Mobilization of lymphatic endothelial precursor cells and lymphatic neovascularization in primary Sjögren's syndrome.

Alessia Alunno,Irene Rosa,Onelia Bistoni,Mirko Manetti,Sara Caterbi,Roberto Gerli,Lidia Ibba‐Manneschi

doi:10.1111/jcmm.12793

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.

Highlights

Primary Sj€ogren’s syndrome is a systemic autoimmune disorder characterized by chronic inflammation of exocrine glands leading to impaired secretory function [1]
Since lymphatic neovascularization is a key feature of chronic inflammation, a role of this process in inflammatory autoimmune diseases has been speculated [3]
We investigated for the first time lymphvasculogenesis and lymphangiogenic mediators, namely lymphatic endothelial precursor cells (LEPCs) and VEGF-C/VEGF receptor (VEGFR)-3 axis [9,10,11, 23], in Primary Sj€ogren’s syndrome (pSS) and demonstrated that they are increased in this disease

Summary

Introduction

Primary Sj€ogren’s syndrome (pSS) is a systemic autoimmune disorder characterized by chronic inflammation of exocrine glands leading to impaired secretory function [1]. Minor salivary gland (MSG) biopsies of patients with pSS, routinely evaluated for diagnostic purposes, have to display, according to commonly used classification criteria [2], cell aggregates with >50 periductal/ perivascular mononuclear cells (i.e. foci), a pattern defined as focal lymphocytic sialadenitis (FLS). An increased blood vessel density that parallels the extent of glandular inflammation and an activation of VEGF-A/VEGF receptor (VEGFR)-2 and neuropilin-1 co-receptor pro-angiogenic system have been recently described in pSS [4,5,6], the lymphatic vessel counterpart is almost unexplored. Two studies attempted to quantify the lymphatic vascular bed extension in pSS MSGs through the detection of mature lymphatic endothelial cells (ECs), but a 2016 The Authors

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