Research Viewpoints

Logo Karger Publishers Spark

Pillar Articles: Behavioral Conditioned Immunosuppression – The Anti-Metalnikov Effect

Viewpoint On:

Ader R. Letter: Behaviorially conditioned immunosuppression. Psychosom Med. 1974;36:183-184

Ader R, Cohen N. Behaviorally conditioned immunosuppression. Psychosom Med. 1975;37:333-340

Robert “Bob” Ader was born in 1932 in the Bronx, New York City. He graduated from the Horace Mann School, a remarkable place of famous alumni (1). In 1953, he finished a bachelor’s degree in psychology from Tulane University in New Orleans. He earned the Ph.D. in psychology from Cornell University in 1957. After moving to Rochester, state of New York, Robert Ader spent his entire career at the University of Rochester. He was director of the Division of Behavioral and Psychosocial Medicine in the University of Rochester’s department of psychology and director of the Center for Psychoneuroimmunology Research. He died in December 2011 in the age of 79.

His partner Nicolas Cohen was born in 1938. He received his bachelor in biology from Princeton University in 1959 and his Ph.D. from the University of Rochester, N.Y., in 1966. Between 1965 and 1967, as a postdoctoral scholar, he trained in microbiology and immunology at the University of California in Los Angeles. He joined the University of Rochester, N.Y., Department of Microbiology and Immunology in 1967. He took a sabbatical at the Basel Institute for Immunology, Basel, Switzerland in 1975-76. He was Director of the Division of Immunology (1979-2004). He retired in 2004.

The Idea of Ader and Cohen

While Metalnikov and Chorine in the late 1920s demonstrated conditioned immunoactivation (2), Ader and Cohen focused on immunosuppression. The first important paper of the two authors appeared in 1975 (3). In this paper, they described that an illness-induced taste aversion was conditioned in rats by pairing saccharin with cyclophosphamide, an immunosuppressive agent. To induce a clearly defined immunological readout, they injected sheep red blood cells into the animals that induced hemagglutinating antibodies measured 6 days after antigen administration. High titers were observed in placebo-treated rats, in non-conditioned animals and in conditioned animals that were not subsequently exposed to saccharin. No agglutinating antibody was detected in conditioned animals treated with cyclophosphamide at the time of antigen administration (positive control to show immunosuppression through the agent). Conditioned animals exposed to saccharin at the time of or following the injection of antigen were significantly immunosuppressed (the important conditioned group). For the first time, these data showed strong inhibition of the immune system through Pavlovian conditioning. It complemented the work of Metalnikov and Chorine form the late 1920s (the anti-Metalnikov effect). This work was replicated one year later (4). Important studies of Ader and Cohen followed (5, 6).

In a review paper, Ader wrote (7) “This study (3) demonstrated that, like other physiological processes, the immune system was subject to classical (Pavlovian) conditioning, providing dramatic evidence of an inextricable relationship between the brain and the immune system.”

In one form or the other, immune conditioning stood the test of time (8), and some of the experiments have also been published in Neuroimmunomodulation (9-15).

References

  1. https://en.wikipedia.org/wiki/List_of_Horace_Mann_School_alumni
  2. Metalnikov S, Chorine V. Role des reflexes conditionnels dans l’immunite. Ann Inst Pasteur (Paris) 1926;40:893–900 [we reported on Metalnikov / Chorine in a special Pillar Article]
  3. Ader R, Cohen N. Behaviorally conditioned immunosuppression. Psychosom Med. 1975;37:333-340
  4. Rogers MP, Reich P, Strom TB, Carpenter CB. Behaviorally conditioned immunosuppression: replication of a recent study. Psychosom Med. 1976;38:447-451
  5. Bovbjerg D, Ader R, Cohen N. Behaviorally conditioned suppression of a graft-versus-host response. Proc Natl Acad Sci U S A. 1982;79:583-585
  6. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science. 1982;215:1534-1536
  7. Ader R. Historical perspectives on psychoneuroimmunology. In: Friedman TW, Klein AL, Friedman AL (Eds.) Psychoneuroimmunology, stress and infection. CRC Press, Boca Raton, 1995, pp. 1-21.
  8. Hadamitzky M, Lückemann L, Pacheco-López G, Schedlowski M.: Pavlovian Conditioning of Immunological and Neuroendocrine Functions. Physiol Rev. 2020;100:357-405
  9. Bauer D, Busch M, Pacheco-López G, Kasper M, Wildschütz L, Walscheid K, Bähler H, Schröder M, Thanos S, Schedlowski M, Heiligenhaus A.: Behavioral conditioning of immune responses with cyclosporine a in a murine model of experimental autoimmune uveitis. Neuroimmunomodulation. 2017;24:87-99
  10. Vidal J, Chamizo VD.: The conditioned stimulus elicits taste aversion but not sickness behavior in conditioned mice. Neuroimmunomodulation. 2010;17:325-32
  11. Pacheco-López G, Niemi MB, Kou W, Baum S, Hoffman M, Altenburger P, del Rey A, Besedovsky HO, Schedlowski M.: Central blockade of IL-1 does not impair taste-LPS associative learning. Neuroimmunomodulation. 2007;14:150-156
  12. Haour F.: Mechanisms of the placebo effect and of conditioning. Neuroimmunomodulation. 2005;12:195-200
  13. Mei L, Li L, Li Y, Deng Y, Sun C, Ding G, Fan S.: Conditioned immunosuppressive effect of cyclophosphamide on delayed-type hypersensitivity response and a preliminary analysis of its mechanism. Neuroimmunomodulation. 2000;8:45-50
  14. Exton MS, von Hörsten S, Strubel T, Donath S, Schedlowski M, Westermann J.: Conditioned alterations of specific blood leukocyte subsets are reconditionable. Neuroimmunomodulation. 2000;7:106-14
  15. Rogers CF, Ghanta VK, Demissie S, Hiramoto N, Hiramoto RN.: Lidocaine interrupts the conditioned natural killer cell response by interfering with the conditioned stimulus. Neuroimmunomodulation. 1994;1:278-83

