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,
,
Departments of
*
Medicine and
Pediatrics, Division of Rheumatology, Allergy and Immunology, and Samana Rose Stein Institute for Research on Aging, University of California at San Diego, La Jolla, CA 92093; and
University Medical Center, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
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-
and increased production
of the osteoclast differentiation factor, receptor activator of NF-
B
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.
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