The autoantigen DNA topoisomerase I interacts with chemokine receptor 7 and exerts cytokine‐like effects on dermal fibroblasts
Bibliographic record
Abstract
OBJECTIVE: Previous studies have demonstrated that, once released into the extracellular environment, the systemic sclerosis (SSc)-associated autoantigen DNA topoisomerase I (topo I) binds specifically to the surface of fibroblasts via an unknown receptor. We extended these results by identifying topo I-mediated cellular effects and characterizing the specific target of topo I on fibroblast surfaces. METHODS: Purified topo I was used to investigate intracellular signaling pathway activation and tested for cell migration. To demonstrate the expression of specific chemokine receptors on fibroblasts, we performed immunoblotting and flow cytometry. To evaluate the direct interaction between chemokine receptor and topo I, a protein-protein based enzyme-linked immunosorbent assay (ELISA) was used. Finally, topo I coupled to the fluorochrome phycoerythrin (PE) was used to investigate competition of topo I specific binding on fibroblast surfaces with chemokine ligand. RESULTS: Topo I stimulated the phosphorylation of phospholipase Cγ1, c-Raf, ERK-1/2, and p38 MAPK, intracellular signaling pathways that stimulated fibroblast migration via a G(αi) protein-coupled receptor. CCR7 was found to interact directly with topo I. Furthermore, its ligand, CCL21, competed in vitro for this interaction and in vivo with the binding of PE-coupled topo I to fibroblast surfaces. CONCLUSION: These new roles of topo I in fibroblast physiology and the identification of its target on the cell surface demonstrate that topo I is a bifunctional autoantigen and open up new perspectives of study in the field of SSc-associated anti-topo I autoantibodies.
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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".