The spirochete Borrelia burgdorferi, the etiologic agent of Lyme disease, causes severe subacute arthritis in susceptible inbred mouse strains, such as C3H/HeN, but only mild arthritis in resistant strains such as C57BL/6. The degree of Lyme arthritis severity is controlled in part by host genetics and several quantitative trait loci have been identified which contribute to this regulation. In addition, the anti-inflammatory cytokine IL-10 assumes an important role in the control of arthritis in C57BL/6 mice. However, the identification of genes and signaling pathways that dictate arthritis severity has remained elusive. In an attempt to elucidate such genes and pathways, the power of microarray analysis was combined with information gleaned from gene manipulation models. As a result of this approach, two novel gene profiles were identified: an IFN-inducible profile in arthritis-susceptible C3H and IL-10(-/-) mice, and an epidermal/differentiation profile in C57BL/6 mice. Application of this information to TLR2(-/-) mice, which also develop severe arthritis, indicated that they also upregulated IFN-responsive genes. These results provided new insight into the regulation of Lyme arthritis development and illustrated the utility of combining gene expression analyses with genetically manipulated mouse models in unraveling mechanisms underlying specific disease processes.