Systemic Activation of Neutrophils by Immune Complexes Is Critical to IgA Vasculitis.

Journal of immunology (Baltimore, Md. : 1950) 2022 Sep 15

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In IgA vasculitis (IgAV) perivascular deposition of IgA1 immune complexes (IgA-ICs) is traditionally considered the fundamental trigger for polymorphonuclear neutrophil (PMN)-mediated damage. We propose that IgA-IC deposition, although mandatory, is not sufficient alone for IgAV. Serum IgA-IC levels and IgA-IC binding to PMNs were quantified in IgAV patients and controls. Activation of PMNs was evaluated by neutrophil extracellular trap (NET) release, adherence, and cytotoxicity assays and in a flow system to mirror conditions at postcapillary venules. In vitro results were related to findings in biopsies and a mouse vasculitis model. During acute IgAV flares we observed elevated serum levels of IgA-ICs and increased IgA-IC binding to circulating PMNs. This IgA-IC binding primed PMNs with consequent lowering of the threshold for NETosis, demonstrated by significantly higher release of NETs from PMNs activated in vitro and PMNs from IgAV patients with flares compared with surface IgA-negative PMNs after flares. Blocking of FcαRI abolished these effects, and complement was not essential. In the flow system, marked NETosis only occurred after PMNs had adhered to activated endothelial cells. IgA-IC binding enhanced this PMN tethering and consequent NET-mediated endothelial cell injury. Reflecting these in vitro findings, we visualized NETs in close proximity to endothelial cells and IgA-coated PMNs in tissue sections of IgAV patients. Inhibition of NET formation and knockout of myeloperoxidase in a murine model of IC vasculitis significantly reduced vessel damage in vivo. Binding of IgA-ICs during active IgAV primes PMNs and promotes vessel injury through increased adhesion of PMNs to the endothelium and enhanced NETosis. Copyright © 2022 by The American Association of Immunologists, Inc.

Citation

Sarah Mayer-Hain, Kathleen Gebhardt, Matthias Neufeld, Jan M Ehrchen, Karen Molyneux, Jonathan Barratt, Eva Nattkemper, Dennis Gerloff, Johannes Roth, Thomas Vogl, Karin I Pappelbaum, Cord Sunderkötter. Systemic Activation of Neutrophils by Immune Complexes Is Critical to IgA Vasculitis. Journal of immunology (Baltimore, Md. : 1950). 2022 Sep 15;209(6):1048-1058