Deciphering A Proliferation Inducing Ligand's Involvement in the Pathogenesis of Childhood IgAN
Bibliographic record
Abstract
Background: IgA nephropathy follows a multi-hit development involving circulating immune complexes (CICs) containing Gd-IgA1 and sCD89, contributing to renal inflammation. A Proliferation-Inducing Ligand (APRIL) is suspected to contribute to the autoimmune response in adult IgAN. However, its involvement in childhood IgAN (cIgAN), often exhibiting more inflammation, remains unknown, as does its activation mechanism. This study aims to clarify how APRIL is activated and determine its role in cIgAN. Methods: We studied 86 cIgAN and 48 control patients from France and Canada. We quantified plasma and urinary APRIL levels and plasma CICs, and compared them to biological, clinical, and histological characteristics. Immunohistochemistry of cIgAN patients’ kidney biopsies was performed to visualize APRIL staining patterns. We also evaluated APRIL expression in mesangial cells (HMCs) after stimulation and assessed APRIL receptors presence on podocytes. Results: We observed elevated levels of Gd-IgA1, sCD89-IgA1, sCD89 and circulating APRIL in the plasma, and circulating APRIL in the urine, of cIgAN patients compared to control (p<0.05). APRIL plasma levels correlated with histological inflammation (Oxford score). Western Blotting suggested that APRIL is trapped within CICs, colocalizing with IgA in similar-sized complexes. ELISA and immunoprecipitations confirmed IgA-APRIL and CD89-APRIL complexes presence in cIgAN samples, correlating with plasma APRIL levels and being linked to worst initial clinical presentation and prognosis with kidney failure. Immunostaining revealed APRIL deposits in the glomerular mesangium. Stimulating HMCs with cIgAN plasma or recombinant sCD89 induced APRIL mRNA and protein production and its secretion. It induced the production of a new form of APRIL, the same one found in CICs. APRIL production by HMCs was confirmed by immunofluorescence. TACI and BCMA seemed to be expressed by podocytes. Conclusion: Our research highlights that APRIL is implicated in cIgAN pathogenesis, potentially activated by sCD89 in HMCs. We discovered a novel HMC-derived APRIL form, retained in CICs, which may participate in the mesangial-podocyte crosstalk. Finally, APRIL emerges as a candidate biomarker potentially reducing reliance on biopsy, and an interesting therapeutic target in cIgAN.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".