Neuropeptide regulation of immediate and delayed hypersensitivity

Peptide mediators of sensory nerves that are released in tissues by noxious stimuli or inflammatory reactions rapidly elicit local and systemic responses similar to those of immediate hypersensitivity. These sensory neuropeptides affect functions of smooth muscles, blood vessels, leukocytes, and epithelial glands both directly and indirectly, through the actions of mediators released from mast cells stimulated by the peptides. Stereospecific receptors transduce the effects of neuropeptides of the peripheral nervous system (PNS) and central nervous system (CNS) on diverse functions of human, murine and guinea pig mononuclear and polymorphonuclear leukocytes, mast cells, and basophils in vitro and in vivo. Stimulatory and inhibitory effects of neuropeptides on leukocytes are attained in vitro at concentrations which are similar to those in the circulation and in tissues. The dissociation constant (KD) for the binding of a neuropeptide to its leukocyte receptor is within the range of concentrations that evoke cellular responses critical to immunity and hypersensitivity. Neuropeptides exhibit both cellular and stimulus specificities, as exemplified by the greater potency of substance P in activating mucosal than connective tissue mast cells and the capacity of somatostatin to inhibit the release of mediators from basophils challenged by IgE-dependent mechanisms, but not by basic peptides or ionophores. The selective release of distinct neuropeptides from different subsets of sensory nerve endings, the specificity of neuropeptide recognition by mast cells, basophils, lymphocytes, and other target cells, and the diversity of relevant activities of the neuropeptides suggest that the nervous system may initiate and modulate immediate and delayed hypersensitivity by unique mechanisms.