{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:09:16Z","timestamp":1788948556584,"version":"build-2803163510"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sj\u00f6gren\u2019s 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\u2013symptom 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\u2013symptom, tissue\u2013function, biomarker\u2013phenotype, 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1882936","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:40:28Z","timestamp":1788946828000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From immune activation to symptom burden: mechanisms and translational implications of immune\u2013symptom uncoupling in Sj\u00f6gren\u2019s disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingying","family":"Le","sequence":"first","affiliation":[{"name":"The Second Clinical Medical College of Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyan","family":"Gu","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zouyin","family":"Su","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College of Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00340-5","article-title":"Identification of distinct subgroups of Sj\u00f6gren\u2019s disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts","volume":"6","author":"Nguyen","year":"2024","journal-title":"Lancet Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(24)00039-0","article-title":"Precision medicine in Sj\u00f6gren\u2019s disease","volume":"6","author":"Gandolfo","year":"2024","journal-title":"Lancet Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204615","article-title":"Validation of EULAR primary Sj\u00f6gren\u2019s syndrome disease activity (ESSDAI) and patient indexes (ESSPRI)","volume":"74","author":"Seror","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.200907","article-title":"Correlation between subjective and objective severity of oral and ocular dryness in primary Sj\u00f6gren syndrome","volume":"48","author":"Ripsman","year":"2021","journal-title":"J Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/acr.23165","article-title":"Subjective and objective measures of dryness symptoms in primary Sj\u00f6gren\u2019s syndrome: capturing the discrepancy","volume":"69","author":"Bezzina","year":"2017","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(19)30042-6","article-title":"Symptom-based stratification of patients with primary Sj\u00f6gren\u2019s syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials","volume":"1","author":"Tarn","year":"2019","journal-title":"Lancet Rheumatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2017-000443","article-title":"Patient burden of Sj\u00f6gren\u2019s: a comprehensive literature review revealing the range and heterogeneity of measures used in assessments of severity","volume":"3","author":"Hammitt","year":"2017","journal-title":"RMD Open"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.05.004","article-title":"Primary Sj\u00f6gren\u2019s disease: a review of unmet need, outcome measures, therapeutic advances and health economic impacts. 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