Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA.

The mitochondrion supplies energy to the cell and regulates apoptosis. Unlike other mammalian organelles, mitochondria are formed by binary fission and cannot be directly produced by the cell. They contain numerous copies of a compact circular genome that encodes RNA molecules and proteins involved in mitochondrial oxidative phosphorylation. Whereas, mitochondrial DNA (mtDNA) activates the innate immune system if present in the cytosol or the extracellular milieu, it is also the target of circulating autoantibodies in systemic lupus erythematosus (SLE). However, it is not known whether mitochondrial RNA is also recognized by autoantibodies in SLE. In the present study, we evaluated the presence of autoantibodies targeting mitochondrial RNA (AmtRNA) in SLE. We quantified AmtRNA in an inducible model of murine SLE. The AmtRNA were also determined in SLE patients and healthy volunteers. AmtRNA titers were measured in both our induced model of murine SLE and in human SLE, and biostatistical analyses were performed to determine whether the presence and/or levels of AmtRNA were associated with clinical features expressed by SLE patients. Both IgG and IgM classes of AmtRNA were increased in SLE patients (n = 86) compared to healthy controls (n = 30) (p < 0.0001 and p = 0.0493, respectively). AmtRNA IgG levels correlated with anti-mtDNA-IgG titers (rs = 0.54, p < 0.0001) as well as with both IgG and IgM against ß-2-glycoprotein I (anti-ß2GPI; rs = 0.22, p = 0.05), and AmtRNA-IgG antibodies were present at higher levels when patients were positive for autoantibodies to double-stranded-genomic DNA (p < 0.0001). AmtRNA-IgG were able to specifically discriminate SLE patients from healthy controls, and were negatively associated with plaque formation (p = 0.04) and lupus nephritis (p = 0.03). Conversely, AmtRNA-IgM titers correlated with those of anti-ß2GPI-IgM (rs = 0.48, p < 0.0001). AmtRNA-IgM were higher when patients were positive for anticardiolipin antibodies (aCL-IgG: p = 0.01; aCL-IgM: p = 0.002), but AmtRNA-IgM were not associated with any of the clinical manifestations assessed. These findings identify mtRNA as a novel mitochondrial antigen target in SLE, and support the concept that mitochondria may provide an important source of circulating autoantigens in SLE.

Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations.

Mitochondria are organelles that govern energy supply and control cell death. Mitochondria also express bacterial features, such as the presence of inner membrane cardiolipin and a circular genome rich in hypomethylated CpG motifs. While mitochondrial extrusion by damaged organs or activated cells is thought to trigger innate immunity, it is unclear whether extracellular mitochondria also stimulate an adaptive immune response. We describe the development of novel assays to detect autoantibodies specific to two distinct components of the mitochondrion: the mitochondrial outer membrane and mitochondrial DNA. Antibodies to these two mitochondrial constituents were increased in both human and murine systemic lupus erythematosus (SLE), compared to controls, and were present at higher levels than in patients with antiphospholipid syndrome or primary biliary cirrhosis. In both bi- and multi-variate regression models, antibodies to mitochondrial DNA, but not whole mitochondria, were associated with increased anti-dsDNA antibodies and lupus nephritis. This study describes new and optimized methods for the assessment of anti-mitochondrial antibodies, and demonstrates their presence in both human and murine SLE. These findings suggest that different mitochondrial components are immunogenic in SLE, and support the concept that extracellular mitochondria may provide an important source of circulating autoantigens in SLE.

Advanced glycation end products, aortic stiffness, and wave reflection in peritoneal dialysis as compared to hemodialysis.

BACKGROUND: Modification of vascular extracellular matrix by advanced glycation end products (AGEs) may result in vascular stiffness. Because of higher exposure to glucose, we hypothesized that patients on peritoneal dialysis (PD) may have higher tissue levels of AGEs, increased vascular stiffness, and enhanced central augmentation pressure as compared to hemodialysis patients (HD). METHODS: In a cross-sectional study, 43 PD were matched to 43 HD based on age, gender, diabetes, and dialysis vintage. Tissue levels of AGEs were assessed by skin autofluorescence (skin AF). Aortic stiffness was measured by carotid-femoral pulse wave velocity (cf-PWV), and heart rate-adjusted augmentation pressure (AP@75) was performed by arterial tonometry. RESULTS: Baseline characteristics were similar in both groups except for lower prevalence of cardiovascular disease (CVD) and higher exposure to smoking in PD. Skin AF and cf-PWV were not statistically different, but PD patients had a lower AP@75 (P = 0.023). However, after adjustments for prevalence of CVD and smoking status, skin AF was higher in PD by 0.587 AU (95 % CI 0.091-1.215, P = 0.020), and cf-PWV was higher in PD by 2.20 m/s (95 % CI 0.56-3.84, P = 0.009), while AP@75 was not different. Overall, there was a significant association between skin AF and cf-PWV and AP@75. CONCLUSION: Skin AF and aortic stiffness were higher in PD after adjustments for imbalances in baseline characteristics. Independent of dialysis modality, there was a positive association between skin AF, aortic stiffness, and enhanced wave reflection.