Background/Purpose: Lupus nephritis (LN) occurs in 50% of patients with systemic lupus erythematosus (SLE) for which we lack biomarkers, and an understanding of its pathogenesis. We have previously demonstrated that IgG in LN is aberrantly glycosylated and can injure podocytes.

Methods: We evaluated the IgG glycome by N-glycan profiling in a pediatric cohort of 40 children with SLE and 20 paired pre and post treatment LN samples using LS-MS Mass Spectrometry. We used enzymatic treatments to evaluate the role of glycans in podocyte injury. Data were analyzed using GEE analysis, Spearman test, t-test and regression analysis. Podocyte phenotype was evaluated by wound healing assay, cytoskeleton evaluation (F-actin) and podocyte specific proteins by RT-PCR and western blotting.

Results: We found that the overall glycosylation was reduced 6 months post treatment in patients with LN. Furthermore, those decorated with terminal galactose were increased while those with terminal sialic acid were reduced. In addition, neutral glycans were increased after treatment while negatively charged glycans were decreased. To evaluate whether these differences were due to treatment rather than LN activity, we analyzed the IgG glycome in SLE without LN, LN, LN in remission 6-month after treatment. We found that neutral glycans and negatively charged glycan chains changed with LN activity. Furthermore, the presence or absence of sialic acid and galactose correlated with parameters that influence active nephritis (renal SLEDAI, dsDNA, C3, cellular crescents and proteinuria). A switch from tri to bi -antennary complex type N-Glycans was noted in those with decling GFR. More interestingly, treatment of IgG with PNGase- F, which removes glycan chains, prevented cytoskeleton and motility changes in podocytes that were induced in LN. In addition, nephrin expression was preserved following PNG-ase treatment.

Conclusion: The IgG glycome in pediatric SLE patients is altered and is further aberrantly glycosylated in LN. The magnitude of change is associated with LN activity. More importantly, the glycans on IgG can lead to podocyte injury in LN. Our data shed light on the role of IgG glycosylation in the development of podocyte injury and propose the development of approaches using the IgG glycome to diagnose and monitor LN. Further, it highlights IgG glycosylation as an important pathogenic mechanism in LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-sweet-in-lupus-igg-glycosylation-in-lupus-nephritis/