Sensory Neuropeptides Prime the Splenic Marginal Zone for Optimal Humoral Immunity

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 IgM^hiIgD^loCD21^hiCD23^lo 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.