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

Nayar, Saba; Campos, Joana; Smith, Charlotte G; Iannizzotto, Valentina; Gardner, David H; Colafrancesco, Serena; Pipi, Elena; Kollert, Florian Kim; Hunter, Kelly J; Brewer, Charlotte; Buckley, Christopher Dominic; Bowman, Simon J; Priori, Roberta; Valesini, Guido; Juarez, Maria; Fahy, William A; Fisher, Benjamin A; Payne, Andrew; 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. BMJ Publishing Group 10.1136/annrheumdis-2017-212619

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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:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology

UniBE Contributor:

Kollert, Florian Kim

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0003-4967

Publisher:

BMJ Publishing Group

Language:

English

Submitter:

Burkhard Möller

Date Deposited:

26 Jul 2019 09:19

Last Modified:

23 Oct 2019 05:57

Publisher DOI:

10.1136/annrheumdis-2017-212619

PubMed ID:

30472652

Uncontrolled Keywords:

B cells autoantibodies autoimmune diseases sjøgren's syndrome treatment

BORIS DOI:

10.7892/boris.125140

URI:

https://boris.unibe.ch/id/eprint/125140

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