title: Mobilization of lymphatic endothelial precursor cells and lymphatic neovascularization in primary Sjögren's syndrome.
abstract: Although lymphatic neovascularization may be a key feature of chronic inflammation, it is almost unexplored in primary Sjögren's syndrome (pSS). A recent study revealed a pro-lymphangiogenic function of interleukin (IL)-17, a leading player in pSS pathogenesis. The aims of the study were to investigate lymphangiogenic mediators and lymphatic vasculature in pSS, as well as their possible association with IL-17. Circulating lymphatic endothelial precursor cells (LEPCs) and Th17 cells were enumerated in pSS patients and healthy donors. VEGF-C and IL-17 levels were assessed in paired serum samples. Lymphatic vasculature, VEGF-C/VEGF receptor (VEGFR)-3 and IL-17 were evaluated in pSS minor salivary glands (MSGs) and compared with normal and non-specific chronic sialadenitis (NSCS) MSGs. Circulating LEPCs were expanded in pSS and correlated with circulating Th17 cells, IL-17 and VEGF-C. In pSS MSGs, a newly formed lymphatic capillary network was found within periductal inflammatory infiltrates and the number of interlobular lymphatic vessels was significantly increased compared with normal and NSCS MSGs. Strong VEGF-C expression was detected in pSS ductal epithelial cells and periductal inflammatory cells. Numerous VEGFR-3(+) infiltrating mononuclear cells were exclusively observed in pSS MSGs. VEGFR-3 expression was strongly increased in lymphatic capillaries of pSS MSGs. IL-17(+) inflammatory cells were preferentially observed around lymphatic vessels in pSS MSGs. This study supports the notion that lymphvasculogenesis and lymphangiogenesis are active in pSS, thereby unmasking a novel aspect of disease pathogenesis. In addition, our results suggest another possible pathogenic role of IL-17 in pSS, further supporting its therapeutic targeting in this disease.
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Alunno
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ibba-Manneschi
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Onelia
authors.initials: O
authors.lastname: Bistoni
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Rosa
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Caterbi
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gerli
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Manetti
mesh_terms: D016022:Case-Control Studies; D003937:Diagnosis, Differential; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D042583:Lymphangiogenesis / Q000235:genetics / Q000276:immunology; D042601:Lymphatic Vessels / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D012470:Salivary Glands, Minor / Q000276:immunology / Q000473:pathology*; D012793:Sialadenitis / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000276:immunology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000276:immunology
chemical_list: D020381:Interleukin-17; D042582:Vascular Endothelial Growth Factor C; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: IL-17; Th17 cells; lymphangiogenesis; lymphatic endothelial precursor cells; lymphvasculogenesis; minor salivary glands; primary Sjögren's syndrome
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