Phosphatidylinositol 3-Kinase Delta: A Potential Target Pathway in Sjogren Syndrome

In individuals with primary Sjogren syndrome (pSS), activation of the phosphatidylinositol 3-kinase delta isoform (PI3Kδ) pathway within the salivary glands has been shown to contribute to immunopathogenesis of the disease, according to study results published in Annals of the Rheumatic Diseases.

Recognizing the key role played by B cells in the pathogenesis of pSS, the investigators sought to explore PI3Kδ pathway activation in patients with pSS, along with the functional consequences of blocking PI3Kδ in a murine model of focal sialadenitis that mimics some of the features of patients with pSS.

Using target validation assays, a significant expression of phosphorylated ribosomal protein S6 (pS6), which is a downstream mediator of the PI3Kδ pathway, was observed in the salivary glands of patients with pSS. Furthermore, the distribution of pS6 was shown to co-localize with T-cell and B-cell markers in pSS aggregates, as well as with the CD138+ plasma cells that infiltrate the glands of affected patients.

In a murine model of focal sialadenitis, in vivo blocking of PI3Kδ activity with the PI3Kδ-selective inhibitor seletalisib was associated with decreased accumulation of lymphocytes and plasma cells in the glands of treated mice in both the prophylactic and therapeutic regimens. Moreover, the production of lymphoid cytokines and chemokines linked to ectopic lymphoneogenesis, as well as autoantibody production and saliva flow, was significantly affected by treatment with seletalisib.

The investigators concluded that the results of this study support exploration of the therapeutic potential of PI3Kδ pathway inhibition as a treatment option in patients with pSS. The data derived from this study suggest that PI3Kδ is engaged in several cell types within pSS inflammatory infiltrates and may be involved in the perpetuation of the local autoimmune response in patients with pSS.

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Reference

Nayar S, Campos J, Smith CG, et al. Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren’s syndrome [published online November 24, 2018]. Ann Rheum Dis. doi:10.1136/annrheumdis-2017-212619