From immune activation to symptom burden: mechanisms and translational implications of immune-symptom uncoupling in Sjögren's disease.

Sjögren's disease (SjD) is a heterogeneous autoimmune disease in which systemic activity, local tissue pathology, objective glandular or ocular function, biomarkers, and patient-reported symptoms frequently fail to align or change in parallel. We define immune-symptom uncoupling as partial, non-linear, or temporally asynchronous discordance across these domains rather than complete biological separation. This focused narrative review was informed by targeted, structured searches of PubMed and the Web of Science Core Collection through July 9, 2026. We distinguish four recurrent forms: systemic activity-symptom, tissue-function, biomarker-phenotype, and response-layer discordance. The most consistent clinical evidence concerns weak alignment between systemic disease activity and dryness, pain, or fatigue. Multimodal and longitudinal studies further indicate that histopathology, ultrasonography, objective glandular function, and patient-reported dryness provide complementary rather than interchangeable information. Interferon activity, B-cell-associated markers, and autoantibody profiles may identify pathway activity, endotypes, or organ-risk biology without proportional symptom burden, while therapeutic studies show that biological response may occur without parallel systemic, tissue-level, functional, or symptomatic improvement. Tissue compartmentalization, active functional or bioenergetic dysregulation, structural injury and reduced functional reserve, SjD-related neurological involvement, central sensitization and symptom amplification, comorbid or contextual modifiers, and temporal asynchrony are plausible contributors; however, much of the mechanistic evidence remains observational or cross-sectional, and prospective causal validation is limited. Clinically, discordance should prompt targeted evaluation of local, functional, neurological, and contextual contributors rather than automatic escalation of immunosuppression or dismissal of symptoms. In trials, aligning the therapeutic target, enrolled population, primary endpoint, and assessment window with the expected response layer may reduce treatment-effect dilution and improve interpretation of negative or layer-specific findings. This framework supports more precise interpretation of disease activity, symptom burden, biomarkers, and treatment response while defining priorities for prospective multidomain studies.