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

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.