The pathogenesis of transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) in primary Sjogren's syndrome and its intricate regulation of B cells

Background and Objectives: Primary Sjogren's syndrome (pSS) is an autoimmune disorder primarily affecting exocrine glands, with B cells playing a key role in its pathogenesis. This study aim to investigates TACI expression on B cells and its significance functions in pSS. Methods We recruited 34 treatment-naive pSS patients and 37 matched healthy controls (HC), to analyze B cell subsets and TACI ratios, along with serum BAFF and sTACI levels. For TACI function, B cells were treated with raw station, siRNA-TACI, and sTACI analog, assessing effects on proliferation and differentiation. TACI-associated signaling pathways were explored by confirming biased miRNA expression via RT-qPCR, screening target genes, and manipulating target gene expression. Results pSS patients showed altered peripheral blood B cell subsets, with increased CD19 ⁺ CD24 ^hi CD38 ^hi regulatory B (Breg) cells and decreased CD19 ⁺ CD24 ⁺ CD38 ⁻ memory B cells, alongside down-regulated TACI expression on B cell subsets and elevated BAFF and sTACI levels in serum. Untreated TACI ⁺ B cells in pSS showed increased proliferative capacity. TACI downregulation led to more proliferation, and dysfunctional Breg cells. Telitacicept reduced B cell proliferation, increased transmembrane TACI expression on B cells, and lowered IgG levels. Additionally, hsa-miR-30b-5p was down-regulated in pSS, with its inhibition impairing Breg cell differentiation and IL-10 secretion, correlating with TACI levels, while SMAD1-Id2 was identified as its target gene in the TGF-β/Hippo pathway. Conclusions B cell impairment, especially in Breg subsets, is linked to low TACI expression, which is associated with reduced hsa-miR-30b-5p, activating the TGF-β/Hippo pathway through SMAD1/Id2, contributing to pSS pathogenesis.