Transcriptome analysis suggests a central role for complement and C5aR1 in neutrophil activation in APS.

Antiphospholipid syndrome (APS) is characterized by thrombosis and/or recurrent pregnancy loss in the presence of persistently positive antiphospholipid antibodies (aPL). APS, particularly the most severe variant, catastrophic APS (CAPS) is associated with complement activation and a high incidence of complement regulatory gene mutations [ [1] Chaturvedi S. Braunstein E.M. Yuan X. et al. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood. 2020; 135: 239-251 Crossref PubMed Scopus (112) Google Scholar ]; moreover, complement inhibition has been effective in preventing recurrent thrombosis in some patients with APS [ [2] Hubben A. McCrae K.R. Emerging therapies in antiphospholipid syndrome. Transfus. Med. Rev. 2022; 36: 195-203 Crossref Scopus (0) Google Scholar ]. The pathogenesis of thrombosis in APS is not well understood, and likely multifactorial [ [3] Knight J.S. Branch D.W. Ortel T.L. Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management. Bmj. 2023; 380e069717 Google Scholar ]. aPL have been reported to activate multiple cell types, including endothelial cells, platelets and monocytes to induce a prothrombotic phenotype [ [4] Knight J.S. Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin. Immunopathol. 2022; 44: 347-362 Crossref PubMed Scopus (35) Google Scholar ]. Recent studies have also suggested an important role of neutrophils in the pathogenesis of APS [ [3] Knight J.S. Branch D.W. Ortel T.L. Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management. Bmj. 2023; 380e069717 Google Scholar ]. Neutrophils from APS patients express an interferon gene signature [ [5] Knight J.S. Meng H. Coit P. et al. Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight. 2017; 2 Crossref Google Scholar ], and neutrophils isolated from normal individuals are activated by aPL to release prothrombotic neutrophil extracellular traps (NETs) [ [4] Knight J.S. Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin. Immunopathol. 2022; 44: 347-362 Crossref PubMed Scopus (35) Google Scholar ]. However, there is little information available concerning the role of complement in activation of individual cell types by aPL. Transcriptomics is a novel approach that can offer insight into the importance of such interactions.