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Noradrenergic and peptidergic innervation of lymphoid tissue
Abstract
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 immuno-reactivity 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. The presence of noradrenergic innervation and possible peptidergic innervation of a variety of lymphoid tissues suggests that these nerves may serve as an important link between the nervous system and elements of the immune system. Neural modulation of immune responses could utilize a number of possible mechanisms to influence the function of individual cells. Resolution of these mechanisms will require both in vitro testing of individual transmitters or modulators singly and in combination, and in vivo studies that take into account the local microenvironment and temporal influences of hormones and transmitters on specific cell types.
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Modulation of Immune Function by Morphine: Implications for Susceptibility to Infection
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“…involved in this process has been shown to be an increased synthesis of nitrous oxide by macrophages in splenocyte cultures, which then inhibit Con A-stimulated proliferation of splenic lymphocytes (Bryant et al. 1991; Flores et al. 1994; Fecho et al. 1993, 1994, 1996; Felten et al. 1985).”
InfluentialFink, T., & Weihe, E. (1988) · Neuroscience Letters · doi:10.1016/0304-3940(88)90783-5 · Cited by 156
Dénes, Á., Boldogkoi, Z., Uhereczky, G., Hornyák, Á., Rusvai, M., Palkovits, M., & Kovács, K. J. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.03.060 · Cited by 155
Innervation of lymphoid organs and implications in development, aging, and autoimmunity
Bellinger, D. L., Lorton, D., Felten, S. Y., & Felten, D. L. (1992) · International Journal of Immunopharmacology · doi:10.1016/0192-0561(92)90162-e · Cited by 154
Self-citationBlockade of adrenoreceptors inhibits the splenic response to stroke
Ajmo, C. T., Collier, L. A., Leonardo, C. C., Hall, A. A., Green, S. M., Womble, T. A., Cuevas, J., Willing, A. E., & Pennypacker, K. R. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.044 · Cited by 150
“Most of these fibers innervate the white pulp, specifically modulating lymphocytes, eosinophils, mast cells, and macrophages (Felten et al., 1985).”
BackgroundCatecholamines Inhibit the Antigen-Presenting Capability of Epidermal Langerhans Cells
Seiffert-Sinha, K., Hosoi, J., Torii, H., Ozawa, H., Ding, W., Campton, K. L., Wagner, J. A., & Granstein, R. D. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.12.6128 · Cited by 149
“Indeed, sympathetic fibers reach primary and secondary lymphoid organs including the spleen, thymus, and lymph nodes (11, 12), where they terminate near or in direct contact with lymphocytes.”
BackgroundThe Nicotinic Acetylcholine Receptor: Structure and Autoimmune Pathology
Conti-Tronconi, B. M., McLane, K. E., Raftery, M. A., Grando, S. A., & Protti, M. P. (1994) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409239409086798 · Cited by 148
Sympathetic nervous system and inflammation: A conceptual view
Jänig, W. (2014) · Autonomic Neuroscience · doi:10.1016/j.autneu.2014.01.004 · Cited by 142
“Are tertiary lymphoid organs innervated by postganglionic sympathetic noradrenergic neurons as has been shown for the primary and secondary lymphoid organs (Felten et al., 1985, 1987)?”
BackgroundOrigin of noradrenergic innervation of the spleen in rats
Bellinger, D. L., Felten, S. Y., Lorton, D., & Felten, D. L. (1989) · Brain Behavior and Immunity · doi:10.1016/0889-1591(89)90029-9 · Cited by 146
Self-citationNoradrenergic and Peptidergic Innervation of Lymphoid Organs
Felten, S. Y., & Bellinger, D. L. (1997) · KARGER eBooks · doi:10.1159/000058655 · Cited by 146
Innervation of the spleen in the rat: Evidence for absence of afferent innervation
Nance, D. M., & Burns, J. (1989) · Brain Behavior and Immunity · doi:10.1016/0889-1591(89)90028-7 · Cited by 141
Nerve Growth Factor and Autoimmune Diseases
Aloe, L., Skaper, S. D., Leon, A., et al. (1994) · Autoimmunity · doi:10.3109/08916939409009542 · Cited by 144
Role of opioid neuropeptides in immunoregulation
Stefano, G. B. (1989) · Progress in Neurobiology · doi:10.1016/0301-0082(89)90038-5 · Cited by 144
Madden, K. S., Moynihan, J. A., Brenner, G. J., Felten, S. Y., Felten, D. L., & Livnat, S. (1994) · Journal of Neuroimmunology · doi:10.1016/0165-5728(94)90183-x · Cited by 142
Self-citationTarcic, N., Ovadia, H., Weiss, D. W., & Weidenfeld, J. (1998) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(97)00186-0 · Cited by 142
Neuropeptide Innervation of Lymphoid Organsa
Bellinger, D. L., Lorton, D., Romano, T. D., Olschowka, J. A., Felten, S. Y., & Felten, D. L. (1990) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1990.tb40464.x · Cited by 139
Self-citationMadden, K. S., Felten, S. Y., Felten, D. L., Hardy, C. A., & Livnat, S. (1994) · Journal of Neuroimmunology · doi:10.1016/0165-5728(94)90182-1 · Cited by 138
“Documentation of sympathetic noradrenergic (NA) innervation of primary and secondary lymphoid organs (Calvo, 1968; Giron et al., 1980; Bulloch and Pomerantz, 1984; Felten et al., 1985; Livnat et al., 1985), and the demon- * Corresponding author.”
BackgroundSelf-citationEffects of experimental psychological stress on distribution and function of peripheral blood cells.
BROSSCHOT, J. F., Benschop, R. J., Godaert, G. L. R., de Smet, M. B., Olff, M., Heijnen, C. J., & BALLIEUX, R. E. (1992) · Psychosomatic Medicine · doi:10.1097/00006842-199207000-00002 · Cited by 139
“Simulation studies with epinephrine injections showed that administration of epinephrine results in redistribution of lymphocytes out of storage areas into the blood stream (38-41).”
Background
Metadata
- Authors
- Felten, D. L., Felten, S. Y., Carlson, S. L., Olschowka, J. A., & Livnat, S.
- Affiliations
- University of Rochester Medicine (US)
- ORCID
- Carlson, S L
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 1985-08-01
- Volume
- 135
- Issue
- 2
- Pages
- 755-765
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W79466244
- Cited by
- 1,025
- References
- 0
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 15 · 2023: 17 · 2022: 23 · 2021: 23 · 2020: 13 · 2019: 21 · 2018: 26 · 2017: 12 · 2016: 23 · 2015: 16 · 2014: 22 · 2013: 20 · 2012: 24
- FWCI
- 12.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- noradrenergic innervation, sympathetic nerve fibers, lymphoid tissue, thymus, spleen, lymph nodes, gut-associated lymphoid tissue, bone marrow, vasoactive intestinal peptide, neuropeptide Y, substance P, neurokinin-1 receptor, neurokinin-2 receptor, neurokinin-3 receptor, neurotensin, substance P antagonist
- MeSH terms
- Adrenergic Fibers, Animals, Appendix, Bone Marrow, Intestines, Lymph Nodes, Lymphocytes, Lymphoid Tissue, Nerve Tissue Proteins, Norepinephrine, Rabbits, Spleen, Thymus Gland, Neurotransmitter Agents, Mice, Rats
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