Deciphering Complement Activation Mechanisms in Childhood IgA Nephropathy
Bibliographic record
Abstract
Background: The complement pathway plays a crucial role in the development of IgA nephropathy (IgAN), as evidenced by the association of complement C3 with IgA deposits. However, the specific mechanisms that trigger complement pathway activation remain poorly understood. Recent research has implicated soluble CD89 (sCD89) in kidney inflammation among childhood IgAN (cIgAN) patients. Thus, this study seeks to understand how sCD89 activates collectin 11—a crucial initiator of the lectin pathway—ultimately resulting in the formation of C5b-9 and subsequent kidney inflammation. Methods: A prospective cohort of cIgAN patients was enrolled in the study (n=52). The levels of soluble C5b-9 (sC5b-9) and collectin-11 (C-11) were determined in both the urine and plasma of these patients using ELISA. These levels were correlated with biological, histological and clinical data. Kidney biopsies were assessed for inflammation and C5b-9 deposition. Next, we evaluated the expression and secretion of C-11 in human mesangial cells (HMCs) using RT-PCR and ELISA respectively. HMCs were stimulated with cIgAN plasma or recombinant sCD89 (rsCD89). Additionally, to detect the presence of C-11 within circulating immune complexes (CICs) we used sCD89 immunoprecipitation. Results: Our research findings demonstrate several significant associations in cIgAN patients. sC5b-9 correlates with lower eGFR and increased proteinuria. Elevated levels of sC5b-9 were also linked to cellular inflammation, glomerulosclerosis and fibrotic crescents. Notably, we found that plasma sC5b-9 is linked to endocapillary deposition of C5b-9 in kidney glomeruli. Furthermore, C-11 levels are elevated in cIgAN patients compared to healthy controls. There exists a positive correlation between plasma C5b-9 and C-11 levels. Our in vitro results indicate that C-11 is expressed and secreted by the HMCs, with its upregulation upon stimulation by cIgAN plasma and rsCD89. Interestingly, we also observe the presence of C-11 within the CICs. Conclusion: Our study indicates that both sC5b-9 and C-11 are associated with disease severity in cIgAN. They show promise as prognostic markers for cIgAN, potentially obviating the need for invasive kidney biopsy procedures. Additionally, the interplay between C-11 and sCD89 may provide insights into the underlying mechanisms of complement pathway activation 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 | 0.001 |
| 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".