Aging-Associated Autoimmunity in Genetically Diverse UM-HET3 Mice Shows a Female Sex Bias

C57BL/6 (B6) mice, often considered a non-autoimmune control strain, spontaneously develop autoantibodies and lymphocytic infiltration in the salivary glands (SG) with aging. However, as an inbred strain, B6 mice have a limited genetic background and do not fully represent a genetically diverse population. To assess whether genetic diversity influences the development of age-related autoimmunity, we studied UM–HET3 mice, a four-way cross that is commonly used in aging research. By 14–20 months of age, females showed significantly higher frequencies and endpoint titers of anti-nuclear antibodies. Older females also exhibited increased levels of splenic atypical/age-associated B cells and follicular helper T cells, populations associated with the production of autoantibodies. Similar immune cell changes were observed in the SG, with some female mice developing organized lymphocytic foci consisting of T and B cells. Our findings demonstrate that UM–HET3 mice naturally develop systemic autoimmunity and sialadenitis with age, with a clear female bias. Since female UM–HET3 mice have a longer median lifespan than males, these autoimmune responses may reflect benign autoimmunity, representing a heightened immune response associated with aging.