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The presence of peptidergic and noradrenergic sympathetic nerve fibers in specific compartments of both primary and secondary lymphoid organs of the rodent is well established. These nerve fibers directly contact lymphocytes and macrophages, as well as vascular and trabecular smooth muscle. We investigated the noradrenergic and neuropeptide-Y innervation of lymphoid organs in the cetacean, Delphinapterus leucas (beluga whale). The spleen, thymus, tonsil, gut-associated lymphoid tissue, and assorted lymph nodes were collected from five belugas, obtained during sanctioned hunts, and processed for catecholamine fluorescence histochemistry and for tyrosine hydroxylase and neuropeptide-Y immunocytochemistry. Innervation studies revealed fluorescent nerve fibers, tyrosine hydroxylase, and neuropeptide-Y positive nerve fibers in parenchymal lymphoid compartments, where they were closely associated with cells of the immune system, and in vascular and trabecular compartments. In lymphoid zones, tyrosine hydroxylase and neuropeptide-Y positive nerve fibers were observed in the periarteriolar lymphatic sheath and marginal zone of the spleen; in the outermost portion of the cortex, the corticomedullary zone, and medulla of the lymph nodes; in the parafollicular zones, and diffuse lymphocyte layer below the epithelium of the tonsil; in the outermost portion of some thymic lobules; and in the lamina propria of the gut. These findings are similar to those described for other mammals and substantiate an anatomical link between the nervous and immune systems in the beluga, whereby central nervous system activity may influence autonomic outflow to lymphoid organs and effect immunologic reactivity.

Lymphoid organs from belugas, Delphinapterus leucas, ranging in age from less than one to 16 years, were harvested during a sanctioned hunt to investigate morphology. The spleen is divisible into red and white pulp and a stroma consisting of a reticular network, a collagenous capsule, and trabeculae containing smooth muscle bundles. White pulp areas appear to be devoid of follicles and consist mainly of periarteriolar lymphatic sheaths (PALS), that are larger in younger than in older belugas. Definitive marginal zones between red and white pulp are difficult to discern in older belugas. Lymph nodes are similar to those of other mammals; they possess a follicular cortex surrounding a vascular medulla composed of lymphatic cords and sinuses. Smooth muscle is abundant in the medullary region, usually in close proximity to sinuses. The expansive nodular mass at the root of the mesentery, often referred to as the "pseudopancreas," is similar to lymph nodes in microscopic architecture. Pharyngeal tonsils and gut-associated lymphoid tissue (GALT) are found along the digestive tract and display an "active" morphology. Tonsils are comprised of lobules of follicles separated by vascular connective tissue. Epithelial-lined crypts communicate with the pharyngeal lumen. GALT consists of diffuse and follicular lymphocytes within the intestinal mucosa and submucosa. The thymus is well developed in the younger belugas, with lobules divisible into densely packed cortical zones of thymocytes and more loosely arranged medullary lymphocytes. Hassall's corpuscles are occasionally visible within the medulla. Cetaceans diverged evolutionarily from other mammals over 55 million years ago. This study investigates changes in lymphoid organ morphology in a species that now inhabits a unique ecological niche. This study also lays the groundwork for functional investigation of the beluga immune system, particularly as it relates to differences between healthy and stranded animals.

Noradrenergic (NA) and peptidergic nerve fibres are present in both primary and secondary lymphoid organs, distributing with the vasculature, trabecular and capsular smooth muscle, and within the parenchyma among cells of the immune system. NA nerve terminals directly abut lymphocytes and macrophages in spleen and lymph nodes. In these organs, norepinephrine has fulfilled the basic criteria for neurotransmission with cells of the immune system as targets. In vitro and in vivo studies have demonstrated NA modulation of primary and secondary antibody responses, cytotoxic T cell responses, natural killer cell activity, and proliferation and differentiation of both T and B lymphocytes. Substance P (SP) has been shown to modulate inflammatory responses, lymphocyte proliferation, and other immunologic reactivity. We investigated the role of NA and SP nerve fibres within lymph nodes in experimental allergic auto-immune arthritis in Lewis rats. Denervation of NA nerve fibres in popliteal and inguinal lymph nodes with 6-hydroxy-dopamine resulted in earlier onset and enhanced severity of arthritic changes as well as inflammation in bilaterally induced experimental arthritis, while denervation of SP nerve fibres in popliteal and inguinal lymph nodes with capsaicin resulted in delayed onset and diminished severity of the inflammatory changes ipsilaterally, and prevention of contralateral arthritic changes in unilaterally induced experimental arthritis. These findings suggest that NA and SP nerve fibres in lymph nodes can modulate the time course of onset and the severity of experimental arthritis in Lewis rats. These modulatory effects are distinctly different from the effects of NA and SP nerve fibres in the joints themselves.

