Abstract
Several studies have confirmed that the myeloid-derived suppressor cells (MDSCs) are closely associated with autoimmune diseases, but their exact role in these processes remains largely unclear. Here, we investigated the role MDSCs in patients with primary membranous nephropathy (PMN). Compared to healthy controls (HCs), PMN patients showed significantly increased number of HLA-DR−CD11b+CD33+ MDSCs in the peripheral blood, including both CD14+CD66b− monocytic and CD14−CD66b+ granulocytic MDSCs. The frequency of MDSCs was positively correlated with the level of serum anti-phospholipase A2 receptor (anti-PLA2R), 24-h urine protein quantification, and disease activity in PMN patients. Consistently, enhanced T helper 2 (Th2) and T helper 17 (Th17) immune responses were positively associated with plasma anti-PLA2R levels, 24-h urine protein quantification, and the disease activity in PMN patients. Moreover, compared to HCs, MDSCs from PMN patients exhibited significantly elevated arginase-1 (ARG-1) production and increased potential to promote Th17 differentiation in vitro in an ARG-1–dependent manner. This study directly demonstrates a pathogenic role for MDSCs in human PMN and provides a molecular mechanism for the pathogenesis of PMN. Our data show that MDSCs may promote PMN disease progression mainly by enhancing Th17 response. Therefore, MDSCs may be an important diagnostic, therapeutic, and prognostic marker for PMN diseases.
Highlights
Primary membranous nephropathy (PMN), a common cause of the nephrotic syndrome in adults, is an organ-specific autoimmune disease [1,2,3,4,5,6,7,8]
We first measured the frequency of myeloid-derived suppressor cells (MDSCs) and their subsets isolated from peripheral blood mononuclear cells (PBMCs) of PMN patients using flow cytometry
We found that PMN patients had significantly increased frequency of IL-4+CD4+ cells compared to healthy controls (HCs), indicating that T cells from PMN patients tended to be more polarised into T helper 2 (Th2) cells, and MDSCs from both HCs and PMN patients inhibited naïve CD4+ T differentiation into Th2 cells (Figures 7A,B)
Summary
Primary membranous nephropathy (PMN), a common cause of the nephrotic syndrome in adults, is an organ-specific autoimmune disease [1,2,3,4,5,6,7,8]. Some studies have shown that PMN is a Th2-related autoimmune disease [13,14,15]. Compared to controls and other forms of glomerulonephritis, the percentage of IL-4+CD4+ and IL-10+CD4+ cells are significantly increased (the former is positively correlated with proteinuria), and the Th1/Th2 ratio is significantly lower in PMN patients [15, 16]. Th2 cytokines promote the production of immunoglobulin (Ig) G4 type antibodies by B lymphocytes in PMN [13]. Th17 cells are found in renal biopsies of human glomerulonephritis and renal autoimmunity, and may serve as a therapeutic target in the future [17,18,19]. The relationship between Th17 cells and PMN remains unclear
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