Antimyeloperoxidase (anti-MPO) antibodies, but not antiproteinase 3 (anti-PR3) antibodies, have a prominent impact on monocytes stimulated with toll-like receptor (TLR) agonists in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), according to researchers from the King’s College London in the UK.
When monocytes were stimulated with lipopolysaccharide (LPS) or resiquimod (R848), the researchers observed a marked and consistent reduction in the secretion of the anti-inflammatory cytokine interleukin-10 (IL-10), as well as significant changes in cell-surface markers in the presence of anti-MPO immunoglobulin G (IgG), but not anti-PR3 IgG.
Moreover, anti-MPO IgG prolonged monocyte survival even in the absence of TLR stimulation. These effects were dependent on the Fc receptor CD32a.
“The activation of a profibrotic transcriptional response by anti-MPO but not anti-PR3 IgG may give insights into the differences in disease phenotype,” the researchers wrote in the Journal of Autoimmunity.
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The study demonstrated that anti-MPO IgG had variable effects on the transcriptional response of monocytes upon TLR stimulation. Despite the variability, the researchers were able to identify a core set of transcripts likely to play an important role in the response.
In the absence of TLR stimulation, anti-MPO IgG had a substantial impact on the transcriptional response, with significant enrichment of genes related to the extracellular matrix and extracellular matrix-associated proteins.
The team conducted extensive experiments on monocytes isolated from peripheral blood mononuclear cells from healthy controls. They exposed monocytes to various conditions, including TLR agonists, anti-MPO IgG, and anti-PR3 IgG, alongside appropriate controls. Then, they performed a comprehensive analysis of the whole transcriptome of monocytes.
In addition, the researchers used blood or plasma exchange fluid obtained from patients with AAV and circulating MPO-ANCA or PR3-ANCA.
Flórez-Barrós F, Bearder S, Pavlidis P, Robson MG. Antimyeloperoxidase antibodies modulate inflammatory responses and activate profibrotic pathways in human monocytes. J Autoimmun. 2023;139:103060. doi:10.1016/j.jaut.2023.103060