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Abstract Sjögren’s syndrome (SS) is a prevalent systemic autoimmune disease with substantial impacts on women’s health worldwide. Although oral Haemophilus parainfluenzae is reduced in SS, its significance remains unclear. This study aimed to elucidate the pathophysiological role of H. parainfluenzae in SS. Reduced salivary H. parainfluenzae levels in SS patients were confirmed through quantitative PCR. Oral H. parainfluenzae inoculation in NOD mice alleviated focal sialadenitis, improved salivary function, and reduced IFN-γ+CD3+ and IFN-γ+CD8+ T cells in salivary gland-draining lymph nodes, maintaining immune homeostasis against a biased type 1 response. Inoculation also enhanced salivary microbiota diversity, balanced the Firmicutes-to-Proteobacteria ratio, and reduced the overwhelming presence of Pseudomonas mendocina. In vitro, H. parainfluenzae-preconditioned A253 cells limited CD8 T cell expansion with reduced IFN-γ production. These findings suggest that H. parainfluenzae improves oral microbial diversity, promotes homeostatic T-cell immunity, and protects against SS, supporting its potential as a next-generation probiotic.

Abstract Salivary gland epithelial cells (SGECs) have been implicated in the pathogenesis of Sjögren’s syndrome due to aberrant antigen-presentation function. This study examined the hypothesis that oral dysbiosis modulates the antigen-presentation function of SGECs, which regulates CD4 T cell proliferation in primary Sjögren’s syndrome (pSS). Saliva samples from 8 pSS patients and 16 healthy subjects were analyzed for bacterial 16S ribosomal DNA. As a result, 39 differentially abundant taxa were identified. Among them, the phylum Proteobacteria comprised 21 taxa, and this phylum was mostly enriched in the healthy controls. The proteobacterium Haemophilus parainfluenzae was enriched in the healthy controls, with the greatest effect size at the species level. Treatment of A253 cells in vitro with H. parainfluenzae upregulated PD-L1 expression, and H. parainfluenzae-pretreated A253 cells suppressed CD4 T cell proliferation. The suppression was partially reversed by PD-L1 blockade. Among low-grade xerostomia patients, salivary abundance of H. parainfluenzae decreased in pSS patients compared to that in non-pSS sicca patients. Our findings suggest that H. parainfluenzae may be an immunomodulatory commensal bacterium in pSS.