My laboratory investigates the mechanism of inflammatory arthritis development, using the murine model of Lyme disease. Our goals are to identify the events associated with arthritis development in this model of acute, infection-associated disease, with the understanding that these events may set the stage for chronic autoimmune arthritis in MHC susceptible individuals. Mice of the C3H strain develop severe arthritis when infected with Borrelia burgdorferi, whereas C57BL/6 mice develop mild arthritis. We generated intercross populations between C3H and C57BL/6 mice and identified six Quantitative Trait Loci (QTL) that regulate arthritis severity. Reciprocal congenic lines have been developed that transfer each of the QTL singly to the opposite strain and have been assessed for penetrant phenotype. Five congenic lines transferred arthritis severity phenotypes including edema, tendon sheath thickness and hyperproliferation, PMN infiltration, and reactive/reparative responses. We are in the process of narrowing the interval associated with each QTL with the ultimate goal to identify the allelic gene responsible for differences in arthritis severity.

Our second approach is to study the responses to the bacterial that contribute to the inflammatory responses associated with arthritis development. We demonstrated that the Borrelia outer surface lipoproteins activate mammalian cells through toll-like receptor 2, and hypothesized that this signaling pathway would be necessary for arthritis development. However, infection of mice deficient in TLR2 and in the signaling molecule MyD88 developed more severe arthritis than the wild type animal, and suggested expanded types of cellular infiltrate. Thus, the TLR/NF-B signaling pathway is essential for host defense to B. burgdorferi, but not for arthritis development. To characterize the genetic pathways induced during the development of arthritis in B. burgdorferi infected mice we performed global gene expression profiling using microarrays of joint tissue. Two entirely distinct patterns of early gene activation occur in mice destined to develop severe verses mild arthritis. In severely arthritic mice a gene expression profile was dominated by interferon-inducible genes, most likely downstream of type I interferon. In contrast, the pathway was not activated in arthritis resistant mice, rather a profile reminiscent of epidermal development was featured. Our results suggest that a very early choice in gene expression profile in made following infection with B. burgdorferi, and that activation of an IFN pro-inflammatory pathway results in arthritis development wheras activation of an anti-inflammatory epidermal/wound repair pathway actively prevents the development of arthritis.

Staff

• Ying Ma, MS Research Associate
• Jennifer Miller, Ph.D., Post-doctoral Fellow
• Abbas Zoufer, Laboratory Technician
• Lynn Sonderegger, Graduate Student
• Jiantao Bian, Graduate Student
• Eric Larsen, Undergraduate