Andor Szentivanyi and the Beta Adrenergic Theory of Allergy and Asthma

Andor Szentivanyi and the Beta Adrenergic Theory of Allergy and Asthma

Historical Perspectives

Fifty six years ago Andor Szentivanyi and colleagues were the first to document with exact scientific methodology in animal experiments that the nervous system regulates anaphylactic reactions and antibody production. Andor SzentivanyiAt that time Szentivanyi was a resident at the Medical School of Debrecen in Hungary. He observed that adrenaline did not inhibit the asthmatic attack in a patient. This observation inspired him and his colleagues to do animal experiments using anaphylactic shock as a model system. It was observed that hypothalamic lesions inhibited the development of anaphylactic shock in immunized animals [1]. Hypothalamic tuberal cinereum lesions (TBL) inhibited anaphylaxis in pre-immunized guinea pigs, and in later experiments also in rabbits. Anaphylaxis was elicited in immunized animals by the intravenous injection of the immunizing antigen.

Antibody production was also inhibited if TBL was done prior to immunization. TBL did not affect the reaction of antibodies with the specific antigen, nor did the release of tissue materials mediating anaphylaxis. Hypothalamic lesions temporarily increased the resistance of the animals to histamine and inhibited the anaphylactic reaction even when the animals were provided with passively transferred antibodies, which elicited lethal shock in control animals.

The Schultz-Dale test, which was performed with small pieces of intestine in vitro, was also inhibited by TBL. The Arthus reaction, turpentine induced inflammation and the Sanarelli-Shwartzman phenomenon were unaffected. Lesions of other areas of the hypothalamus or of the central nervous system were ineffective in modulating immune phenomena. Further, electrical stimulation of the mammillary region of the hypothalamus had an inhibitory effect on the anaphylactic response and increased the resistance of animals to histamine [2-4]. In 1964, Korneva and Khai confirmed that hypothalamic lesions in rabbits, guinea pigs and rats inhibited the production of complement fixing antibodies [5].

Szentivanyi devoted his career of 56 years to research on the pathomechanisms of allergy and asthma. His animal experiments showed the importance of the beta-adrenergic receptor in anaphylactic reactions [6]. In 1968, Szentivanyi wrote a review article about his beta adrenergic theory in allergy and asthma [7]. He concluded that bronchial asthma, whether it is due to ‘extrinsic’ or ‘intrinsic’ causes, is ultimately elicited by the same mediators, such as histamine, serotonin, catecholamines, slow reactive substances plus cytokines. These are released during asthmatic reactions and should be considered as an additional group of mediators in many tissues and in most species. Glucocorticoids are natural inhibitors of inflammation. He proposed that the fundamental mechanism of atopic abnormality in asthma is the abnormal function of the beta-adrenergic system, irrespective of what triggered the reaction. He concludes:

The beta adrenergic theory regards asthma not as an ‘immunological disease, but as a unique pattern of bronchial hypersensitivity to a broad spectrum of immunological, psychic, infectious, chemical and physical stimuli. This gives to the antigen-antibody interaction the same role as that of a broad category of non-specific stimuli, which function only to trigger the same defective homeostatic mechanism in the various specialized cells of bronchial tissue” [7].

This article became a citation classic and has been re-printed as a classical article of lasting value in “Milestones in Allergy,” L Berrens, ed., Mosby/Doyma Libros, Barcelona, Spain, in 1995 [8]. Indeed, this paper has popularized the dominant role of the central nervous system in inflammatory diseases and of the importance of multi-disciplinary approaches for the understanding of such diseases.

Szentivanyi was faithful to the idea of beta adrenergic malfunction in atopy and asthma for his entire scientific career of 56 years. This was the common hypothesis he followed through the numerous papers, reviews, book chapters and books he published.  He investigated alpha- and beta-adrenergic receptors; adenylate cyclase, cyclic-AMP and signal transduction; isolated, characterized and pharmacologically modulated phosphodiesterase; observed the systemic effect of immunization and of endotoxin on the adrenergic and cholinergic systems, on metabolism and on immune inflammatory mediators; performed clinical studies on asthma and related conditions. His major observations are as follows:

  1. Beta-adrenergic sub-sensitivity exists in patients with atopic dermatitis who never received adrenergic medication. This indicates that therapeutic desensitization cannot account for the dysfunction of the beta-adrenergic system.
  2. The beta-adrenergic reactivity of lung tissue, of lymphocytes and bronchial cells from patients with atopic asthma was found to be abnormal and various patterns of drug vs. disease-induced sub-sensitivity could be recognized [9-14].
  3. Bronchial hyper-reactivity to cholinergic agents in asthma was not mediated through cholinergic mechanisms but it was caused by the adrenergic abnormality, which was due to the so called “denervation super-sensitivity” [15-18].
  4. Lymphocytes of asthmatic patients showed a significant decrease in adrenaline binding to beta-adrenergic receptors, which was independent of therapy [10,11,14].

