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.

Expression of interleukin‐17 in primary Sjögren's syndrome and the correlation with disease severity: A systematic review and meta‐analysis

“…Lymphocytic infiltration in exocrine glands is the most important histological characteristic of patients with pSS. Previous studies have shown that IL‐17 is mainly expressed in the periductal and perivascular infiltrates of the salivary glands, with the level of expression correlated with the severity of glandular inflammation . However, among the 7 studies reporting IL‐17 expression under conditions of weak and strong lymphocytic infiltration, no significant overexpression of IL‐17 in severe inflammatory patients is found.…”

Leptin/OB-R pathway promotes IL-4 secretion from B lymphocytes and induces salivary gland epithelial cell apoptosis in Sjögren's syndrome

“…Apoptotic death of ECs has been described by three different mechanisms [ 9 – 15 ]. First, ECs may be intrinsically activated and die due to membrane folding through autocrine Fas/FasL interactions.…”

“…Damage to exocrine cells accompanies lymphocyte infiltrates of ductal epithelial cells (ECs), which results in oral and ocular dryness [ 9 – 15 ]. However, these aggregates evolve from mild to focal, focal to diffuse, and vary in composition according to the severity of the disease.…”

Decreased circulating lymphatic endothelial progenitor cells in digital ulcer-complicated systemic sclerosis

“…On their surface, LEPC display CD34 and CD133, likewise their blood vascular counterpart (ie, EPC), but they present vascular endothelial growth factor receptor (VEGFR)-3 (also called Flt4) instead of VEGFR-2 6. Interestingly, an expansion of circulating LEPC has been recently shown in rheumatic diseases such as spondyloarthritis and primary Sjögren’s syndrome 7 8. As far as SSc is concerned, heterogeneous data have been reported on the numbers and functions of EPC,2 but no data are currently available on LEPC.…”