We now have substantial evidence demonstrating noradrenergic sympathetic and peptidergic innervation of both primary and secondary lymphoid organs. We have established criteria for norepinephrine, and some of the neuropeptides, as neurotransmitters, and have found changes in immune responsiveness following pharmacological manipulation of noradrenergic sympathetic or peptidergic nerves. Classic receptor binding studies have demonstrated a wide variety of target cells that possess beta-adrenoceptors and receptors for neuropeptides on cells of the immune system, including lymphocyte subsets, macrophages, accessory cells, or stromal elements. In this chapter we describe noradrenergic and peptidergic innervation of primary and secondary lymphoid organs in development, at maturation and during the normal aging process, and discuss possible functional implications of direct neural signals onto cells of the immune system at critical time points in the lifespan of an animal. Further, we examine for involvement of noradrenergic sympathetic and peptidergic innervation in the development and progression of several autoimmune disorders, including adjuvant-induced arthritis, New Zealand mice strains as a model for hemolytic anemia and lupus-like syndrome, and the experimental allergic encephalomyelitis model for multiple sclerosis.

Sympathetic noradrenergic nerve fibers innervate both the vasculature and parenchymal fields of lymphocytes and associated cells in several lymphoid organs, including the thymus, spleen, lymph nodes, gut-associated lymphoid tissue (GALT), and bone marrow, in a variety of mammalian species. This innervation is both regional and specific, and generally is directed into zones of T lymphocytes and plasma cells rather than into nodular regions or B lymphocyte regions. In the thymus, noradrenergic fibers enter with nerve bundles and plexuses around blood vessels, travel into the cortex from subcapsular plexuses and with the vasculature, and branch into the parenchyma of the thymic cortex. The vasculature and parenchymal regions of both the outer and deep cortex are innervated by these fibers. In the spleen, noradrenergic fibers enter with the vasculature, travel along the trabeculae and along the branching vasculature, and are distributed mainly in the white pulp along the central artery and associated periarterial lymphatic sheath. Fibers branch from a dense plexus around the central artery and travel into the parenchyma, where they end among fields of lymphocytes and other cell types. In lymph nodes, noradrenergic fibers enter at the hilus, travel along the vasculature and in a subcapsular plexus, and branch into the parenchyma in paracortical and cortical regions, where they end among lymphocytes. In the GALT, represented in these studies by rabbit appendix, sacculus rotundus, and Peyer's patches, noradrenergic fibers enter at the serosal surface, travel longitudinally with the muscularis interna, turn radially into internodular plexuses, plunge directly through the thymus-dependent zones, and ramify profusely among lymphocytes, enterochromaffin cells, and plasma cells in the interdomal regions. In the bone marrow, noradrenergic fibers enter with blood vessels, distribute deeply into the marrow on those vessels, and branch sparsely into the substance of the marrow. Immunocytochemical observations revealed the presence of neuro-peptide-like immunoreactivity in the thymus and spleen. Vasoactive intestinal peptide (VIP)-like immunoreactivity is found in varicose profiles in the thymus within the cortex. In the spleen, immunoreactive profiles showing neuropeptide Y-like, Met-enkephalin-like, cholecystokinin-8 (CCK)-like, and neurotensin-like immunoreactivity are present along the central artery of the white pulp and its smaller branches, with only sparse fibers of most of these peptides entering the parenchyma. CCK-like profiles are present in abundance in the white pulp among parenchymal elements.(ABSTRACT TRUNCATED AT 400 WORDS)