Szentivanyi also examined the effects of inflammation on beta-adrenergic receptors. He studied glucocorticoid (GC) action in disease and regarded GCs as important inhibitory hormones [19-23].

Szentivanyi’s work and ideas inspired me in a major way. In 1992, the World Congress of Immunology was held in Budapest and I was invited to organize a satellite symposium on Psychoneuroimmunology. I organized this meeting with Judit Szelényi in Budapest and we invited Szentivanyi as a Guest of Honor to deliver the keynote lecture to the symposium [24]. This was the beginning of our collaboration and friendship, which intensified over the years [25]. In 2000, we have initiated the book series, Neuroimmune Biology, and worked together on 9 volumes till his passing away [26-61]. He was to write a Preface to volume 9 as yet, but this commitment could not be fulfilled [62]. He was very proud of Neuroimmune Biology and anticipated a bright future for these books.

Szentivanyi listed nearly 500 publications and 29 books to his credit. Throughout his lifetime he received numerous awards and distinctions and has been advisor/consultant to many scientific and public organizations. He was one of the founders of the Faculty of Medicine at the University of South Florida and built and organized many departments and Institutions associated with this School as Dean of Medicine. He served this University with full devotion for over 35 years.

Andor was a humanist, a pacifist, a tireless champion of the poor and disadvantaged; he fought against social and political injustice, and was always ready to take risks and sacrifices for his principles. His legacy is of lasting value for Medicine and indeed for Mankind.

