Regulatory T cell therapy for Sjögren's disease: From pathogenesis to targeted treatment

Sjögren's disease (SjD) is a chronic systemic autoimmune disorder characterised by lymphocytic infiltration of the salivary and lacrimal glands, leading to the hallmark symptoms of dry eyes and dry mouth. Beyond glandular dysfunction, many patients experience systemic complications-including B cell hyperactivity, organ-specific inflammation, and a markedly increased risk of non-Hodgkin lymphoma-that are frequently under-recognised and poorly managed. Current treatments remain largely empirical and symptomatic, with limited efficacy in modifying disease progression or restoring immune tolerance. Recent advances have illuminated profound dysregulation in both innate and adaptive immunity, revealing novel therapeutic targets now under investigation in clinical trials, including type I interferon signalling, B cell activation, and co-stimulatory pathways. Central to this dysregulation is T cell-driven pathology: CD8⁺ T cell cytotoxicity, defective regulatory T cell (Treg) function, and HLA class II-mediated presentation of self-antigens to autoreactive CD4⁺ T cells are key mechanisms in disease initiation and persistence. A growing body of evidence implicates Ro autoantigens-Ro60 and Ro52-as central targets in SjD pathogenesis. Anti-Ro antibodies are present in approximately 70 % of patients and serve as both diagnostic markers and indicators of systemic involvement. Ro antigens and their corresponding antibodies are consistently detected in inflamed salivary tissues, underscoring their potential as compelling targets for antigen-specific therapy. This review examines the immunopathogenic role of Ro-specific T cell responses in SjD and outlines how engineered Treg-based therapies may enable precise immune modulation, restore tolerance, and provide durable disease control for patients with this complex autoimmune condition.