Development of NOD-DR3 as the Spontaneous Humanized Mouse Model for Sjögren’s Disease

Background: Sjögren’s disease (SjD) is a chronic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, leading to secretory dysfunction. While conventional mouse models have advanced understanding of disease mechanisms, translational limitations exist due to differences in immune system components, particularly MHC molecules. The NOD-DR3 mouse strain, expressing human HLA-DR3, a prominent genetic risk factor for SjD, offers a humanized model that has not been previously characterized for SjD phenotypes. Objective: To comprehensively characterize NOD-DR3 mice as a novel humanized model for SjD, evaluating functional, serological, histological, and immunological disease features with particular focus on sex dimorphism. Methods: Aged NOD-DR3 mice (20–32 weeks) were assessed for salivary flow rates, autoantibody profiles (ANA, anti-Ro52, anti-Ro60, anti-La), glandular focal scores, and immune cell infiltration patterns. Comparisons were made with established SjD models (NOD-Aec1/2, NOD) and healthy C57B6/J controls, with sex-stratified analyses. Results: NOD-DR3 mice exhibited significantly reduced salivary flow rates, comparable to those in established models. Seventy percent were ANA-positive, with pronounced sex-dependent patterns: males showed higher ANA frequency with nucleolar patterns, while females displayed elevated anti-Ro/La antibodies with speckled patterns. Notably, NOD-DR3 demonstrated the most severe lacrimal gland infiltration among all strains. Cellular analysis revealed striking sex dimorphism, with females showing 12-fold higher B-cell infiltration and enhanced Th17 responses, while males exhibited elevated macrophage and Th1 profiles. Conclusions: NOD-DR3 mice recapitulate cardinal SjD features with robust sex dimorphism, establishing this humanized model as a valuable translational platform for investigating HLA-restricted disease mechanisms and evaluating therapeutic interventions.