177. Molecular determinants of myeloperoxidase-ANCA glomerulonephritis: transcriptomic analysis across three species identifies the inflammasome as a conserved pathogenic pathway

Background: Human myeloperoxidase (MPO)-anti-neutrophil cytoplasm antibodies (ANCA) vasculitis causes crescentic glomerulonephritis that results in glomerular destruction. This has been modelled in rats (Experimental Autoimmune Vasculitis or EAV, an active model) and mice (Murine Experimental Vasculitis or MEV, a passive model). To investigate conserved and divergent molecular pathways involved in glomerular injury, we analysed the glomerular transcriptome in EAV, MEV and in humans with MPO-ANCA vasculitis. We reported previously that 179 (3.0%) of the 6006 genes with altered expression were common across all three species, with 27 of these (0.4%) regulated in opposite directions between human and both rodent species. Methods: Species-specific transcriptional networks were generated following glomerular microdissection and microarray analysis and compared with a co-citation network matching algorithm. Immunohistochemistry (IHC) was used to quantify tissue protein expression. Results: The murine model shared more similarly regulated genes with the human disease than the rat model. Three molecular pathways, dedicated primarily to inflammation, integrin activation and antigen presentation, were upregulated in all three species. Of the 43 other co-regulated pathways (none of which were shared by both mouse and rat), 14 (12 and 2 in mouse and rat respectively) were regulated in the opposite direction between rodent and human, the core inflammasome component gene Pycard (also known as ASC) was strongly upregulated (Fig 1A) in all three tissues. We therefore went on to assess tissue protein expression of ASC speck in the inflamed glomeruli by IHC. We found similar marked upregulation of ASC speck in all three species (Fig 1b-D). Conclusions: We have identified both conserved and divergent molecular pathways in the glomeruli of vasculitic glomeruli, the latter potentially exploitable as features underpinning the rapid recovery of rodent vasculitis with minimal scarring. The inflammasome pathway is also strongly upregulated in all three species, suggesting another potential therapeutic target. Disclosures: None Figure 1. (A) Volcano plot illustrating upregulated and down-regulated genes in glomerular tissue of humans with MPO-AAV. Protein expression of ASC speck in glomeruli of (B) rats, (C) mice and (D) humans with MP