Aberrant Glycosylation of <scp>IgG</scp> in Children With Active Lupus Nephritis Alters Podocyte Metabolism and Causes Podocyte Injury
Bibliographic record
Abstract
OBJECTIVE: Podocytes are integral to the maintenance of the glomerular filtration barrier. Their injury results in proteinuria and disease progression in lupus nephritis (LN). Aberrant IgG glycosylation drives podocyte injury in LN and leads to cytoskeletal rearrangement, motility changes, and decreased nephrin production. Based on these findings, we hypothesized that IgG glycosylation patterns differentiate systemic lupus erythematosus (SLE) with and without LN and that this aberrant glycosylation reprograms podocyte metabolism. METHODS: IgG was isolated from 40 pediatric SLE and from 7 healthy control samples. N-glycan analysis was performed using mass spectrometry. IgG deglycosylation was performed through enzymatic treatment by Peptide N-Glycosidase F for functional studies in podocytes. Untargeted metabolomics was performed in cultured podocytes after exposure to healthy IgG, LN-derived IgG, or deglycosylated LN-IgG and analyzed by metabolite set enrichment analysis. Digital droplet polymerase chain reaction was used to evaluate urine cells and podocytes in culture for pyruvate kinase expression. RESULTS: The glycosylation pattern of IgG from children with LN was different from that in children with SLE without kidney involvement. Successful treatment led to normalization of IgG glycosylation. Cultured podocytes treated with LN-derived IgG had a lower rate of glycolysis compared to podocytes incubated with deglycosylated LN-IgG or IgG from healthy volunteers. Untargeted metabolomics of podocytes revealed glycolysis as the most enriched pathway in LN and identified five key metabolites (pyruvic acid, phosphoenolpyruvic acid, 2-phosoglycerate, 3 phosphoglycerate, and fructose 1,6 bisphosphate) in which their levels significantly differed among podocytes exposed to LN-derived IgG (LN-IgG) compared to healthy IgG and deglycosylated LN-IgG. This analysis also revealed clustering around a rate limiting step of glycolysis catalyzed by PKM (Pyruvate Kinase M). Urine analyses revealed elevated pyruvic acid and greater expression of pyruvate kinase in podocytes shed in urine in patients with LN compared to levels in patients with SLE without kidney involvement. Podocytes in culture had elevated PKM levels when exposed to LN-IgG compared to IgG from patients with nonrenal SLE and LN in remission. CONCLUSION: Aberrant IgG glycosylation develops in children with LN and adversely alters podocyte metabolism, rendering these cells vulnerable to injury. Successful treatment reverses IgG glycosylation to patterns comparable to those in patients with nonrenal SLE. These data lay a strong foundation for larger translational studies evaluating the potential of IgG glycosylation as a predictive and pharmacodynamic biomarker for LN. This work also supports a need for the development of approaches to control the aberrant glycosylation of self-targeting IgG in patients with LN as a mechanism to minimize podocytopathy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".