The causes of systemic lupus erythematosus (SLE) are unknown, however, the pathogenesis is attributed, at least in part, to T-cell dysfunction. Preliminary studies reveal activation of the mechanistic target of rapamycin complex 1 (mTORC1) in lupus T cells which precedes disease flares and causes pro-inflammatory lineage specification in SLE patients. Upstream of mTORC1, depletion of reduced glutathione (GSH), enhanced production of reactive oxygen intermediates (ROI), and defective mitophagy are newly identified. Outcomes of a double-blind placebo-controlled clinical trial show that therapeutic reversal of GSH depletion by N-acetylcysteine (NAC) blocks mTORC1 in vivo. Therefore, the proposed studies will address a critical knowledge gap by determining how metabolic pathways that control oxidative stress and normal T-cell development contribute to lupus pathogenesis. The central hypothesis is that primarily GSH depletion drives the pathogenesis of SLE through mTORC1-dependent expansion of pro-inflammatory T cells. The rationale for the proposed research is that, after elucidating the genetically controlled metabolic pathways that promote GSH depletion and mTORC1 activation and thus trigger lupus pathogenesis, new and potentially synergistic approaches can be used for prevention and treatment of SLE. Guided by compelling preliminary data, our hypothesis will be tested in three Specific Aims: 1) to delineate the metabolic program that causes the accumulation of oxidative stress-generating mitochondria in lupus T cells; 2) to identify the role of GSH depletion in mTORC1-dependent T-cell lineage specification in longitudinal studies of SLE patients; and 3) to determine the role of GSH depletion in the pathogenesis of systemic autoimmunity in lupus-prone mice.
Under Aim 1, S-nitrosylation of ND3 subunit in complex I of the electron transport chain and lupus-linked mitochondrial DNA (mtDNA) polymorphisms in ND2 and ATP6 will be assessed as causes of increased ROI production.
Under Aim 2, GSH depletion and mTORC1 activation will be genetically targeted in vitro for reversing pro-inflammatory T-cell development focusing on CREM-a/IL-4-mediated trans-differentiation of CD8 T cells to DN T cells and HIF1a/IL-17-mediated depletion of Tregs in SLE patients.
Under Aim 3, GSH depletion will be modeled by the inactivation of transaldolase and evaluated as a cause of disease pathogenesis in lupus-prone mice. The proposed research is significant because it will advance our understanding of T-cell lineage development in normal and autoimmune conditions with relevance for identifying new treatment targets in SLE. The approach is innovative as it departs from the status quo by utilizing metabolic pathway genes to regulate T-cell development. The results will open new horizons in our understanding of the metabolic pathways that control oxidative stress and its role in disease pathogenesis while providing new mechanistic targets for treatment of SLE.
The proposed research is focused on the pathogenesis of systemic lupus erythematosus (SLE), a chronic autoimmune disease of unknown etiology. This project is relevant to public health as SLE affects 0.1% of the US population, mainly women of child-bearing age, with 10% mortality in 5 to 10 years. There is an unmet medical need as currently used drugs are only partially effective and carry significant side effects. Development of new treatments has been hampered by gaps in our understanding of pathogenesis. This project will result in new, fundamental knowledge of metabolic pathways that control immune system dysfunction in SLE. The expected discoveries will be relevant for elucidating the pathogenesis and identifying new targets for treatment.
|Lai, Zhi-Wei; Kelly, Ryan; Winans, Thomas et al. (2018) Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391:1186-1196|
|Perl, Andras (2018) mTOR-dependent autophagy contributes to end-organ resistance and serves as target for treatment in autoimmune disease. EBioMedicine 36:12-13|
|Minchenberg, Scott Brian; Chaparala, Geeta; Oaks, Zachary et al. (2018) Systemic lupus erythematosus-myasthenia gravis overlap syndrome: Presentation and treatment depend on prior thymectomy. Clin Immunol 194:100-104|
|Kato, Hiroshi; Perl, Andras (2018) Blockade of Treg Cell Differentiation and Function by the Interleukin-21-Mechanistic Target of Rapamycin Axis Via Suppression of Autophagy in Patients With Systemic Lupus Erythematosus. Arthritis Rheumatol 70:427-438|
|Doherty, Edward; Perl, Andras (2017) Measurement of Mitochondrial Mass by Flow Cytometry during Oxidative Stress. React Oxyg Species (Apex) 4:275-283|
|Perl, Andras (2017) Review: Metabolic Control of Immune System Activation in Rheumatic Diseases. Arthritis Rheumatol 69:2259-2270|
|Oaks, Zachary; Winans, Thomas; Huang, Nick et al. (2016) Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years. Curr Rheumatol Rep 18:73|
|Perl, Andras (2016) Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity. Arthritis Rheumatol 68:2568-2570|
|Buskiewicz, Iwona A; Montgomery, Theresa; Yasewicz, Elizabeth C et al. (2016) Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus. Sci Signal 9:ra115|
|Perl, Andras (2016) Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol 12:169-82|
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