Transglutaminase-2 Specific IgA-Producing Plasma Cells in Experimental IgAN
Bibliographic record
Abstract
Background: The trigger and source of pathogenic IgA production in IgAN remain unclear. Our previous work suggested that with BAFF overexpression in experimental IgAN (BAFF-Tg mouse), IgA antibody-producing cells (IgA-APCs) are detected within the kidneys. We hypothesize that BAFF overexpression creates a de novo niche for gut-derived IgA+ plasma cells (PCs) in the kidney. Once established, BAFF-dependent IgA+ PCs elaborate tissue-resident pathology. We sought to localize and characterize IgA-APCs in experimental IgAN and explore mechanisms promoting their kidney localization. Methods: We used flow cytometry, scRNA-seq, immunofluorescence, ELISPOT, and spatial transcriptomics (Xenium) to compare kidneys from BAFF-Tg and wild-type (WT) mice. Results: We confirmed an increase in IgA+ PCs (CD45+B220-CD98+IRF4+IgA+) in BAFF-Tg but not WT kidneys by flow cytometry and scRNA-seq. Ligand-receptor analysis supported interactions between kidney endothelial cells and IgA-PCs. Spatial transcriptomic data indicated that the glomerular microenvironment in BAFF-Tg mice was enriched with immune cells and showed increased cytokine expression supporting of an immune-activated niche. Differential scRNA-seq analysis revealed increased endothelial expression of transglutaminase 2 (Tgm2) in BAFF-Tg mice (p<0.05), a protein implicated in IgAN. We confirmed increased glomerular and tubulo-interstitial Tgm2 RNA expression by spatial transcriptomics and corresponding increased Tgm2 protein by immunofluorescence. Since Tgm2 can be targeted by IgA in settings like celiac disease, we developed a custom ELISPOT to assess the Tgm2 specificity of IgA. Tgm2-specific IgA-PCs were observed in both intestine and kidneys of BAFF-Tg but not WT mice. Conclusion: Tgm2-specific IgA-PCs are present in BAFF-Tg kidneys. Increased endothelial Tgm2 expression in intestines and glomeruli suggests Tgm2 may act as an autoantigen in the context of BAFF overexpression. Further study is needed to determine if Tgm2-specific IgA-PCs causally drive IgAN.
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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) | 0.000 | 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".