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Besedovsky HO, del Rey A, Sorkin E, Da Prada M, Keller HH. Immunoregulation mediated by the sympathetic nervous system. Cell Immunol. 1979;48(2):346-355

del Rey A, Besedovsky HO, Sorkin E, da Prada M, Arrenbrecht S. Immunoregulation mediated by the sympathetic nervous system, II. Cell Immunol. 1981;63(2):329-334

Adriana del Rey (1950) is an Argentinian-German from Rosario who was educated in Argentina and studied Biology there. From 1975 to 1976, she was research assistant in the Institute of Immunology of the Medical Faculty of the University of Rosario. In 1977, she moved to Switzerland, Davos, to become scientist in the Department of Medicine in the Swiss Research Institute in Davos, where she stayed until 1988. From 1989-1992, she became senior scientist in the Division of Neurobiology in the Department of Research of the Basel Cantonal Hospital, Switzerland. In 1992, she moved to Marburg, Department of Immunophysiology at the University of Marburg, Germany, where she still works and lives.

The curriculum vitae of Hugo Oscar Besedovsky (1939) and Ernst Sorkin (1920 – 2009) have been described in the blog of January 28, 2025, with the title “The Primary Immune Response Changes the Body’s Own Hormones”.

The idea

As described in the preceding blog of January 28, 2025, the authors found a clear response of the hypothalamic-pituitary adrenal (HPA) axis consequently to an antigenic stimulus. They discussed the possibility of a feedback regulation of the HPA axis on the immune system (1). With this information in their hands, Adriana del Rey and her coauthors wanted to investigate the second most important efferent system that connects the brain to the periphery. They hypothesized that the sympathetic nervous system (SNS) directly influences the immune response to a foreign antigen, and – vice versa – that the immune response influences the SNS.

The discovery

In their first publication of 1979, they recognized that surgical and chemical removal of the sympathetic nervous system increased the stimulated immune response in the spleen (plaque forming cell response as an indication of IgM antibody production). In other words, the SNS had a clear inhibitory influence on IgM antibody formation (2). In their hands, an α2-adrenergic agonist – clonidine – dose-dependently inhibited the stimulated antibody response in vitro using spleen cells (2). Other authors, who corroborated the α2-adrenergic inhibition of the primary antibody response, later studied the time dependency of the sympathetic influence on the antibody response (3).

Vice versa, during the immune response during 8 consecutive days, the IgM antibody response started to rise strongly on day 3 to reach a maximum on day 4 and then turned down to zero on day 8 (2), which is typical for the IgM antibody response to a foreign antigen. During the same period of 8 days, the amount of noradrenaline – the sympathetic neurotransmitter from splenic nerve fibers – went down from 100% at the beginning to 25% on day 3 and 30% on day 4 to reach the starting level of 100% between day 6 and 8 (2). These data clearly demonstrated the reciprocal influence of activated immune cells on noradrenaline content in the spleen. The reduction of noradrenaline in the spleen must be viewed as an increased loss of the neurotransmitter relative to the local production in the nerve ending after a period of stimulated SNS activity.

This paper (2) and two follow-up papers (4,5) clearly demonstrated the mutual interaction of splenic immune cells and sympathetic nerve fibers / neurotransmitters. In further studies, the authors demonstrated that the duration of the decrease in splenic noradrenaline depends on the intensity of the immune response (5). Other groups – a little later – supported the same sympathetic neuroimmunomodulation (6,7).

Adriana del Rey and her coworkers wrote (4): “The decrease in catecholamine levels induced by immune responses is therefore likely to reflect the existence of sympathetic immunoregulatory circuits. What one likes to know now is the nature of the links between the immune system and the sympathetic nervous system and how sympathetic signals are coordinated with autoregulatory immunologic circuits.”

The sympathetic regulation of splenic immune reactions stood the test of time, and Neuroimmunomodulation published some relevant experiments (8-12).

References

1. Besedovsky H, Sorkin E, Keller M, Müller J. Changes in blood hormone levels during the immune response. Proc Soc Exp Biol Med. 1975;150:466-470
2. Besedovsky HO, del Rey A, Sorkin E, Da Prada M, Keller HH. Immunoregulation mediated by the sympathetic nervous system. Cell Immunol. 1979;48:346-355
3. Sanders VM, Munson AE. Role of alpha adrenoceptor activation in modulating the murine primary antibody response in vitro. J Pharmacol Exp Ther. 1985;232:395-400
4. del Rey A, Besedovsky HO, Sorkin E, da Prada M, Arrenbrecht S. Immunoregulation mediated by the sympathetic nervous system, II. Cell Immunol. 1981;63(2):329-334
5. del Rey A, Besedovsky HO, Sorkin E, Da Prada M, Bondiolotti GP. Sympathetic immunoregulation: difference between high- and low-responder animals. Am J Physiol. 1982;242:R30-R33
6. Williams JM, Peterson RG, Shea PA, Schmedtje JF, Bauer DC, Felten DL. Sympathetic innervation of murine thymus and spleen: evidence for a functional link between the nervous and immune systems. Brain Res Bull. 1981;6:83-94
7. Miles K, Quintáns J, Chelmicka-Schorr E, Arnason BG. The sympathetic nervous system modulates antibody response to thymus-independent antigens. J Neuroimmunol. 1981;1:101-105
8. Esquifino AI, Cardinali DP. Local regulation of the immune response by the autonomic nervous system. Neuroimmunomodulation. 1994;1:265-273
9. Leo NA, Callahan TA, Bonneau RH. Peripheral sympathetic denervation alters both the primary and memory cellular immune responses to herpes simplex virus infection. Neuroimmunomodulation. 1998;5:22-35
10. Hori T, Katafuchi T, Take S, Shimizu N. Neuroimmunomodulatory actions of hypothalamic interferon-alpha. Neuroimmunomodulation. 1998;5:172-177
11. Molina PE. Noradrenergic inhibition of TNF upregulation in hemorrhagic shock. Neuroimmunomodulation. 2001;9:125-133
12. Straub RH, Dufner B, Rauch L. Proinflammatory α-Adrenergic Neuronal Regulation of Splenic IFN‑g, IL-6, and TGF-β of Mice from Day 15 onwards in Arthritis. Neuroimmunomodulation. 2020;27:58-68

(Featured image declaration: created by Rainer H. Straub)