Peptidoglycan activates synovial tissue CD4+ T cells in inflammatory osteoarthritis 3923

Abstract Description Peptidoglycan (PG) is the major cell wall component of bacteria and is a pathogen-associated molecular pattern (PAMP). We have shown that PG is a potent CD4+ T cell adjuvant in vitro and is present in macrophages and synovial fibroblasts within inflamed synovial tissue of a majority (33/56, 59%) of advanced osteoarthritis (OA) patients undergoing knee replacement surgery, with no history of joint infection. We hypothesized that PG in synovial tissue is driving synovial inflammation via activation of tissue-localized CD4+ T cells. Using traditional histopathology, immunohistochemistry, and spatial imaging (Akoya Phenocycler Fusion) of discarded synovial tissue from 25 advanced OA patients following knee replacement surgery, we observed PG within inflammatory foci that contained large numbers of CD4+ and CD8+ T cells. There was a significant correlation between CD4-CD8 T cell spatial distance and overall inflammation score by histopathology (Pearson’s r = 0.59, p = 0.003). Furthermore, PG levels correlated with the spatial distance between CD4+ T cells and CD31+ endothelial cells (r = 0.45, p = 0.03), as well as patient-reported outcome scores (r = 0.647, p = 0.006). These results suggest that CD4+ T cells are activated by presence of PG, and CD4+ T cell interactions between CD8+ T cells and endothelial cells may be driving inflammatory synovitis, shedding light on possible mechanisms of pathogenesis in advanced OA. Funding Sources U.S. Department of Defense CDMRP Award W81XWH-22-1-0728 Topic Categories Immune Mechanisms of Human Disease (HUM)