Plasma ST6GAL1 regulates IgG sialylation to control IgA nephropathy progression

Abstract

Background: Our previous study revealed that plasma levels of a-2,6-sialyltransferase 1 (ST6GAL1) were increased in patients with IgA nephropathy (IgAN). ST6GAL1 catalyzes terminal sialylation of IgG to shift the antibody effector function to the anti-inflammatory pattern. However, the role of plasma ST6GAL1 in the progression of IgAN and underlying mechanisms are still unknown. Methods: A total of 180 IgAN patients were included. The kidney outcomes were defined as the eGFR decline or proteinuria remission. Peripheral blood mononuclear cells (PBMCs) were either stimulated with purified sialylated IgG (SA-IgG) or with non-sialylated IgG (NSA-IgG) from IgAN patients to detect the levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) in supernatant. Results: Compared with the lower ST6GAL1 (reference), the risk of eGFR decline decreased for the higher ST6GAL1 group after adjustment for baseline eGFR, systolic blood pressure (SBP), and proteinuria. The results showed that patients with higher ST6GAL1 levels had a higher rate of proteinuria remission. ST6GAL1, expressed as a continuous variable, was a protective factor for eGFR decline and proteinuria remission. An in vitro study showed that the administration of recombinant ST6GAL1 (rST6GAL1) decreased the levels of IL-6 and TNF-α in PBMCs. Furthermore, the administration of rST6GAL1 resulted in the enrichment of SA-IgG in a concentration-dependent manner. In addition, as compared to control, purified SA-IgG-treated PBMCs showed a significant decrease in the expression of IL-6 and TNF-α. Conclusion: Our study indicated that elevated ST6GAL1 was associated with a slower progression of IgAN, which may play a protective effect by increasing IgG sialylation to inhibit the production of proinflammatory cytokines in PBMCs.

Downregulation of ST6GAL1 Promotes Liver Inflammation and Predicts Adverse Prognosis in Hepatocellular Carcinoma

“…It has been shown that ST6GAL1 could prevent intestinal inflammation by regulating T cell immunity levels and play a protective effect on IgA nephropathy by inhibiting the production of proinflammatory cytokines in patients. 15,16 While the deficiency of ST6GAL1 could cause exaggerated acute neutrophilic inflammation, increase radiation-induced gastrointestinal damage, and promote the transformation of synovial fibroblasts into a pro-inflammatory phenotype in mice. [17][18][19] For HCC, it has been reported that serum ST6GAL1 levels were positively correlated with tumor FGF19 expression in patients with surgically resected HCC, and could be a novel serum biomarker for lenvatinib-susceptible FGF19-driven HCC.…”

IgG N-glycan Signatures as Potential Diagnostic and Prognostic Biomarkers

“…Recent reports focus on treating autoimmune disease with therapeutic intravenous bulk IgG containing increased levels of sialic acid on the Fc region [ 141 ]. More research should be devoted to identifying compounds that modulate host plasmablast glycosyltransferase expression to alter immunologic responses during disease states and autoimmunity [ 56 , 142 ].…”