Sex, Sugars, and Systemic Lupus Erythematosus: Glycomic Signatures Reveal Clues to Lupus Nephritis Risk and Severity

Background: Systemic lupus erythematosus (SLE) affects mostly women however men with SLE have worse outcomes including lupus nephritis (LN). We have previously demonstrated that aberrant IgG glycosylation is a key feature of LN and drives podocyte injury in LN. Methods: IgG from healthy volunteers and those with SLE was isolated. N-glycan mass spectromtery was performed. RNA sequencing data was evaluated for defects in N-glycosylation biosysthesis. Podocytes in culture were exposed to IgG and phenotyped for injury by evaluating actin cytoskeleton, nephrin expression and motility. Results: We found significant differences in IgG glycosylation between healthy men and women. Specifically, healthy women had a proinflammatory glycome with a lesser degree of sialylation and galactosylation while healthy men had an antiinflammatory glycome. This difference was reversed in SLE and lupus nephritis. In LN, there was a severe degree of undergalactosylation and undersialylation compared to healthy individuals . However men with LN had a greater degree of loss of galactose and sialic acid compared to women with LN. Overall the glycome in men with LN was significantly more pro-inflammatory compared to women with LN. This was associated with worse outcomes(Renal-SLEDAI) and a greater degree of podocyte injury in-vitro. RNA sequencing data sets revealed significant differences in the N-glycan biosysthesis pathway between healthy individuals and those with LN specifically in genes regulating enzymes for transferring sialic acid and galactose on proteins. These differences were present when comparing healthy men and women and those with LN. Conclusion: Our findings uncover sex-specific differences in IgG glycosylation that are reversed in lupus nephritis, with men exhibiting a markedly more pro-inflammatory glycome associated with greater disease severity and podocyte injury. These glycomic changes are driven by altered expression of key genes in the N-glycan biosynthesis pathway. The observation that healthy women have a more pro-inflammatory glycome may help explain their higher susceptibility to SLE, while the exaggerated glycomic shift in men with LN may contribute to their more severe disease course. These insights highlight the importance of sex-informed approaches and suggest that targeting glycosylation pathways may offer novel therapeutic opportunities in SLE and lupus nephritis. Funding: Other NIH Support - K99/R00, Private Foundation Support