Grant: Project Grant

Mitochondria are structures inside living cells essential to life. Mitochondria have their own genetic material called DNA and a membrane with the only source of cardiolipin in humans. If released outside their protective cell into the blood circulation, they may be recognized as foreign by our immune system and cause confusion in our immune response. We observed that the number of mitochondria outside of cells in the plasma of persons with lupus was significantly higher than in controls and that free mitochondrial DNA (mtDNA) was abnormally high. As persons with lupus develop antibodies to several self-antigens and, interestingly to the mitochondrial cardiolipin, we looked at whether the immune system reacted to mitochondria in lupus. For this, we reviewed the literature on known anti-mitochondrial antibodies (AMA) and we developed a new system to detect newly described AMA. Using these new tests, we found significantly higher levels of both antibodies in persons with lupus than in controls. Our objective is to understand the clinical implications of the immune response to mitochondria by mapping the known and newly described AMA in a large cohort of patients newly diagnosed with lupus. We will investigate if specific AMA are associated with clinical manifestations of lupus such as disease damage, activity, severity and specific organ involvement at presentation and over time and we will define how AMA may define clusters of patients with common clinical manifestations. The characterization of the clinical associations with the new lupus-specific AMA and the identification of the targets of all the known AMA will lead to the development of clinically relevant applications such as diagnostic or prognostic tests and may reveal new targets for therapies in lupus.