Making “Sense” Of Persistent Polyclonal B Cell Lymphocytosis
Bibliographic record
Abstract
Abstract Neuronal regulation of the hematopoietic stem cell niche includes elements of the sympathetic nervous system however, a role for sensory neurons has not been explored. While investigating sensory nerves in hematopoiesis, we unexpectedly found mice deficient in the neurotransmitter substance P (Tac-1-/-) to exhibit peripheral blood lymphocytosis that is persistent from 8 weeks to at least 35 weeks of age. Flow cytometry showed the increased population to be comprised of polyclonal B-lymphocytes. Hematopathology review demonstrated abnormal peripheral blood bi-nucleated lymphocytes and enlarged splenic marginal zones. Lymph nodes were not affected. To confirm that sensory nerve disruption and not hematopoietically derived substance P was the cause, wildtype C57BL/6 mice were chemically denervated and found to exhibit similar peripheral blood lymphocytosis. By immunohistochemistry, sensory nerves synapsed at splenic marginal zones, consistent with previous reports and providing a neuro-anatomical link for the observed lymphoid hyperplasia. A human correlate to this hematological phenotype featuring long-term peripheral polyclonal B cell lymphocytosis, bi-nucleated lymphocytes and expanded splenic marginal zones is Persistent Polyclonal B-cell Lymphocytosis (PPBL), a rare disorder affecting predominantly female chronic smokers. The pathoetiology of this disorder is unknown but its strong association with smoking supports a novel hypothesis where chronic smoking leads to respiratory tract sensory nerve desensitization with possibly more systemic effects, including on the spleen, thereby mimicking the substance P deficient environment of Tac-1-/- mice. Indeed, pulmonary function tests on chronic smokers have shown a sub-population of patients with hyporeactivity to respiratory sensory nerve stimulation, explained molecularly by increased activation thresholds. It will be interesting to determine if PPBL patients fall into this category. In Tac-1-/- mice, further characterization of the expanded B cell population, immunoglobulin profiles, VDJ utilization and effect of neurokinin-1 receptor modulators is proposed. These results support a neuroimmune regulatory network involving sensory nerves with potential relevance in both lymphoid homeostasis and lymphoproliferative disease. Disclosures: No relevant conflicts of interest to declare.
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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 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".