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Loss of Nicotinamide Nucleotide Transhydrogenase Potentiates Autoimmunity in the C57BL/6J Mouse Strain
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Perl, Andras
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Summer 2023
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2023-06
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In Chapter I, we will discuss recent studies showing that mTOR pathway activation plays a critical role in the pathogenesis of autoimmune diseases. The mTOR pathway is a central regulator of growth and survival signals, integrating environmental cues to control cell proliferation and differentiation. Activation of mTOR underlies inflammatory lineage specification, and mTOR blockade-based therapies show promising efficacy in several autoimmune diseases. In Chapter II, we will discuss nicotinamide nucleotide transhydrogenase, NNT, an enzyme localized to the inner mitochondrial membrane which contributes to mitochondrial NADPH production. In C57BL/6J mice, the spontaneous loss of NNT creates a natural model for researching oxidative stress and its ability to potentiate autoimmune disease via the mTOR/AKT pathway. We identify the loss of NNT as a driver of autoimmune pathogenesis, including in multiple sclerosis and ulcerative colitis models. In sum, we highlight the link between upstream pathways of mTOR activation, particularly oxidative stress, and the downstream pathological shift in autoimmune disease due to mTOR activation. We show the novel finding that loss of NNT in the C57BL/6J mouse potentiates autoimmune pathogenesis, and that restoration of wild-type NNT reduces disease burden in select autoimmune models via restoration of redox balance.