Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity

The Journal of Clinical Investigation
Kenneth K C BramwellJanis J Weis

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 o...Continue Reading

References

Jul 1, 1990·The Journal of Infectious Diseases·S W BartholdK D Moody
Jan 1, 1985·Immunogenetics·A C Whitmore, S P Whitmore
Nov 1, 1987·Annals of Internal Medicine·A C SteereE Taylor
Jul 1, 1983·Proceedings of the National Academy of Sciences of the United States of America·A J LusisK Paigen
Jun 18, 1982·Science·W BurgdorferJ P Davis
Sep 13, 1996·Science·N Risch, K Merikangas
Mar 29, 1996·Clinica Chimica Acta; International Journal of Clinical Chemistry·A LombardoA Burlina
Nov 29, 1996·Cell·V KouskoffD Mathis
Aug 28, 2001·Nucleic Acids Research·S YeI N Day
Feb 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Carole VoglerWilliam S Sly
Jan 14, 2004·Glycobiology·Maria FullerJohn J Hopwood
Sep 3, 2004·Genome Research·Petko M PetkovMichael V Wiles
Aug 6, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Nicolas W J SchröderRalf R Schumann
Apr 6, 2006·International Journal of Medical Microbiology : IJMM·Slawomir A PancewiczKrzysztof Zwierz
Apr 6, 2006·The Journal of Experimental Medicine·Allen C SteereLee Ann Baxter-Lowe
Jun 27, 2006·Molecular Microbiology·Steven J Norris
Aug 1, 2006·Journal of Biochemistry·Oliver J HoltGillian M Griffiths
Aug 22, 2006·European Journal of Clinical Investigation·D HajioffA Keilmann
Nov 23, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hillary CrandallJanis J Weis
Apr 26, 2008·PLoS Genetics·Michelle M A FernandoJohn D Rioux
Sep 11, 2008·The Journal of Infectious Diseases·Gary P WormserIra Schwartz
Feb 19, 2009·Human Mutation·Shunji TomatsuWilliam S Sly
Jun 11, 2009·Scandinavian Journal of Infectious Diseases·Slawomir PancewiczKrzysztof Zwierz
Oct 3, 2009·Nature Reviews. Rheumatology·Ronald F van Vollenhoven
Dec 19, 2009·Proceedings of the National Academy of Sciences of the United States of America·Calogera M SimonaroEdward H Schuchman
May 31, 2011·Nature Genetics·Hyuna YangFernando Pardo-Manuel de Villena
Jul 15, 2011·Human Molecular Genetics·Michela PalmieriAndrea Ballabio
Sep 17, 2011·Nature·Thomas M KeaneDavid J Adams
Dec 20, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·F Lynn SondereggerJanis J Weis
Jan 11, 2012·Rheumatology·Kimberly Morishita, Ross E Petty
Jan 11, 2012·Rheumatology·Vassili Valayannopoulos, Frits A Wijburg
Jan 11, 2012·Nature Reviews. Microbiology·Justin D RadolfLinden T Hu
Jun 26, 2012·The Journal of Clinical Investigation·Linda K BockenstedtAlexia A Belperron
Apr 23, 2013·EMBO Molecular Medicine·Carmine SpampanatoNina Raben

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Citations

May 24, 2016·North American Journal of Medical Sciences·Julianna HirschGleb Slobodin
Jun 14, 2014·Frontiers in Cellular and Infection Microbiology·Kenneth K C BramwellJanis J Weis
Oct 8, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jackie K PaquetteJanis J Weis
Feb 5, 2019·Molecular and Cellular Biochemistry·Pei HeFei-Yan Deng
Jan 23, 2019·Molecular Microbiology·Danielle M TuftsYi-Pin Lin
Nov 30, 2019·The Tohoku Journal of Experimental Medicine·Tomoyuki KatoNorihiko Tsuchiya
Feb 26, 2020·The Journal of Experimental Medicine·Cynthia LouisIan P Wicks
Nov 8, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ying MaJanis J Weis
Jul 15, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kenneth K C BramwellJanis J Weis
Jul 15, 2015·Respirology : Official Journal of the Asian Pacific Society of Respirology·Evgenia C PanagiotopoulouMichael B Anthracopoulos
Dec 14, 2019·European Journal of Medicinal Chemistry·Paul AwoladeParvesh Singh
Jul 7, 2021·Nature Reviews. Rheumatology·Robert B LochheadAllen C Steere
Feb 23, 2019·Journal of Natural Products·Andrew G KunihiroJanet L Funk

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Methods Mentioned

BETA
PCR
genotyping
transgenic
electrophoresis

Software Mentioned

Olympus
GraphPad Prism
cellSens

Related Concepts