Aging-associated autoimmunity in genetically diverse UM-HET3 mice shows an early female sex bias.

Sjögren's disease, an autoimmune disorder characterized by the presence of circulating autoantibodies and lymphocytic infiltrates in salivary glands, predominantly affects women later in life. By leveraging genetically heterogeneous UM-HET3 mice, this study tested the hypothesis that female sex and aging interact to shape susceptibility to autoimmunity and salivary gland inflammation. Female and male UM-HET3 mice were evaluated across the adult lifespan for the development of glandular inflammation and autoantibodies. Aging female mice spontaneously develop Sjögren's-like salivary gland inflammation and systemic autoimmunity, whereas age-matched males exhibit only modest immune alterations. Histopathology and flow cytometry revealed significantly higher numbers of lymphocytic foci and immune cell infiltrates in the salivary glands of older females, including expansions of T follicular helper cells and atypical B cells associated with autoantibody production. Concordantly, aged females produced high-titer IgG autoantibodies recognizing nuclear and cytoplasmic antigens. Notably, even before the onset of overt glandular pathology, young adult females exhibited heightened baseline activation of splenic T and B cells, as well as upregulation of immune-activation genes, compared with males. Together, these findings demonstrate that in a genetically diverse background, female sex and aging synergize to drive spontaneous organ-specific inflammation and systemic autoimmunity. Considering that female UM-HET3 mice have a longer lifespan than male mice, the autoimmune response in females appears to remain benign. Thus, aged UM-HET3 mice provide a tractable model to dissect how gene-environment interactions transform benign age-associated autoimmunity into a pathogenic clinical disease.