Several quantitative trait loci (QTLs) regulating the risk of
experimental arthritis have been identified by genome-wide linkage analyses, but only the MHC has thus far been reported to transfer
arthritis susceptibility in congenic animals. We have produced a congenic strain for Oia3, a genetic factor originally identified as an oil-induced
arthritis (OIA) QTL in
arthritis-prone DA rats. A 46 cM telomeric region of chromosome 10 encompassing Oia3 was transferred from DA rats to MHC-identical but minutely
arthritis-susceptible LEW.1AV1 rats by selective breeding.
Arthritis development was provoked in Oia3-congenic rats by
intradermal injection of different adjuvant
oils. One successful
arthritis trigger was
squalene, which is approved for vaccinations in humans and has been implicated in
Gulf War syndrome. The endogenous
cholesterol precursor
squalene induced T cell infiltration into joints and macroscopic
arthritis in Oia3-congenic rats and DA rats, whereas LEW.1AV1 rats were almost resistant.
Arthritis onset, approximately 14 days post-injection, coincided with arrested
body-weight gain and increased plasma levels of the
inflammation markers
fibrinogen and
alpha 1-acid glycoprotein. Congenic rats displayed intermediate phenotypes compared with the two parental strains, and similar to
rheumatoid arthritis in humans, female preponderance was observed in Oia3-congenic rats. Finally, recombinant rat strains were constructed and were used to map a susceptibility gene(s) in females to a telomeric 4--19 cM Oia3 subregion. The experimental system described allows transformation of multifactorial
arthritis susceptibility into dichotomous phenotypes.