Divergent Immune Trajectories Influence Sex Bias in Aging Salivary Gland Autoimmunity 2309855

Abstract Introduction Sjögren’s disease (SjD) is a systemic chronic autoimmune disorder that disproportionately affects older women. The mechanisms driving this age- and sex- bias remain unclear. Here, using both inbred and genetically diverse mice, we tested how aging and sex interact to drive systemic autoimmunity and salivary gland immunopathology. Methods Inbred (C57BL/6, A/J) and genetically heterogeneous UM-HET3 mice were analyzed across 4—22 months of age. Serum anti-nuclear IgG was quantified by indirect immunofluorescence. Salivary gland immune infiltrates were profiled by immunohistochemistry and spectral flow cytometry. Transcriptional programs were interrogated using NanoString immune panels, bulk RNA-seq, and single-cell RNA-seq. Results Across genetic backgrounds, aging unmasked robust female-biased autoimmunity. Aged females developed high-titer anti-nuclear IgG antibodies and progressive lymphocytic sialoadenitis. Glandular infiltration followed a hierarchical pattern, dominated by T cells, followed by B cell accumulation, age-associated B cell enrichment, CD4 T follicular helper cell expansion, and germinal center formation. In contrast, age-matched males exhibited significantly lower autoantibody titers and were protected from severe sialoadenitis. While a subset of 22-month-old males reached autoantibody titers comparable to females, they rarely developed pronounced glandular pathology. Instead, male salivary glands had sparse B cell representation but prominent CD8 T cell infiltration with a terminally exhausted phenotype. Conclusion Aging is a dominant driver of spontaneous systemic and glandular autoimmunity, but sex-specific immune programs dictate divergent tissue outcomes. In males, terminal CD8 T cell exhaustion is consistent with a localized immunoregulatory niche that may constrain B cell accrual and limit progression to severe sialoadenitis despite systemic autoantibody production. Defining these inhibitory signals may reveal new strategies to suppress glandular inflammation in SjD. Funding Source Supported by NIH/NIDCR DE032911, DE034962, Presbyterian Health Foundation Topic Categories Basic Autoimmunity (BA)