Mechanisms and consequences of Siglec-8 internalization and toxic payload delivery in human eosinophils
Bibliographic record
Abstract
Abstract Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a cell surface protein expressed selectively on human eosinophils, mast cells, and basophils that induces eosinophil apoptosis and inhibits mast cell mediator release. Hence, Siglec-8 is an ideal target for diseases involving these cells. However, the effective delivery of therapeutic agents to these cells through Siglec-8 requires an understanding of the dynamics of Siglec-8 surface expression, which have not been elucidated. We observed by flow cytometry that Siglec-8 endocytosis in eosinophils proceeds slowly and plateaus at 80% loss in response to antibody or polyvalent synthetic ligand. Surprisingly, based on sensitivity to pharmacological inhibition, Siglec-8 appears to be internalized in both a clathrin- and lipid raft-dependent manner. Actin cytoskeletal rearrangement and tyrosine kinase and PKC activity are necessary for endocytosis. Interestingly, Siglec-8 is shuttled to the cell surface in a manner dependent on actin rearrangement, microtubule polymerization, and the activities of tyrosine kinases, dynamin, and PI3K. Neither process is significantly affected by inhibitors of Src family kinases or PTPs. Internalized Siglec-8 localizes to the lysosome, and sialidase treatment of eosinophils enhances ligand binding, indicating the presence of masking sialylated cis ligands on the cell surface. Finally, conjugating the ribosome-inactivating protein saporin to an anti-Siglec-8 mAb enhanced cell death induction in unstimulated eosinophils. The dynamics of Siglec-8 surface expression therefore appear to be suitable for sustained targeting and may deliver drugs to effectively treat diseases involving these cell types, including malignancies.
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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 | 0.000 | 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) | 0.001 | 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".