Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome.

Nayar, Saba and Campos, Joana and Smith, Charlotte G and Iannizzotto, Valentina and Gardner, David H and Colafrancesco, Serena and Pipi, Elena and Kollert, Florian and Hunter, Kelly J and Brewer, Charlotte and Buckley, Christopher Dominic and Bowman, Simon J and Priori, Roberta and Valesini, Guido and Juarez, Maria and Fahy, William A and Fisher, Benjamin A and Payne, Andrew and Allen, Rodger A and Barone, Francesca (2019) Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome. Annals of the rheumatic diseases, 78 (2). pp. 249-260. ISSN 1468-2060. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: https://ard.bmj.com/content/78/2/249.long

Abstract

BACKGROUND

The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS.

METHODS AND RESULTS

Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib.

CONCLUSION

These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: WB Practice of medicine
WE Musculoskeletal. Orthopaedics
Divisions: Ambulatory Care > Rheumatology
Related URLs:
Depositing User: Jamie Edgar
Date Deposited: 01 Nov 2019 12:59
Last Modified: 01 Nov 2019 12:59
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2545

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