Complement-Activated Polymorphonuclear Neutrophils Contribute to C3G Pathogenesis
Bibliographic record
Abstract
Background: C3G is caused by dysregulation of the complement alternative pathway, but there is a gap in the pathogenetic cascade from complement activation (intravascular space) to inflammation and complement deposition in the glomeruli (extravascular space). Recently, biopsies have shown the presence of (activated) polymorphonuclear neutrophils (PMNs) in C3G glomeruli indicating an underappreciated role for PMNs in C3G pathogenesis. Methods: PMNs were investigated in a transwell chamber allowing for different environments. Conditions were chosen to resemble the intravascular space (top well; serum containing) versus extracellular space (bottom well; serum-free conditions). PMNs were stimulated in the top well via various agonists, including complement, and allowed to transmigrate to the bottom well where they were monitored for the formation of Neutrophil Extracellular Traps (NETs) via immunofluorescence and SYTOX assay. Circulating C3G patient PMNs were examined for priming via flow cytometry. Results: Upon complement stimulation, PMNs showed evidence for priming in serum conditions (top well). PMNs travelled to the bottom well following chemoattractant fMLP where they then completed the process of NET formation (NETosis) in serum-free conditions (bottom well). Results were validated ex vivo using C3G patient PMNs and autologous serum (Figure). In addition, incubation of control PMNs in C3G patient serum revealed a correlation between serum-albumin levels and the degree of NET formation. C3G patient PMNs showed upregulation of CD11b compared to controls. Conclusions: Assigning a pathogenetic role to PMNs in C3G identifies a new treatment and monitoring strategy with the potential for improved long-term outcomes and quality of life.PMNs were seeded in the top well of a transwell system and allowed to transmigrate for 12 h. PMNs from both wells were stained for IF with DAPI (blue), Citrullinated histone 3 (CitH3; green) and Myeloperoxidase (MPO; red). Scale bar 20 um. 63x magnification.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".