Viewpoint On:

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. doi: 10.3181/00379727-150-39057. PMID: 1208563.

Hugo Oscar Besedovsky (26.10.1939 – ) is a contemporary Argentinian-German from Rosario with Russian roots who was educated in Argentina, studied medicine in Argentina and became physiologist and pediatrician in Argentina in the 1960s. Due to his interest in Science and challenging times in Argentina (anti-democratic military government), he moved to Switzerland, in the early 1970s to become a senior scientist in the Department of Medicine in the Swiss Research Institute in Davos. This special Research Institute has a very lively history, as it started with tuberculosis research in 1905, was a physical-meteorological observatory, a research institute for high altitude climate, and became – from 1962 to 1985 – an Institute of Neuroendocrine-Immune Interactions under Ernst Sorkin. Hugo Besedovsky was its Director between 1986 and 1987 (after Sorkin’s retirement). In 1988, the name of the institute was changed into Swiss Institute of Allergy and Asthma Research, a subject that is still the focus today (see: https://www.siaf.uzh.ch/index.html). In 1989 to 1991, Besedovsky became Head of the research group in the Division of Neurobiology in the Department of Research of the Cantonal Hospital Basel, Switzerland. In 1991, he became full professor of Human Physiology at the University of Marburg, Germany, where he still lives and works with his wife Adriana del Rey (see Blog 12). The couple has two daughters.

Ernst Sorkin (1920 – 2009) was born in Basel, Switzerland. He received his Ph.D. in 1946 from the University of Basel, became professor in the same town in 1952 and then moved to Copenhagen as a researcher in the World Health Organization from 1953-1961. Then, he was offered the Director position of the Swiss Research Institute, Davos, in 1961, and he hold this position until 1985 – until retirement. He was also President of the Swiss Society of Immunology and Consultant at the Basel Institute of Immunology. He died in 2009.

The discovery

In their publication (1), the authors wrote:

Investigations on the involvement of hormones in the immune response have generally involved the parenteral administration of hormones to experimental animals and man … these experiments demonstrate that changes in the level of various hormones can considerably influence immune performance. … However, to the best of our knowledge the possibility that the immune response would itself bring about changes in hormone levels has not been previously considered.

Indeed, this was the seminal idea of Besedovsky et al. because they were interested in the physiological effects of a primary immune reaction by looking on the hormonal response. They injected different types of antigens into rats (sheep red blood cells, trinitrophenyl – hemocyanin [TNP]) and mice (TNP-horse erythrocytes) and observed the course of serum corticosterone and serum thyroxine after injection for several days. Parallel to the increase of the stimulated immune response (plaque forming cell response as an indication of antibody production between day 3-8), serum levels of corticosterone rose at day 3-10 by a factor of 3 to 5, and thyroxine levels fall by 20-30% in the same observation period. The data presented in Figure 1 of this publication (1) are impressively clear. The authors wrote:

The present work has far greater implications in that it makes evident that the immune response itself affects hormonal levels in the blood. The corticosterone levels attained at the peak of the immune response in rats were of the same magnitude as the concentrations observed in blood of stressed or ACTH-treated mice which inhibited the capacity of spleen in vitro to respond to sheep red blood cells with plaque formation.

And further down: “The present studies show that during the immune response hormonal changes occur that could regulate at least in part by a feedback mechanism the duration and possibly even the magnitude of the immune response.

For the first time, the authors recognized the possibility of a feedback regulation of the endogenous hormonal apparatus on the immune response, which had been subject of further studies of Besedovsky et al. (2-7, and some more). One of these studies directly investigated the hypothalamic electrical response measured at neurons in the ventromedial hypothalamus (3), which demonstrated the involvement of other important parts of the hypothalamic-pituitary-adrenal axis.

The hormonal response to primary immune reactions stood the test of time and some relevant experiments have also been published in Neuroimmunomodulation (8-15, and several more).

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 H, Sorkin E. Network of immune-neuroendocrine interactions. Clin Exp Immunol. 1977;27:1-12
  3. Besedovsky H, Sorkin E, Felix D, Haas H. Hypothalamic changes during the immune response. Eur J Immunol. 1977;7:323-325
  4. Besedovsky HO, Sorkin E, Keller M. Changes in the concentration of corticosterone in the blood during skin-graft rejection in the rat. J Endocrinol. 1978;76:175-176
  5. Besedovsky HO, Del Rey A, Sorkin E. Antigenic competition between horse and sheep red blood cells as a hormone-dependent phenomenon. Clin Exp Immunol. 1979;37:106-113
  6. Besedovsky HO, del Rey AE, Sorkin E. Immune-neuroendocrine interactions. J Immunol. 1985;135(2 Suppl):750s-754s
  7. Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986;233:652-654
  8. Schotanus K, Makara GB, Tilders FJ, Berkenbosch F. ACTH response to a low dose but not a high dose of bacterial endotoxin in rats is completely mediated by corticotropin-releasing hormone. Neuroimmunomodulation. 1994;1:300-307
  9. Suescun M, Chisari AN, Carino M, Hadid R, Gaillard RC, Spinedi E. Sex steroid regulation of the hypothalamo-pituitary-adrenal axis activity in middle-aged mice during endotoxic shock. Neuroimmunomodulation. 1994;1:315-320
  10. Hadid R, Spinedi E, Giovambattista A, Chautard T, Gaillard RC. Decreased hypothalamo-pituitary-adrenal axis response to neuroendocrine challenge under repeated endotoxemia. Neuroimmunomodulation. 1996;3:62-68
  11. Savino W, Arzt E, Dardenne M. Immunoneuroendocrine connectivity: the paradigm of the thymus-hypothalamus/pituitary axis. Neuroimmunomodulation. 1999;6:126-136
  12. Ando T, Dunn AJ. Mouse tumor necrosis factor-alpha increases brain tryptophan concentrations and norepinephrine metabolism while activating the HPA axis in mice. Neuroimmunomodulation. 1999;6:319-329
  13. Hadid R, Spinedi E, Chautard T, Giacomini M, Gaillard RC. Role of several mediators of inflammation on the mouse hypothalamo-pituitary-adrenal axis response during acute endotoxemia. Neuroimmunomodulation. 1999;6:336-343
  14. Kusnecov AW, Rossi-George A. Potentiation of interleukin-1beta adjuvant effects on the humoral immune response to antigen in adrenalectomized mice. Neuroimmunomodulation. 2001;9:109-118
  15. Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation. 2015;22:6-19

 

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