Background In systemic lupus erythematosus (SLE), mitochondria and their inner components may be released into the extracellular space, potentially eliciting a pro-inflammatory response by the immune system. While cardiolipin was long known as a mitochondrial target of autoantibodies, we reported in previous case-control studies that autoantibodies to whole mitochondria (AwMA), mitochondrial DNA (AmtDNA) and mitochondrial RNA (AmtRNA) are also targeted by SLE autoantibodies. We aim to characterize levels of these autoantibodies throughout SLE disease progression.

Methods Anti-mitochondrial antibodies (AMA, IgGs) targeting whole mitochondria (AwMA), mtDNA (AmtDNA) or mtRNA (AmtRNA) were measured by direct-ELISA, using sera from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. Samples comprised healthy controls (n=127) and 3453 samples obtained from 816 SLE patients, between the diagnosis up to 7 years afterward. Institution of the SLICC cohort obtained approval from their local research ethic boards and written consent from every participant. Eligibility to the cohort, within 15 months of diagnosis, was conditional to the positivity to 4, or more, ACR criteria for the classification of SLE. AMA levels are expressed as the median optical density measured at 405 nm ± interquartile range. Differences in AMA levels between healthy donors and baseline SLE samples were assessed, using Mann-Whitney tests and Spearman tests were used to assess correlations between levels of the various AMA.

Results Preliminary results indicate that, among the various subsets of IgGs targeting mitochondrial components, AwMA and AmtRNA but not AmtDNA were significantly increased in newly diagnosed SLE patients, in comparison with healthy individuals (respectively: p=0.004, p<0.0001, and p=0.1. figure 1). While AwMA levels remain constant for two years into the disease (Enrollment: 0.11±1.37), an increase is observed after the third year (year 3: 0.17±0.67). A similar effect is measured for AmtRNA levels (Enrollment: 0.21±2.46. Year 3: 0.36±1.81). AwMA levels are correlated to those of AmtDNA and AmtRNA (p<0.0001. Respectively r_s=0.32 and r_s=0.38) and levels of both anti-mitochondrial nucleic acids displayed stronger correlations (p<0.0001; r_s=0.55).

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Abstract 1708 Figure 1

Levels of circulating IgG against whole mitochondria (AwMA), mitochondrial DNA (AmtDNA) or RNA (AmtRNA) were assessed by direct ELISA. (A) AwMA and AmtRNA but not AmtDNA were significantly increased in newly diagnosed SLE patients (i.e. enrollment), compared to healthy controls. Mann-Whitney test. Data are median ± standard deviation (SD). Ns: not significant (p>0.05). ***p < 0.001. ****p < 0.0001. (B) Levels of AMA were assessed at various time points during the disease for subsequent biostatistical analyses. Data are median ± SD. The dotted line represents the median value for the healthy group.

Conclusions Levels of circulating autoantibodies to whole mitochondria and mtRNA at baseline allow discriminating between healthy individuals and SLE patients. While levels of AMA appear to be fluctuating throughout the disease, further biostatistical analyses will be performed to assess associations between AMA and clinical manifestations and outcomes of the disease. These data will allow to appreciate the quality of AMA as biomarkers in the prediction of clinical outcomes, damages, or the clustering of patients in SLE.

Acknowledgments Dr. Paul R. Fortin’s (PRF) work is supported by a Canada Research Chair. This study was supported by Canadian Institutes of Health Research (CIHR) grants to PF and Dr. Éric Boilard (EB). Yann LC Becker and EB are recipients of awards from the Fond de Recherche en Santé du Québec (FRSQ).