Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility th at both genetic and environmental factors act synergistically at several st ages or checkpoints to influence disease pathogenesis in susceptible popula tions. These observations predict that individuals susceptible to spontaneo us autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this poss ibility, mouse strains with differing genetic susceptibility to murine lupu s were examined for acceleration of autoimmune features characteristic of s pontaneous systemic autoimmune disease following exposure to the immunostim ulatory metals nickel and mercury. Although NiCl2 exposure did not exacerba te autoimmunity HgCl2 significantly accelerated systemic disease in a strai n-dependent manner. Mercury-exposed (NZB x NZW)F-1 mice had accelerated lym phoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune compl ex deposits. Mercury also exacerbated immunopathologic manifestations in MR L+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental f actors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatability complex genes also contribute d to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL /lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl 2-induced exacerbation of autoimmunity. Such genetic predisposition may hav e to be considered when assessing the immunotoxicity of xenobiotics. Additi onal comparative studies using autoimmune-prone and nonautoimmune mice stra ins with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations suscepti ble to autoimmune diseases.