title: Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity.
abstract: 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.
authors: Kenneth K C
authors: KK
authors: Bramwell
authors: Ying
authors: Y
authors: Ma
authors: John H
authors: JH
authors: Weis
authors: Xinjian
authors: X
authors: Chen
authors: James F
authors: JF
authors: Zachary
authors: Cory
authors: C
authors: Teuscher
authors: Janis J
authors: JJ
authors: Weis
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D025065:Borrelia burgdorferi; D002478:Cells, Cultured; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007596:Joints / Q000473:pathology; D008193:Lyme Disease / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017384:Sequence Deletion; D012720:Severity of Illness Index
chemical_list: D006025:Glycosaminoglycans; D005966:Glucuronidase