de Ocampo, C.; Peiss, A. K.; Leung, H. Y.; Janssen, L. M.; Kono, D. H.; Mayeux, J. M.; Pollard, K. M.

Aging is associated with increased spontaneous autoantibody production and chronic inflammation, yet its impact on xenobiotic-induced autoimmunity remains unexplored. This study investigates the effect of age on mercury-induced autoimmunity (HgIA) in B10.S mice, a model of xenobiotic-induced autoimmunity characterized by anti-nucleolar autoantibodies (ANoA). Mature (3 months), adult (6 months), middle-aged (12 months), and old-age (24 months) mice were exposed to mercury (HgCl2) or phosphate-buffered saline (PBS) for 4-5 weeks. While spontaneous anti-nuclear antibodies (ANA) increased with age in PBS-treated mice (34% in middle-aged, 57% in old-age mice), HgIA incidence declined in old age mice, with only 59% (26/44) developing significant ANoA titers compared to 91-100% in younger cohorts. Notably, 56% (10/18) of initially ANoA-negative old mice had detectable ANoA at a lower dilution, indicating a reduced but not absent response. ANoA negativity in old age mice was associated with lower immunoglobulin levels, reduced anti-chromatin antibodies, and diminished germinal center formation, suggestive of immunosenescence. Flow cytometry revealed age-related declines in CD4+ T cells, with mercury exposure augmenting T-cell differentiation in younger but not old mice. These findings demonstrate that aging enhances spontaneous autoimmunity but impairs xenobiotic-induced autoimmunity, with a subset of old age mice retaining partial responsiveness at lower dilutions, highlighting the complex interplay between immunosenescence and environmental triggers.