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Abstract
Introduction Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease. Patients who present with clinical symptoms and immunologic abnormalities suggestive of SLE but do not meet the classification criteria are diagnosed with incomplete SLE (iSLE).1 In SLE, chronic inflammation may lead to excessive production of reactive oxygen species (ROS), inducing oxidative stress. Serum free thiols reliably reflect systemic oxidative stress since they are readily oxidized by reactive species. Lastly, the transcription factor Nrf2 (NF-E2 related factor 2) is a central regulator of cellular anti-oxidative and anti-inflammatory responses and its abundance is regulated through binding to Keap1 (Kelch ECH-associating protein 1) in the cytosol.2
Objective The aim of this study was to investigate oxidative stress in iSLE patients compared to SLE and healthy controls (HC) by measuring levels of serum free thiols and expression of Nrf2, KEAP1 and the downstream target genes. Correlations among genes and free thiols were analysed.
Methods Thirty-seven iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 42 SLE patients with quiescent disease (fulfilling ACR criteria, SLEDAI ≤4), and HC were included. Serum free thiols levels were measured as previously described.3 mRNA levels of Nrf2 and its downstream target genes were measured in whole blood by using RT-qPCR.
Results Levels of free thiols were significantly decreased in SLE patients compared to HC, and median levels of iSLE also seemed lower than in HC. indicative of a less favorable redox status (figure 1).
Although median levels of several genes were lower in patient groups, only expression of KEAP1 and Catalase (CAT) was significantly decreased in iSLE and SLE compared to HC (figure 2). No correlation was found between serum free thiols and oxidative stress genes, although gene expression was interrelated in SLE and iSLE (data not shown).
Conclusion A tendency of reduced serum free thiols levels and reduced gene expression of the Nrf2 pathway was found in iSLE and SLE patients, indicating a reduced anti-oxidative capacity. The relation of Nrf2 and its downstream target genes with inflammation and disease progression in patients is still under investigation.
Funding L. Liu is supported by the Chinese Scholarship Council, grant number: 202006170049.
Disclosure of Interest None declared.
Serum free thiol levels in iSLE and SLE patients and healthy controls. (i)SLE, (incomplete) systemic lupus erythematosus, HC, healthy controls
Expression of NFE2L2, KEAP1 and downstream genes in iSLE, SLE and HC. NFE2L2/Nrf2: Transcription factor NF-E2 related factor 2, KEAP1: Kelch-like ECH-associated protein 1, CAT: Catalase, NQO1: NAD(P)H: quinone oxidoreductase 1, HMOX1: Haem oxygenase 1, TXN1: Thioredoxin 1, (i)SLE: (incomplete) systemic lupus erythematosus, HC: healthy controls. ns: not significant, statistical significance: * p < 0.05, ** p < 0.005, *** p < 0.0005.
References
Lambers WM, et al. From incomplete to complete systemic lupus erythematosus; a review of the predictive serological immune markers. Semin Arthritis Rheum, 2021;51(1):43–48.
Barati MT, DJ Caster. The Potential of Nrf2 Activation as a Therapeutic Target in Systemic Lupus Erythematosus. Metabolites, 2022;12(2).
Bourgonje AR, et al. Serum free thiols are superior to fecal calprotectin in reflecting endoscopic disease activity in inflammatory bowel disease. Antioxidants (Basel), 2019;8(9).
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