The endogenous adjuvant squalene can induce a chronic T-cell-mediated arthritis in rats

Squalene is a cholesterol precursor, which stimulates the immune system non specifically, We demonstrate that one intradermal injection of this adjuvan t lipid can induce joint-specific inflammation In arthritis-prone DA rats. Histopathological and immunohistochemical analyses revealed erosion of bone and cartilage, and that development of polyarthritis coincided with infilt ration of alpha beta(+) T cells. Depletion of these cells with anti-alpha b eta TcR monoclonal antibody (R73) resulted in complete recovery, whereas an ti-CD8 and anti-gamma delta TcR injections were ineffective. The apparent d ependence on CD4(+) T cells suggested a role for genes within the major his tocompatibility complex (MHC), and this was concluded from comparative stud ies of MHC congenic rat strains, in which DA,IH rats were less susceptible than DA rats. Furthermore, LEW.1AV1 and PVG.1AV1 rats with MHC identical to DA rats were arthritis-resistant, demonstrating that non-MHC genes also de termine susceptibility. Some of these genetic influences could be linked to previously described arthritis susceptibility loci in an F2 intercross bet ween DA and LEW.1AV1 rats (ie, Cia3, Oia2 and Cia5), Interestingly, some F2 hybrid rats developed chronic arthritis, a phenotype not apparent in the p arental inbred strains. Our demonstration that an autoadjuvant can trigger chronic, immune-mediated joint-specific inflammation may give clues to the pathogenesis of rheumatoid arthritis, and it raises new questions concernin g the role of endogenous molecules with adjuvant properties in chronic infl ammatory diseases.