β-Glucuronidase is a key regulator of murine Lyme arthritis severity and rheumatoid arthritis (P4013)

Abstract

Abstract Lyme Disease is the most prevalent arthropod borne illness in the U.S. Up to 60% of patients develop inflammatory arthritis following infection. Host genetics play a key role, as inbred mouse strains exhibit consistent differences in Lyme arthritis severity. Our lab previously described maximal linkage (LOD 10.2) of disease severity to the Bbaa2 locus on mouse Chromosome 5. Recently, we developed advanced congenic mice carrying sub-intervals of Bbaa2 from susceptible C3H on an otherwise uniform resistant B6 genetic background. This led to the positional cloning of a novel disease regulator, the lysosomal enzyme β-Glucuronidase (Gusb). C3H mice are Gusb hypomorphs, exhibiting a 90% enzymatic deficiency. Two sub-strains of CBA mice carrying the hypomorphic or wild type Gusb alleles develop severe Lyme arthritis or are protected, respectively. A Gusbnull mouse strain on the B6 background develops severe Lyme arthritis, while heterozygotes are protected. Transgenic overexpression of Gusb in C3H mice to correct the defect led to reduced arthritis severity, indicating a single gene effect. Preliminary data show that Gusb congenic mice also develop more severe disease in the KBxN model of Rheumatoid arthritis, suggesting a conserved role. Deficiencies in Gusb and other lysosomal enzymes lead to lysosomal storage diseases. We found that treatment with Hydroxychloroquine, which accumulates in lysosomes, dramatically reduces Lyme arthritis severity in Gusb congenic mice.