Sensory Neuropeptides Prime the Splenic Marginal Zone for Optimal Humoral Immunity
Bibliographic record
Abstract
Abstract Effective spleen-derived humoral responses are essential for protecting hosts from blood-borne pathogens. Increased susceptibility to infection is therefore a risk post-splenectomy but is also associated with smoking, chemotherapy and aging. In fact, decreased vaccine efficacy in the elderly may be due to splenic hypofunction. While investigating the role of sensory nerves in hematopoiesis, we discovered a lymphocytosis phenotype involving the splenic marginal zone (MZ). Dividing red and white pulp in the spleen, the MZ is a specialized micro-anatomic structure facilitating innate and adaptive crosstalk to incoming antigen. Sensory nerves were found to synapse at this site and in mice deficient in the major sensory neurotransmitter substance P (Tac-1-/-), MZs were expanded histologically and confirmed by flow cytometry as an increase involving the IgMhiIgDloCD21hiCD23lo MZ B cell population. Tac-1-/- mice also exhibited splenomegaly with overall Ki-67 proliferation indices of 40% vs. 5% in controls. In the peripheral blood, Tac-1-/- mice had persistent polyclonal pan-B cell lymphocytosis with an absolute increase of 200% relative to wildtype. Aberrant B cell homeostasis had functional consequences as demonstrated by significantly decreased total basal plasma IgG (P<0.001) but not IgM, suggesting a transitional defect from the low-affinity T-independent (TI) polyspecific response to T-dependent (TD) mature germinal center derived antibodies. Mechanistically, MZ B cell migration to follicles is required for optimal TD responses where they shuttle antigen-laden IgM immune complexes. Since MZ B cell activation can occur independently of the B cell receptor, relying on Toll-like receptors or other pattern recognition receptor ligation – it is reasonable to include neuropeptide release as an additional stimulus coordinating appropriate MZ B cell mobilization. A working hypothesis therefore is inflammatory stimuli conveyed by the sensory nervous system, which may or may not involve perceptible pain sensation, is rapidly conveyed to the splenic MZ via release of substance P. This may provide an integrated communication network facilitating optimal antibody formation, more efficient than relying on diffusion of conventional danger signals or chemokines alone. TI and TD antigen challenge, cell tracing and electrode stimulation experiments are underway to confirm this theory. Splenic sensory nerve manipulation or pharmacological modulation of the substance P axis may have therapeutic applications for boosting humoral immunity in a variety of immune compromised states. 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 | 0.000 |
| 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 | 0.001 |
| 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".