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

Abstract

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed 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 have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.

Occupational exposures and risk of systemic lupus erythematosus

“…Cadmium exposure through drinking water also influenced development of disease in the NZBW mouse strain, even at very low doses [53]. Mercury exposure has also been shown to exacerbate disease development in the NZBW and MLR-mouse strains, though differences in effect were seen depending on genetic background of the model [54], and even very low-dose mercury accelerated development of disease in the a lupus-like chronic graft-versus-host disease model [55]. The mechanisms by which heavy metals might influence development of lupus are diverse [56].…”

Profiling Adverse Immune Effects

“…Some studies have demonstrated that chemicals can increase autoimmune disease in autoimmune-prone mice (e.g., NZB mice) [70,81,82]. Together, these and other examples demonstrate that indeed chemical-induced autoimmunity can be induced in animals.…”

“…For that disease models are warranted. However, most disease models, as mentioned, will often require predisposed animal strains such as systemic lupus erythematosus (SLE)-prone mice [81,82]. Often models using autoimmune-prone mice or rats (including the BN rat) are considered too sensitive and are for that reason undesired by various stakeholders (i.e., pharmaceutical industries, regulatory agencies).…”

A soy diet accelerates renal damage in autoimmune MRL/Mp-lpr/lpr mice

“…These mice are a valuable resource for studying the effects of environmental exposures on a genetically susceptible population [26]. The present study was designed to test whether a soy diet affects the development of autoimmune disease in a genetically susceptible murine model.…”