 

(Featured image declaration: by Alan O’Rourke from flickr.com)

Pillar Articles: Adrenergic Modulation of Leukocytes – anni mirabiles 1968 to 1970

Viewpoint On

Szentvanyi A. The beta-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203-232

Benner MH, Enta T, Lockey Jr S, Makino S, Reed CE. The immunosuppressive effect of epinephrine and the adjuvant effect of beta-adrenergic blockade. J Allergy 1968;41:110-111 (Abstract – never published in paper form)

Smith JW, Steiner AL, Newberry Jr. WM, Parker CW. Cyclic nucleotide inhibition of lymphocyte transformation. Clin. Res. 1969;17:549 (Abstract – later published in J Clin Invest. 1971;50:432-441)

May CD. Effects of compounds which inhibit lymphocyte stimulation on the utilization of glucose by leukocytes. J Allergy 1970;46:21-28

Hadden JW, Hadden EM, Middleton E Jr. Lymphocyte blast transformation. I. Demonstration of adrenergic receptors in human peripheral lymphocytes. Cell Immunol. 1970;1:583-595

For this 7th Pillar Article Series, the editor found it extremely difficult to just mention one single author or a single author group that started “adrenergic modulation of leukocytes”. Therefore, the presentation differs from the usual report.

Andras Szentvanyi is credited for his insight into beta-adrenergic mechanisms in asthma where he clearly mentioned the beta-adrenergic effect on cell proliferation (1). This publication was seen as a theoretical starter although the author already had long-standing experiences on adrenergic effects in asthma. In this publication, Szentvanyi wisely summarized the effect on mitosis of adrenergically-induced intracellular glucose changes, which was studied early in non-immune cells such as fibroblasts (2). Two important abstracts given on research conferences showed inhibitory effects of adrenaline and cyclic adenosine monophosphate (cAMP) on leukocyte proliferation (3, 4). Glucose utilization was again an important aspect for lymphocyte proliferation, and cAMP was inhibitory in experiments with phytohemagglutinin-stimulated cells (5).

With this information present, it was John W. Hadden (23. Oct. 1939 – 1. April 2013) and colleagues in 1970 who showed very clear effects of adrenergic compounds on phytohemagglutinin-stimulated leukocyte proliferation (6). He observed inhibitory effects through β-adrenergic pathways (think of the cAMP effects from above because that is the canonic signaling pathway) and mainly stimulatory effects through α‑adrenergic pathways (inhibition of cAMP). The studies were carried out with tritiated thymidine incorporation into peripheral blood leukocyte cells of healthy donors.

The groups around Charles W. Parker (St. Louis, USA), Charles E. Reed (Wisconsin, USA) and Charles D. May (New York, USA) lost more and more contact to adrenergic immunomodulation. They were strong allergologists, and this field moved on to more immunological and therapeutic aspects of allergy. In contrast, John W. Hadden remained faithful to neuroimmunomodulation for one more decade before he moved to drugs and biologicals for immunotherapy. In 1993, he formed a biotech company that focused on immunotherapy of cancer and infection. He and Andras Szentvanyi edited the first and second volume of Immunopharmacology Reviews in 1990 and 1996, respectively.

