Oligodeoxynucleotides containing CpG motifs can induce T cell-dependent arthritis in rats.

Abstract

To investigate whether CpG oligodeoxynucleotides (ODNs) can induce or accelerate arthritis in rats. The CpG-induced response was studied by recording joint inflammation, cell activation in draining lymph nodes, and levels of the acute-phase reactant alpha(1)-acid glycoprotein (AGP) in sera. The role of T cells was investigated by in vivo administration of monoclonal antibodies specific for the T cell receptor alpha/beta (TCRalpha/beta), followed by analysis of cell phenotypes by flow cytometry. One intradermal injection of CpG ODN emulsified with Freund's incomplete adjuvant (IFA) induced arthritis in LEW and LEW.1AV1 rats, while the control ODN sequence without CpG motifs or IFA alone did not trigger disease. The CpG/IFA and control-ODN/IFA injections induced lymphoplasia as well as elevated levels of interleukin-1beta and interferon-gamma messenger RNA in lymph nodes. The arthritis was preceded by elevated levels of AGP in serum. In vivo administration of anti-TCRalpha/beta antibodies after disease induction caused decreased expression of the TCR-CD3 complex on circulating T cells and ameliorated the arthritis. We demonstrated that injection with immunostimulatory CpG, both in phosphorothioate-modified and native forms, can induce a T cell-dependent joint-specific inflammation in LEW and LEW.1AV1 rat strains. This arthritis is preceded by signs of activation of the innate immune system. Since unmethylated CG dinucleotides are common in bacterial DNA but rare in mammalian DNA, our results indicate that exposure to bacterial DNA during infection may contribute to arthritis induction by amplifying the innate immune response.