline J Poulton, Lauren Blazek, Candace D Henderson, Yichun Hu, Susan L Hogan, Peiqi Hu, Hong Xiao, Eveline Y Wu, Dhruti P Chen, J Charles Jennette, Meghan E Free, Ronald J Falk, Dominic J Ciavatta
• Journal: Kidney international (Kidney Int) Vol. 98 Issue 3 Pg. 744-757 (09 2020) ISSN: 1523-1755 [Electronic] United States
• PMID: 32446935 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Antineutrophil Cytoplasmic
• Autoantigens
• Peroxidase
• Myeloblastin

Topics

• Antibodies, Antineutrophil Cytoplasmic
• Autoantigens (genetics)
• Gene Expression
• Humans
• Leukocytes, Mononuclear
• Myeloblastin
• Neutrophil Activation
• Neutrophils
• Peroxidase (genetics)