Background/Purpose: Extracellular mitochondria may represent a source of antigenic burden in autoimmune disorders, such as in systemic lupus erythematosus (SLE), in which those organelles, released either by neutrophils or activated platelets, contribute to fueling the inflammatory milieu. This occurs through the release of danger-associated molecular patterns, such as N-formyl methionine peptides, and oxidized mitochondrial DNA. The latter is known to be highly interferogenic. Despite the accruing experimental evidence of the relevance of mitochondria to SLE pathogenesis, the clinical utility of anti-mitochondrial antibodies (AMA) in childhood-onset SLE (cSLE) has not thus far been evaluated.  Here we demonstrate, for the first time, that AMA are present in the sera of patients with cSLE, and that IgG levels correlate positively with an IFN type I response, and with disease activity as determined by SLEDAI.

Methods: Purified mitochondria were isolated from HepG2 cells, by Douncer homogenization and differential centrifugation, and incubated with sera from patients with cSLE from the Erasmus University Medical Center biobank. AMA of the IgG, IgM, and IgA isotypes were evaluated by flow cytometry, and expressed as median fluorescence intensity (MFI). Serum IFNα2 levels were measured by single-molecule array (Simoa). For each patient, sera samples from two different timepoints (TP) were compared, being TP-1 the time of a flare, and TP-2 the time of clinically-quiescent disease.

Results: The cohort was comprised of 28 cSLE patients, from which 6 were males and 22 were females. Age at diagnosis ranged from 6 to 17 years-old (mean 14 years-old). SLEDAI at TP-1 ranged from 4 to 20 (median 9.5), and SLEDAI at TP-2 ranged from 0 to 4 (median 2). On average, time difference between TP-1 and TP-2 was of 6 months (±3.7 months). Mean AMA-IgG and AMA-IgM levels were higher at TP-1 than at TP-2 (3504 vs. 2819, p = 0.0155; and 13680 vs. 11482, p = 0.0727, respectively). Both AMA-IgG and AMA-IgM correlated positively with IFNα2 levels (rho = 0.73, p < 0.0001, and rho = 0.63, p = 0.0009, respectively) at TP-1, but no correlation was observed at TP-2. Finally, AMA-IgG, but not AMA-IgM, correlated with markers of disease activity at TP-1, including levels of anti-dsDNA (r=0.66, p=0.0001), and SLEDAI (r=0.41, p=0.026). No meaningful correlations were noticed for AMA-IgA.

Conclusion: AMA-IgG may be a novel marker of disease activity and serum IFNα protein levels in the context of cSLE. Further studies are warranted to determine the pathogenic role of AMA in cSLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-mitochondrial-antibodies-associate-with-disease-activity-and-ifn%ce%b1-expression-in-childhood-onset-systemic-lupus-erythematosus/