Unmethylated oligo-DNA containing CpG motifs aggravates collagen-induced arthritis in mice

Abstract

Objective. To investigate the effects of an intra-dermal injection of an unmethylated oligodeoxynucleo-tide (ODN) containing CpG motifs on the severity of collagen-induced arthritis (CIA). Methods. CIA was induced in DBA/1 LacJ mice by immunization with bovine type II collagen (CII) in Freund's complete adjuvant followed 3 weeks later by immunization with CII in Freund's incomplete adjuvant (yielding CIA mice). Unmethylated ODN containing a CpG motif was injected intradermally into DBA/1 LacJ mice at a dosage of 20 g (yielding CpG-CIA mice) 1 week prior to the first immunization with CII. Unmeth-ylated ODN containing a GpC motif instead of a CpG motif and ODN containing a methylated CpG motif were used to produce controls (GpC-CIA mice and mCpG-CIA mice, respectively). After the second immunization with CII, arthritis scores were measured weekly up to the eighth week. At the eighth week, the mice were killed, histopathologic changes in the ankle joints were examined, and titers of interferon-(IFN) in the supernatants of splenocytes (1 10 7) stimulated in culture by CII for 3 days were determined by enzyme-linked immunosorbent assay. Results. CpG-CIA mice had significantly higher arthritis scores than CIA mice. CpG-CIA mice had more severe histopathologic changes than CIA mice and mCpG-CIA mice. Moreover, splenocytes in CpG-CIA mice produced higher IFN titers in response to CII than did splenocytes in CIA mice and mCpG-CIA mice. Conclusion. Injection of unmethylated oligo-DNA containing CpG motifs aggravated CIA through activation of the Th1-type immune response, suggesting that microbial infection could be one of the mechanisms for aggravation or exacerbation of arthritis or, alternatively , that such infection could be an adjuvant in the induction of arthritis in rheumatoid arthritis.

Immunostimulatory DNA Sequences Influence the Course of Adjuvant Arthritis

“…In this context, Sato et al (16) recently reported that the prior injection of ISS-ODN into mice exacerbated the severity of arthritis induced by immunization with collagen in CFA. Unlike most other bacterial products that activate innate immunity, ISS are poorly immunogenic and can persist for long periods within transfected cells.…”

Microbial nucleic acids pay a Toll in kidney disease

“…Interaction of CpG-DNA-with TLR9 induces antigen-presenting cells to secrete Th1 cytokines, i.e., IL-12 or IFN-␥ (24). Subsequent T cell or B cell responses are modulated toward a Th1-type response, which can be therapeutic in Th2-type diseases like asthma and atopy (74,76) but that may aggravate other types of chronic autoimmune tissue injury, e.g., arthritis, encephalitis, or glomerulonephritis (3,32,51). Furthermore, at high doses CpG-DNA-induced activation of TLR9 can lead to toxic shock (30).…”

Bacterial CpG-DNA Aggravates Immune Complex Glomerulonephritis

“…However, induction of a Th1 response may significantly alter the course of underlying inflammatory disease states toward either resolution or progression, depending on the disease. For example, CpG-ODN-induced Th1-shift correlated with a marked improvement of ragweed-induced asthma in Balb/c mice (34) and, in contrast, aggravated collagen-induced arthritis in DBA/1 LacJ mice (18). Most of the data on the role of the Th1/Th2 balance in renal disease have been derived from the models of nephrotoxic serum nephritis and lupus nephritis in MRL lpr/lpr mice (20).…”

“…However, the immunostimulatory potential of prokaryotic or even hypomethylated self-DNA may also affect underlying chronic inflammatory diseases or autoimmunity (17)(18)(19)(20), e.g., immune complex GN, as Th1/Th2 balance, macrophage activity, and B cell function contribute to the pathogenesis of renal immune complex disease (21,22). We therefore hypothesized that CpG-DNA would aggravate a preexisting immune complex GN, a hypothesis confirmed by our results.…”