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Abstract
Background Systemic Lupus Erythematosus (SLE) is characterized by numerous seemingly unconnected abnormalities. These include: 1) a multisystem inflammatory syndrome, 2) a strong type I Interferon (IFN-I) gene signature in peripheral blood lymphocytes (PBL), 3) an unusual population of CD4-CD8- T-+cells, 4) SLE T cells containing enlarged mitochondria and reactive oxygen species (ROS), and 5) a polymorphism in Mitochondrial antiviral stimulator (MAVS C79F) associated with milder SLE. Our studies provide a unifying model for these abnormalities through augmented T cell homeostatic proliferation, which leads to two parallel cellular pathways: first, progressive upregulation of cytolytic inflammatory molecules, including high levels of Fas-Ligand (FasL), Granzyme B, and IFN-gamma, and second, generation of CD4-CD8- T cells from CD8 +precursors, which manifest disorganized enlarged mitochondria, elevated reactive oxygen species (ROS) that drives oligomerization of MAVS and IFN-I production.
Methods PBL from active SLE patients and age- and sex-matched healthy controls were assessed for increased expression of the T cell homeostatic proliferation phenotype determined from our murine studies: CD45RO+PD-1+SLAMF7+IL-7R-alpha-. The same cells were analyzed for MAVS oligomerization. Young lupus-prone MRL-lpr mice were treated for 11 weeks with the mitochondrially targeted antioxidant MitoQ.
Results Reactive oxygen species (ROS) is sufficient to drive MAVS oligomerization and IFN-I production in cell lines and primary human PBL. However, PBL from SLE patients manifested spontaneous MAVS oligomerization, which paralleled the levels of serum INF-I and SLEDAI score (figure 1). Furthermore, SLE patients had evidence of increased T cell homeostatic proliferation. In addition, SLE patients had evidence of increased I cell homeostatic proliferation, based on increased IL-7R- Ki67 +T cells. Very similar findings were observed in lupus prone MRL-lpr mice. Treatment of MRL-lpr mice over 11 weeks with the mitochondrially-targeted anti-oxidant MitoQ inhibited MAVS oligomerization, reduced serum IFN-I, improved dermatitis, and reduced kidney immune complexes.
MAVS spontaneous oligomerization in SLE patients. (A and B) Whole-cell lysates (A) and plasma (B) of SLE patients (n=8 patients: P1 to P8) were analyzed by semi-denaturing agarose gel electrophoresis to detect MAVS oligomers. Healthy sex-, age-, and ethnicity-matched subjects served as controls (n=8 donors: C1 to C8). (C) MAVS oligomerization in whole-cell lysates (WCL) and plasma of SLE patients (black circles) and healthy control subjects (white circles) was quantified by densitometric measurement of Western blots. For WCLs, the ratio of MAVS monomer to oligomer was measured, whereas in plasma, MAVS oligomers were normalized to albumin abundance. (D) Type I IFN in plasma from control subjects and SLE patients were measured by ELISA. (E) The plasma concentrations of type I IFN and the degree of MAVS oligomerization in SLE patients were compared. The statistical analyses performed were independent t tests (for C and D). (***p<0.0005, ****p<0.00005)
Conclusions Conclusions: Human and murine SLE have evidence of mitochondrial dysfunction, elevated ROS, spontaneous MAVS oligomerization and elevated IFN-I, as well as augmented T cell homeostatic proliferation. These abnormalities can be largely reversed with MitoQ, with alleviation of disease in murine SLE.
Funding Source(s): NIH (NIAID, NIAMS, NIGMS)