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

Abstract

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.

Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA

“…We used our quantitative ELISA to assess whether AmtRNA from the IgG subclass (AmtRNA-IgG) could be detected in an induced model of murine SLE in which the production of circulating IgG against whole mitochondria (AwMA) and mitochondrial DNA (AmtDNA) was previously reported (36). Antibodies against mtRNA were significantly increased ( p = 0.0005) in the sera of SLE mice compared with control mice (Figure 2).…”

“…Conversely, no correlations were observed between AmtRNA and concentrations of anti-dsDNA (Table 6). We also determined whether the levels of AmtRNA correlated with IgG and IgM antibodies targeting mitochondrial epitopes localized in diverse sub-compartments of the organelle (36). Specifically, we measured antibodies recognizing intact whole mitochondria (AwMA), which most likely bind epitopes found on the outer mitochondrial membrane; aCL, which target cardiolipin, a phospholipid located mainly within the mitochondrial inner membrane; and AmtDNA, which recognize mitochondrial DNA.…”

“…However, the actual epitope(s) of some AMA remain unidentified (57). Thus, AmtRNA add to the more recently appreciated AmtDNA and AwMA (36). Adaptive autoimmunity targeting mitochondrial motifs is not unique to SLE: a humoral immune response against mitochondrial autoantigens was reported in various diseases, and described as 9 different types of AMA targeting distinct epitopes (namely, M1 to M9) (36, 57).…”

“…In addition to the measurements provided by the clinical laboratories, our research laboratory performed antibody assays to detect AwMA and AmtDNA, following previously described methods (36).…”

“…Despite the extensive literature regarding antibodies targeting the cardiolipin (also known as the mitochondrial antigen M1) in SLE, the anti-mitochondrial autoantibody repertoire and their antigenic targets remains mostly uncharacterized (12, 34–37). Using intact mitochondria and mtDNA as antigens to screen autoantibodies in SLE patients, we have shown that different sets of autoantibodies also target the mitochondrial outer membrane and mtDNA (36). Given the accumulating evidence for mitochondrial release during inflammatory pathogenesis, these observations point to a role for mitochondria both in the stimulation of the innate immune system and as a potential source of autoantigens.…”