Immunostimulatory DNA sequences influence the course of adjuvant arthritis

Bacterial DNA is enriched in unmethylated CpG motifs that have been shown to activate the innate immune system. These immunostimulatory DNA sequences (ISS) induce inflammation when injected directly into joints. However, the role of bacterial DNA in systemic arthritis is not known. The purpose of the present experiments was to determine whether ISS contributes to the development of adjuvant arthritis in Lewis rats after intradermal injection of heat-killed Mycobacterium tuberculosis (Mtb). The results showed that Mtb DNA was necessary for maximal joint inflammation in adjuvant arthritis but could be replaced by synthetic ISS oligodeoxynucleotides. The arthritis-promoting effect of the Mtb DNA or of the ISS oligodeoxynucleotides correlated with an increased Th1 response to Mtb Ags, as measured by the production of IFN-gamma and increased production of the osteoclast differentiation factor, receptor activator of NF-kappaB ligand (RANKL). The Mtb DNA did not enter the joints but dispersed to the bone marrow and spleen before the onset of systemic joint inflammation. Thus, adjuvant arthritis is a microbial DNA-dependent disease. In this model, we postulate that massive and prolonged activation of macrophages, dendritic cells, and osteoclast precursors in the bone marrow may prime the joints for the induction of inflammatory Th1 immune responses to Mtb Ags.