Author(s) Affiliation

I Berczi – Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB Canada

References
  1. Filipp G, Szentivanyi A, Mess B. Anaphylaxis and nervous system. Acta Med Hung 1952; 2: 163-73.
  2. Szentivanyi A, Filipp G. Anaphylaxis and the nervous system. Part II. Ann Allergy  1958; 16: 143-151.
  3. Filipp G, Szentivanyi A. Anaphylaxis and the nervous system. Part III. Allergy 1958; 16: 306-11.
  4. Szentivanyi A, Szekely J. Effect of injury to, and electrical stimulation of, hypothalamic areas on anaphylactic and histamine shock of the guinea pig. A preliminary report. Ann Allergy 1956; 14: 259-261.
  5. Korneva EA, Khai LM. Effect of destruction of hypothalamic areas on immunogenesis. Fed Proc 1964; 23: T88.
  6. Townley RG, Trapani IL, Szentivanyi A. Sensitization to anaphylaxis and to some of its pharmacological mediators by blockade of the beta-adrenergic receptors. J Allergy 1967; 39(3): 177-79.
  7. Szentivanyi A. The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy 1968; 42: 203-32.
  8. Szentivanyi, A:  The beta adrenergic theory of the atopic abnormality in bronchial asthma.  Reprinted In:  “Milestones in Allergy,” L Berrens, ed., Mosby/Doyma Libros, Barcelona, Spain, 1995; 69-102.
  9. Szentivanyi A. The conformational flexibility of adrenoceptors and the constitutional basis of atopy. Triangle 1979; 18(4): 109-15.
  10. Szentivanyi A, Heim O, Schultze P. Changes in adrenoceptor densities in membranes of lung tissue and lymphocytes from patients with atopic disease. Ann NY Acad Sci. 1979; 332: 295-298.
  11. Szentivanyi A. La flexibilite de conformation des adrenocepteurs et la base constitutionelle du terrain allergique. Rev Franc Allergol 1979; 19: 205-214.
  12. Szentivanyi A, Fitzpatrick DF. The altered reactivity of the effector cells to antigenic and pharmacological influences and its relation to cyclic nucleotides. II. Effector reactivities in the efferent loop of the immune response. In:  Filipp G, editor.  Pathomechanismmus und Pathogenese Allergischer Reaktionen. Werk-Verlag Dr. Edmund Banachewski, Grafelfing bei Munchen 1980; 511-580.
  13. Szentivanyi A, Polson JB, Krzanowski JJ. The altered reactivity of the effector cells to antigenic and pharmacological influences and its relation to cyclic nucleotides. I. Effector reactivities in the efferent loop of the immune response. In: Filipp G, editor. Pathomechanismus und Pathogenese Allergischer Reaktionen. Werk-Verlag, Dr. Edmund Banachewski, Grafelfing bei Munchen 1980; 460-510.
  14. Szentivanyi A, Krzanowski JJ, Polson JB, Anderson WH.  Evolution of research strategy in the experimental analysis of the beta adrenergic approach to the constitutional basis of atopy.  In: Oehling A, Mathov E, Glazer I, Arbesman C, editors. Advances in Allergology and Clinical Immunology. Oxford, Pergamon Press, 1980; 301-308.
  15. Szentivanyi A. Effect of bacterial products and adrenergic blocking agents on allergic reactions.  In: Samter M, Talmage DW, Rose B, Sherman WB, Vaughan JH, editors.  Textbook of Immunological Diseases.  Boston, MA:  Little, Brown and Co, 1971; 356-374.
  16. Szentivanyi A, Krzanowski JJ, Polson JB. The autonomic nervous system: Structure, function, and altered effector responses.  In: Middleton E, Reed CE, Ellis EF, editors. Allergy: Principles and Practice. St. Louis, MO, The CV Mosby Co, 1978;  256-300.
  17. Szentivanyi A, Williams JF. The constitutional basis of atopic disease. In: Bierman CW, Pearlman DS, editors. Allergic Diseases of Infancy, Childhood, and Adolescence. Philadelphia, PA, WB Saunders Co, 1980; 173-210.
  18. Szentivanyi A. Adrenergic and cholinergic receptor studies in human lung and lymphocytic membranes and their relation to bronchial hyperreactivity in asthma.  In:  Patient Care Publications.  Darien, CT, 1982; 175-92.
  19. Hackney JF, Szentivanyi A. The specificity of glucocorticoids in the relaxation of respiratory smooth muscle in vitro. J Allergy Clin Immunol 1975; 55:123 (abstract).
  20. Hackney JF, Szentivanyi A. The unique action of glucocorticoid succinates on respiratory smooth muscle in vitro. The Pharmacologist  1975; 17: 271 (abstract).
  21. Lowitt S, Szentivanyi A, Williams JF.  Endotoxin inhibition of dexamethasone induction of tryptophan oxygenase in suspension culture of isolated rat parenchymal cells. II. Effect of in vivo pretreatment of rats with endotoxin. Biochem Pharmacol 1982; 31: 3403-3406.
  22. Szentivanyi A, Szentivanyi J. Mechanisms of action of corticosteroids. In: Proceedings of the International Symposium on Allergy and Immunology.  Lima, Peru, 1985; 531-534.
  23. Szentivanyi A, Szentivanyi J. Mechanisms of action of corticosteroids. In: Proceedings of the International Symposium on Allergy and Immunology.  Lima, Peru, 1985; 227-241.
  24. Szentivanyi, A and Abarca, C:  The Immune-Neuroendocrine Circuitry – The Next, and Possibly, the Last Frontier of Vertebrate Immunity.  In: “Advances in Psychoneuroimmunology,” Vol. 3, I Berczi and J Szelényi, eds., Plenum Press, New York, 1994; 41-74.
  25. Berczi, I and Szentivanyi, A:  The pituitary gland, psychoneuroimmunology and infection. In:  “Psychoneuroimmunology, Stress, and Infection,” H Friedman, TW Klein, and A Friedman, eds., CRC Press, Boca Raton, FL, 1996; 71-98.
  26. Berczi I, Szentivanyi A, Series editors, Berczi I, Gorczynski R, Editors: Neuroimmune Biology Volume 1; New Foundation of Biology. Elsevier, Amsterdam, 2001.
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  33. Szentivanyi A, Berczi I, Nyanteh H, Goldman A. Introduction. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 5.
  34. Szentivanyi A, Berczi I, Nyanteh H, Goldman A. History. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 7-14.
  35. Szentivanyi A, Berczi I, Nyanteh H, Goldman A. The discovery of immune neuroendocrine circuitry – A generation of progress. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 15-18.
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  38. Szentivanyi A, Berczi I, Nyanteh H, Goldman A. Virus associated immune and pharmacologic mechanisms in disorders of respiratory and cutaneous atopy. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 63-95.
  39. Berczi I, Szentivanyi A. Adhesion molecules. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 99-115.
  40. Berczi I, Szentivanyi A. Immunoglobulins. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 117-127.
  41. Berczi I, Szentivanyi A. Growth and lactogenic hormones, insulin-like growth factor and insulin. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 129-153.
  42. Berczi I, Szentivanyi A. The hypothalamus-pituitary-adrenal axis and opioid peptides. In “Neuroimmune Biology”, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 155-174.
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  45. Berczi I, Szentivanyi A. Cytokines and chemokines. In “Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 191-220.
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  48. Berczi I, Szentivanyi A. Antigen presentation. In Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 301-313.
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  50. Berczi I, Szentivanyi A. The acute phase response. In Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 463-494.
  51. Berczi I, Szentivanyi A. Autoimmune disease. In Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 495-536.
  52. Berczi I, Szentivanyi A. Immunodeficiency. In Neuroimmune Biology, Volume 3: The Immune-Neuroendocrine Circuitry. History and Progress. Berczi I, Szentivanyi A, Editors, Elsevier, Amsterdam, 2003; 537-558.
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Source: Cover Image: The β2-adrenoceptor (blue) coupling to the heterotrimeric G protein GS (red, yellow, green) after binding of an agonist. Author: Brian Kobilka, Stanford University School of Medicine; https://en.wikipedia.org/wiki/History_of_catecholamine_research#/media/File:Receptor.kobilka.jpg Credit: Wikimedia Commons.

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