Lyndsey Strowd

 Introduction. Compared to healthy subjects, patients with rheumatoid arthritis have characteristically excessive G6PD activity which generates an overabundance of reducing elements leading to an over usage of ROS. This depletion of ROS is found to be correlated with insufficient ATM activation further leading to a RA T cell bypass of G2/M checkpoint in the cell cycle. In RA T cells, it is found this poor distribution of mitochondrial ROS generation and reducing antioxidant toxicity results in an imbalance of T effector cell versus Treg cell differentiation. Healthy T cells, with ROS scavenging abilities, were found to differentiate 18- 32% IFN-ϒ producing T cells, as compared with ROS suppressed T cells increased Th1 lineage commitment up to 33-40%. Methods. A human synovium NSG chimeric mouse model was used. This model exhibited RA T cells preferential lineage differentiation to Th1 and Th17 in synovial tissue. In an additional study, a Transwell-assay was performed and RA T cells were found to be hypermigratory even in the absence of chemokines. ROS inducing agents, such as menadione and buthionine sulfoximine (BSO), were used to increase intracellular levels of ROS in RA human synovial chimeras. Through Transwell migration assays, both treatments exhibited downregulation of hypermobility of T cells through downregulation of reductive stress. Results. The infiltrated synovial tissue with RA T cells contained significantly higher amount of IFN-ϒ and IL-17, along with other proinflammatory cytokines than healthy controls. When menadione and buthionine suloximine (BSO) were introduced into the RA human synovial chimeras, both were shown to be beneficial in lowering expression levels of proinflammatory cytokines (e.g. TNF-α, IL-1β, IL-6), proinflammatory T cells (IFNϒ, IL-17). Conclusions. Studies have shown that RA T cells have an imbalance of T effector and Treg cell differentiation in association with higher levels of G6PD in the pentose phosphate pathway (PPP) which generates products: pentoses, ribose-5-phosphate, and NADPH. NADPH is a big player in generating reduced glutathione which protects against ROS toxicity. NADPH, and reduced glutathione was shown to be markedly increased while ROS levels were decreased in RA T cell, as compared to a healthy T cell. Introduction of ROS inducing agents lowered the expression levels of proinflammatory cytokines which may prove to be of interest for potential RA targeting therapies.

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