Background/Purpose: Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by B cell hyper-activation and exocrine gland infiltration that results in loss of glandular function, systemic manifestations and autoantibody production. The phosphatidylinositol 3–kinase delta isoform (PI3Kδ) belongs to a large family of intracellular lipid kinases that regulate metabolism, survival, proliferation, apoptosis, growth, and cell migration. The PI3Kδ pathway has been successfully targeted in B cell malignancies. Given the central role of the B cell in the pathogenesis of Sjögren’s syndrome we investigated evidence for the engagement of the PI3Kδ pathway in SS and the functional consequences of blocking PI3Kδ in an animal model of SS. 

Methods: PI3K pathway activation was investigated in paraffin embedded salivary glands from patients with Sjogren’s Syndrome and non-specific chronic sialoadenitis (NSCS). Staining for phosphorylated ribosomal protein S6 (pS6) was performed in combination with several cellular markers. UCB5857, a small molecule inhibitor of PI3Kδ, was used in vivo in an inducible model of ectopic lymphoneogenesis in murine salivary glands that mimics Sjögren’s syndrome. Wild type (C57BL/6) murine salivary glands were cannulated with AdV5 (10^8 p.f.u.). UCB5857 or vehicle was administered by daily gavage, prophylactically or therapeutically, starting at either day 0, day 3 or day 5 p.c. 6 mice were used per group. Flow cytometry, immunofluorescence (IF) and quantitative real time PCR was used on the murine isolated salivary gland to evaluate the samples at peak of inflammation which is day 15 p.c. for all groups analyzed.

Results: Histological staining for PI3Kδ pathway activation protein, pS6 in human tissues, showed significant expression of pS6 in SS samples, as compared to non-specific sialoadenitis control, confirming engagement of the PI3K pathway. pS6 was detected within the lymphoid aggregates in both T and B cell areas and on the periphery of the lymphoid foci. Interestingly, pS6 staining was predominantly found on CD138+ plasma cells in salivary glands of SS patients.

In vivo, we observed a decrease in the number of T and B cells in cannulated salivary glands of mice prophylactically treated with UCB5857, as compared to vehicle treated mice, confirmed both by flow cytometry on isolated lymphocytes and IF. A reduction in total number of CD45⁺, CD3, (both CD8 and CD4⁺cells) and B cells was observed. The gene expression profile of tertiary lymphoid organ (TLO)-associated genes (CXCL13, CCL19, CCL21) was also significantly impaired in mice treated with UCB5857. This decrease was also observed in mice treated therapeutically from day 3 or day 5 pc. Aggregates in these mice were characterized by decrease in focus score, smaller size of lymphoid aggregates and reduced T/B cell follicular organization.

Conclusion: Preliminary data suggest that PI3Kδ is engaged in several cells present in the salivary glands of patients with SS and might contribute to disease pathogenesis. Accordingly, prophylactic and therapeutic blocking of PI3Kδ results in disaggregation of the inflammatory foci and resolution of salivary gland inflammation in an animal model of SS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phosphatidylinositol-3-kinase-delta-pathway-a-novel-therapeutic-target-for-sjogrens-syndrome/