Abstract
Changes in protein glycosylation are a hallmark of immune-mediated diseases. Glycans are master regulators of the inflammatory response being important molecules for the discrimination between "self"/"non-self". We here explored whether lupus nephritis (LN) exhibit an altered cellular glycosylation aiming to identify a unique glycosignature that characterizes LN pathogenesis. A comprehensive tissue glycomics characterization was performed in a cohort of human biopsy-proven LN clinical samples from SLE patients. A combination of advanced tissue mass spectrometry imaging (MSI); in situ glyco-characterization and ex vivo glycophenotyping of human kidney biopsies were performed to structurally map the N-glycans repertoire in LN samples. LN revealed a unique glycan signature characterized by an increased abundance and spatial distribution of unusual mannose-enriched glycans that are typically found in lower microorganisms; this glycosignature was specific of LN as it was not observed in other kidney diseases. Exposure of mannosylated glycans in LN was found to occur at the cell surface of kidney cells promoting an increased recognition by specific glycans-recognizing receptors, expressed by immune cells. This abnormal glyco-signature of LN was demonstrated to be due to a deficient complex N-glycosylation and a proficient O-mannosylation pathway. Moreover, levels of mannosylation detected in kidney biopsies from LN patients at diagnosis were demonstrated to predict the development of chronic kidney disease (CKD) with 93% of specificity. Cellular mannosylation is a marker of LN, predicting the development of CKD, and thus constituting a potential glycobiomarker to be included in the diagnostic and prognostic algorithm of LN.
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