Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome
Autor: | Rodger A. Allen, Charlotte G Smith, Elena Pipi, Saba Nayar, Florian Kim Kollert, Valentina Iannizzotto, Maria Juarez, Christopher D. Buckley, Roberta Priori, Fahy William Anthony, Serena Colafrancesco, Francesca Barone, David H. Gardner, Charlotte Brewer, Kelly J Hunter, Benjamin A Fisher, Payne Andrew Charles, Joana Campos, Simon J Bowman, Guido Valesini |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Pathology Pyridines autoantibodies Sjögren's Syndrome Salivary Glands Pathogenesis Mice 0302 clinical medicine Immunology and Allergy 610 Medicine & health B-Lymphocytes Ribosomal Protein S6 medicine.diagnostic_test Salivary gland treatment Kinase Sjogren's Syndrome medicine.anatomical_structure Quinolines Cytokines medicine.symptom sjøgren's syndrome Signal Transduction medicine.medical_specialty Plasma Cells Immunology Inflammation Biology Immunofluorescence autoimmune diseases B cells Sialadenitis General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Rheumatology stomatognathic system medicine Animals CXCL13 PI3K/AKT/mTOR pathway 030203 arthritis & rheumatology Autoantibody Molecular biology Disease Models Animal 030104 developmental biology Phosphatidylinositol 3-Kinase |
Zdroj: | 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 Annals of the Rheumatic Diseases |
Popis: | Sjogren’s syndrome (SS) is a chronic autoimmune disease characterised 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 family of intracellular lipid kinases that regulate metabolism, survival, proliferation, apoptosis, growth, and cell migration and has been successfully targeted in B-cell malignancies. Given the central role of the B-cells in the pathogenesis of SS 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. PI3K pathway activation was investigated in salivary gland (SG) biopsies from patients with SS or non-specific chronic sialoadenitis (NSCS). Samples were stained for phosphorylated ribosomal protein S6 (pS6), a downstream effector in the PI3Kδ pathway. UCB5857, a small molecule inhibitor of PI3Kδ, was used either prophylactically or therapeutically in vivo in an inducible model of ectopic lymphoneogenesis in murine SGs that mimics SS. Flow cytometry, immunofluorescence and quantitative PCR was used on the murine isolated SG to evaluate the samples at peak of inflammation which is day 15 post-cannulation. Histological staining for pS6 showed significant expression of pS6 in SS samples relative to NSCS control, confirming engagement of the PI3K pathway. pS6 was detected within lymphoid aggregates in both T- and B-cell areas and on the periphery of the lymphoid foci in SG biopsies. pS6 staining was predominantly found on CD138 + plasma cells in SG biopsies. Mice treated either prophylactically or therapeutically with UCB5857 displayed decreased lymphocyte infiltration in cannulated salivary glands relative to vehicle treated mice. Additionally, a gene expression profile associated with ectopic lymphoneogenesis (CXCL13, CCL19, CCL21) was significantly impaired in mice treated with UCB5857. Lymphoid aggregates in these mice were characterised by decrease in focus score, smaller size and reduced T/B-cell follicular organisation. Preliminary data implicates activation of PI3Kδ pathway in several cells within the SGs of SS patients that may contribute towards pathology. Accordingly, prophylactic and therapeutic blocking of PI3Kδ results in disaggregation of the inflammatory foci and resolution of SG inflammation in an animal model of SS. |
Databáze: | OpenAIRE |
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