Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA

Abstract

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 ( r s = 0.54, p < 0.0001) as well as with both IgG and IgM against β-2-glycoprotein I (anti-β 2 GPI; r s = 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-β 2 GPI-IgM ( r s = 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.

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

“…Additionally, both mRNA and protein levels of the NMDA subunits NR1 and NR2C are decreased in post-mortem SCZ brain tissue ( Weickert et al, 2013 ). Recent evidence suggests that NMDAR function might be inhibited in SCZ by autoantibodies, which are produced against an organism’s own tissue and are implicated in autoimmune disorders such as lupus ( Becker et al, 2019 ). Circulating autoantibodies against glutamate and NMDARs were found to be present in approximately 20% of psychotic SCZ patients ( Jézéquel et al, 2017 ).…”

Neutrophils—Important Communicators in Systemic Lupus Erythematosus and Antiphospholipid Syndrome

“…Hence, decreased NOX2 activity, increased mitochondrial ROS production and mitochondrial dysfunction may expose cardiolipin, hypothetically leading to development of APS. Mitochondria decorated in NETs or as a consequence of impaired mitophagy (55, 110) are important for autoimmune reactions toward this antigen, and anti-mitochondrial antibodies are detected in both SLE and APS (113, 114). Thus, an altered mitochondrial function may drive the disease toward APS.…”

Extracellular Mitochondria in Traumatic Brain Injury Induced Coagulopathy

“…Fourth, exMTs released into the circulation can be highly antigenic and thus stimulate the production of autoantibodies against mitochondrial DNA, RNA, and lipids, which are detected in patients with systemic lupus erythematosus. 66 Anticardiolipin antibody has been detected in mice with severe TBI 23 and in patients with TBI or stroke. 29,30 Finally, mitochondrial cardiolipin can activate the Nlrp3 inflammasome, 67 a protein complex consisting of the nucleotide-binding oligomerization domainlike receptor Nlrp3, the adaptor protein ASC (apoptosis-associated specklike protein containing a C-terminal caspase-recruitment domain [CARD]), and the cysteine protease caspase-1.…”