Defining Molecular Mechanisms in Antibody-Mediated Rejection Using Unbiased Proteomics in Donor-Specific Antibody-Positive and -Negative Recipients
Bibliographic record
Abstract
Background: Kidney transplantation is the optimal treatment for patients with end-stage kidney disease. Unfortunately, many kidney allografts fail prematurely due to antibody-mediated rejection (AMR). AMR is caused by donor-specific antibodies (DSAs) against human leukocyte antigens (HLA) on the graft endothelium. DSAs may cause injury through endothelial activation, complement activation, or interactions with Fcγ receptors (FcγRs) on immune cells. Intriguingly, 30-60% of DSA-positive kidney allograft recipients never develop rejection, and 30-50% of patients that exhibit AMR do not have any detectable DSAs, suggesting the presence of unidentified contributors to the pathogenicity of AMR. Our goal is to define the molecular mechanisms of AMR and uncover these underlying contributors to injury. Methods: Indication biopsies from 115 patients with DSA+AMR, DSA-AMR, no rejection despite having DSAs (DSA+NR), and T cell mediated rejection (TCMR) were subjected to unbiased proteomics analysis using LC-MS/MS on Q-Exactive mass spectrometer. Significance between groups was established using ANOVA, with p<0.05 considered significant. Results: We analyzed the glomerular and tubulointerstitial compartments of each biopsy separately. Of the 1203 proteins quantified in the tubulointerstitium, 30 were significantly differentially expressed, and of the 628 quantified in the glomeruli 15 were significantly differentially expressed (ANOVA, p<0.05). Importantly, the expression of complement factors was increased in DSA-AMR tubulointerstitium when compared to DSA+AMR and DSA+NR. However, in the glomeruli complement proteins were dominant in DSA+ AMR. Furthermore, proteins downstream of FcγR activation and phagocytosis were increased in the glomeruli of DSA-AMR and DSA+AMR biopsies when compared to DSA+NR. In the tubulointerstitium, proteins implicated in phagocytosis were highest in DSA-AMR. Conclusion: The differential expression of complement proteins and proteins implicated in FcγR-mediated phagocytosis suggests distinct patterns of injury in the two kidney compartments and an unanticipated role of complement and phagocytosis in DSA-AMR.
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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 | 0.001 | 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) | 0.000 | 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 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".