Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusbh. C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusbh allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs). Development of Lyme and rheumatoid arthritis in Gusbh-expressing mice was associated with heightened accumulation of GAGs in joint tissue. We propose that GUSB modulates arthritis pathogenesis by preventing accumulation of proinflammatory GAGs within inflamed joint tissue, a trait that may be shared by other lysosomal exoglycosidases.
Kenneth K.C. Bramwell, Ying Ma, John H. Weis, Xinjian Chen, James F. Zachary, Cory Teuscher, Janis J. Weis
Radiation chimeras were generated between B6 and B6.C3H-Bbaa2 in all pairwise combinations. We achieved high level (>90%) engraftment of B cells and myeloid lineages (Supplemental Figure 6). (A) Chimera serum GUSB activity levels were determined by the donor cell source. (B and C) The C3H Bbaa2 locus contributed to more severe Lyme arthritis, primarily through the activity of radiation resistant joint resident cells. Notably, the B6→Bbaa2 group developed severe Lyme arthritis despite high serum GUSB levels, and the Bbaa2→B6 group was resistant despite low serum GUSB levels (n = 16 to 20 rear ankle joints, 8 to 10 mice per group; overall P < 0.0001). Significance of ankle swelling assessed by 1-way ANOVA followed by Dunnet’s multiple comparison test versus the B6→B6 transplant control. Significance of overall lesion scores assessed by Mann-Whitney test versus the B6→B6 transplant control, with Bonferroni correction. *P < 0.05; **P < 0.01; ****P < 0.0001.