Background Recent studies have shown that DNA, in addition to functioning as hereditary material, is able to activate the immune system. In particular, bacterial DNA displays in vivo and in vitro immunostimulatory properties. These properties have been attributed to certain unique properties of bacterial DNA including high content of unmethylated cytosines in CpG dinucleotides. Although eukaryotic nuclear DNA is not immunostimulatory, we have found that mitochondrial DNA (mtDNA), like bacterial DNA, can activate inflammation.

Objectives The aims of our studies were to assess the arthritogenicity in mice of endogenous mtDNA sequences and to assess a potential role in human inflammatory disease.

Methods Highly purified mtDNA as well as synthetically produced oligonucleotides were injected intra-articularly into murine knee joints. The development of arthritis was evaluated histopathologically. In addition, we analysed by PCR the synovial fluids (SF) of rheumatoid arthritis (RA) patients for the presence of free mtDNA.

Results Intra-articular injection of mtDNA and fragments of the mitochondrial genome containing unmethylated CpG sequences gave rise to arthritis in mice. This inflammation was mediated by macrophages and their products, such as TNF-alpha. In contrast, T/B lymphocytes or granulocytes did not participate in the onset or progression of the disease. The SF of 40/54 RA patients tested contained extracellular, PCR-amplifiable mtDNA.

Conclusion Our results indicate that endogenous mtDNA is pro-inflammatory and may participate in the induction and/or propagation of arthritis in man.