The Effect of Xenobiotic Exposure on Spontaneous Autoimmunity in (SWR × SJL)F1 Hybrid Mice

Abstract

F1 hybrids of SWR (H-2 q ) and SJL (H-2 s ) mice spontaneously develop a lupuslike condition in an age-dependent manner, and these two H-2 haplotypes also confer susceptibility to induction of systemic autoimmunity by heavy metals such as mercury, silver, and gold with anti-fibrillarin antibodies (AFA) as marker. The aim of this study was to determine how the mixing of two susceptible genomes might influence expression of idiopathic and induced autoimmunity over a period of 14 mo of exposure to mercury and silver. Spontaneous autoimmunity first appeared as antinuclear antibodies (ANA) in females at 10 wk of age and in males at 10 mo of age, and was followed by development of anti-chromatin antibodies. Antibodies to double-stranded DNA developed in 60% of males and 20% of females. Thirty percent of males and 10% of females developed a coarsely speckled ANA pattern associated with high titers of anti-Sm antibodies. Glomerular immune complex (IC) deposits and a proliferative glomerulonephritis were seen at 17 mo of age. The F1 hybrids treated with metals showed no exaggeration of spontaneous autoimmunity. However, the metals suppressed the spontaneous development of anti-Sm and antichromatin antibodies. The metal-induced AFA, linked to the H-2 s and H-2 q haplotype, reached a maximum after 3–4 mo of treatment and then declined; 33% of the silver-treated hybrids finally became AFA-negative, despite continuous treatment. The decline in ANoA during metal treatment is contrary to the situation in metal-treated SJL mice. This indicates that dominant SWR background genes suppressed induction of certain autoimmune traits in the (SWR × SJL)F1 hybrid mice. This work was supported by a grant from the Swedish Research Council, Branch of Medicine (project 9453), to P.Hultman, and by NIH grants ES09802, ES08080, ES08666, and ES07511. We thank Robert L. Rubin, The Scripps Research Institute, for supplying chromatin preparations, and Elham Nikookhesal for technical assistance. Yngve Åberg, PhD, provided statistical assistance.