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
(A) 100 μl K/BxN serum was administered to B6 and B6.C3H-Gusbh congenic mice by intraperitoneal injection on days 0 and 2. Ankle swelling of both rear ankle joints was monitored on days 1, 2, 4, and 7. Congenic mice developed significantly more robust ankle swelling starting on day 4 that was further exacerbated on day 7, and this finding was corroborated by blinded joint histopathology measurements (B) (n = 14 rear ankle joints for each group). Pairwise significance of ankle swelling calculated by Student’s t test. Significance of overall lesion score assessed by Mann-Whitney test. *P < 0.05; **P < 0.01.