AI-05 Platelet response to immune complexes
Bibliographic record
Abstract
Background There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both acute and chronic inflammation in a multitude of clinical conditions through their interaction with members of the Fcγ receptor (FcγR) family. FcγRIIA is the most abundantly expressed FcγR in human blood circulation. However, mice do not express FcγRIIA, and murine platelets are completely devoid of FcγRs. Methods To model IC-mediated response more accurately, as they occur in humans, transgenic FcγRIIA (FcγRIIATGN) mice expressing FcγRIIA on platelets and certain leukocytes, were used in this study. As acute model, we intravenously injected ICs in FcγRIIAnull and FcγRIIATGN mice and monitored mouse reaction and platelet activation. To model platelet response to chronic exposure to ICs, we backcrossed NZB mice with FcγRIIATGN mice, generating NZB::FcγRIIATGN mice and crossed the mice with NZW mice, thus generating NZB::NZW::FcγRIIATGN and NZB::NZW::FcγRIIAnull mice. Platelet activation was monitored through time in these mice. Results Platelet activation by acute exposure to ICs through a mechanism requiring expression of platelet FcγRIIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet dense granules secondary to platelet outside-in signaling by αIIbβ3 and its ligand fibrinogen. On FcγRIIA activation, platelets underwent sequestration, but surprisingly they returned in the blood circulation with emptied granules after activation. Strikingly, reminiscent observations were made in lupus NZB::NZW::FcγRIIATGN mice. We found significant platelet activation and circulating degranulated platelets, uniquely in mice expressing FcγRIIA. Conclusions Platelet activation in IC-mediated pathogenesis is well recognized. In lupus patients, platelets are found activated in blood circulation, however, to what extend ICs and FcγRIIA contribute to platelet activation was unknown. Here, we showed that the expression of FcγRIIA is critical to adequately examine platelet role in lupus. Acknowledgements This work was supported by a Foundation grant from the Canadian Institutes of Health Research (CIHR) to EB. PRF is recipient of a tier 1 Canada Research Chair on Systemic Autoimmune Rheumatic Diseases. NT and IM are recipient of fellowships from The Arthritis Society.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.047 | 0.012 |
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".