Background/Purpose:

Systemic lupus erythematosus (SLE) patients’ T cells exhibit mitochondrial dysfunction, characterized by the persistent elevation of the mitochondrial transmembrane potential (Δψ_m) or mitochondrial hyperpolarization (MHP), that predisposes to oxidative stress, activation of the mammalian target of rapamycin (mTOR), and pro-inflammatory death via necrosis. Here, we evaluated metabolic checkpoints of mitochondrial dysfunction as biomarkers of disease activity in patients with SLE.

Methods:

49 female SLE patients and 41 female healthy controls were matched for 209 independent study visits. SLE disease activity was assessed by using the British Isles Lupus Assessment Group (BILAG), SLE Disease Activity Index (SLEDAI), and Fatigue Assessment Scale (FAS). Peripheral blood lymphocytes (PBL) and untouched T cells (using Dynal negative T-cell isolation kit) were freshly isolated on the same morning from patients and controls matched for ethnicity and age within 10 years and investigated in parallel for Δψ_m, mitochondrial mass, glutathione, NO and ROI production, cytosolic ([Ca²⁺]_c) and mitochondrial calcium levels ([Ca²⁺]_m), T and B cell subset distribution, and mTOR activity by flow cytometry with or without CD3/CD28 co-stimulation.

Results:

The SLEDAI (9.8 ± 0.5), BILAG (25.0 ±0.7) and FAS (26.3 ±0.4) scores showed significant correlations (SLEDAI and BILAG scores: r = 0.5138; p = 0.0014;. FAS and SLEDAI: r = 0.3570; p = 0.0326; FAS and BILAG, r = 0.4341; p = 0.0082). SLEDAI positively correlated with necrotic T cells (r = 0.383; p=0.007), necrotic CD4+ T cells (r = 0.418; p=0.003), and necrotic CD4-/CD8- double negative (DN) T cells (r = 0.347; p=0.016). SLEDAI negatively correlated with Foxp3+/CD25+/CD4+ Tregs (r = -0.293; p=0.043) and CD3/CD28-induced mTOR activation in CD4+ (r = -0.310; p=0.032) and CD8+ T cells (r = -0.410; p=0.004). Among the immunological biomarkers of SLEDAI, C3 negatively correlated with viable CD8+ T cells (r = -0.388; p=0.008) and positively correlated with viable CD4+ T cells (r = 0.405; p=0.005) . C4 negatively correlated with MHP of T cells (r = -0.370; p=0.011) and DN T cells by TMRM fluorescence (r = -0.428; p=0.003). C4 positively correlated with viable CD4+ T cells (r = 0.302; p=0.041) and necrotic CD8+ T cells (r = 0.307; p=0.038). Anti-DNA positively correlated with the increased mitochondrial mass in DN T cells (r = 0.438; p=0.002), increased H₂O₂ levels in CD8+ T cells (r = 0.447; p=0.002), and increased [Ca²⁺]_c in T cells (r = 0.480; p=0.001), CD4+ T cells (r = 0.467; p=0.001), CD8+ T cells (r = 0.487; p=0.001), DN T cells (r = 0.456; p=0.001),  and CD19+ B cells (r = 0.432; p=0.003). 

Conclusion:

MHP, necrosis rate, and [Ca²⁺]_c, particularly in DN T cells, represent biomarkers of disease activity in patients with SLE.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarkers-of-mitochondrial-dysfunction-correlate-with-disease-activity-in-sle/