Abstract / Summary
Sjögren’s disease (SjD) is a systemic autoimmune disease of the exocrine glands, long framed as a lymphocyte-driven disorder in which immune cells destroy the target tissue. Genomic, epigenetic, microbiome, and single-cell and spatial studies have since shown the glandular epithelium and the microbial environment to be active participants rather than passive bystanders. This review asks whether host susceptibility and microbiome change can be joined into one continuous axis, following it from genetic and epigenetic susceptibility, through microbiome change read functionally rather than taxonomically, to the crosstalk that converts microbial signals into a host response and the cell states carrying it in human tissue. Two axes run through the whole sequence: the type I interferon (IFN) response and short-chain fatty acid (SCFA) metabolism. Read against them, every disease-modifying therapy with validated efficacy so far acts in the downstream B-cell effector axis, whereas the upstream IFN axis has yielded no established treatment. Because the microbial layer and the salivary gland transcriptome or proteome have never been measured in the same patients, the model proposed here remains a testable hypothesis rather than a completed causal chain. The aim is to specify that model, the falsification conditions it carries, and the study design its verification requires.