The journal Neuroimmunomodulation published more than 80 papers related to the link between catecholamines and immunomodulation, some of which are given in the reference list (7-11).

References

  1. Szentvanyi A. The beta-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203-232
  2. Lettré H, Albrecht M. Zur Wirkung von β-Phenyläthylaminen auf in vitro gezüchtete Zellen. Hoppe-Seylers Zeitschrift f. physiol. Chemie (now: Biological Chemistry) 1941;271:200-207
  3. Benner MH, Enta T, Lockey Jr S, Makino S, Reed CE. The immunosuppressive effect of epinephrine and the adjuvant effect of beta-adrenergic blockade. J Allergy 1968;41:1110-111 (Abstract)
  4. Smith JW, Steiner AL, Newberry Jr. WM, Parker CW. Cyclic nucleotide inhibition of lymphocyte transformation. Clin. Res. 1969;17:549 (Abstract)
  5. May CD. Effects of compounds which inhibit lymphocyte stimulation on the utilization of glucose by leukocytes. J Allergy 1970;46:21-28
  6. Hadden JW, Hadden EM, Middleton E Jr. Lymphocyte blast transformation. I. Demonstration of adrenergic receptors in human peripheral lymphocytes. Cell Immunol. 1970;1:583-595
  7. Genaro AM, Cremaschi GA, Gorelik G, Sterin-Borda L, Borda ES. Downregulation of beta adrenergic receptor expression on B cells by activation of early signals in alloantigen-induced immune response. 2000;8:114-21
  8. Page GG, Ben-Eliyahu S. Natural killer cell activity and resistance to tumor metastasis in prepubescent rats: deficient baselines, but invulnerability to stress and beta-adrenergic stimulation. 2000;7:160-168
  9. Oberbeck R, Schmitz D, Wilsenack K, Schüler M, Pehle B, Schedlowski M, Exton MS. Adrenergic modulation of survival and cellular immune functions during polymicrobial sepsis. 2004;11:214-223
  10. Kitamura H, Shiva D, Woods JA, Yano H. Beta-adrenergic receptor blockade attenuates the exercise-induced suppression of TNF-alpha in response to lipopolysaccharide in rats. 2007;14:91-96
  11. Straub RH, Dufner B, Rauch L. Proinflammatory α-Adrenergic Neuronal Regulation of Splenic IFN-γ, IL-6, and TGF-β of Mice from Day 15 onwards in Arthritis. Neuroimmunomodulation. 2020;27:58-68

Pillar Articles: Personality, Rheumatoid Arthritis and the Inflamed Brain

Viewpoint On

Moos RH, Solomon GF. Minnesota multiphasic personality inventory response patterns in patients with rheumatoid arthritis. J Psychosom Res. 1964;8:17-28

George Freeman Solomon was born on 25th November 1931 in Freeport, State of New York (he died on 7th October 2001 in Los Angeles, California). Stimulated by his father Joseph, a child psychiatrist, Solomon dedicated his entire life to “psychoimmunology”. He was a founding member of the PsychoNeuroImmunology Research Society and its fourth president in 1997-1998 (www.pnirs.org).

His partner was Rudolf Hugo Moos, a professor of psychiatry born in 1934 in Berlin and still professor emeritus in Stanford University Medical Center. The grandfather of Moos – also named Rudolf Moos – was the founder of the still-existing German shoe company Salamander in 1903. The Jewish family of Moos was forced to immigrate to the U.K. in 1939 and later to the USA.

In their common work, Solomon and Moos linked personality and disease, which they studied in patients with rheumatoid arthritis (RA) in 1964 (1, 4-6). For these studies, they used the Minnesota Multiphasic Personality Inventory (MMPI). They carried out their work in the Stanford University School of Medicine, Palo Alto, California. In 1964, they wrote:

“The rheumatoid arthritic patients scored significantly higher on scales reflecting (1) physical symptoms; (2) depression, apathy and lack of motivation; (3) general “neurotic” symptoms; (4) psychological rigidity and (5) similarity to other psychosomatic conditions. The arthritics appeared to be more neurotic, depressed, anxious, masochistic, and over-controlled than their healthy family members.”

They cited older work from the late 1940s of D. Cohen (3) and D. Wiener (4) who similarly studied patient with arthritis with comparable results, but due to unclear disease classifications in Cohen’s and Wiener’s early publications, the work of Solomon and Moos was much stricter and focused on definite RA. They followed established criteria of the American Rheumatism Association, later called American College of Rheumatology (ACR). Direct comparisons of women with RA and their unaffected healthy sisters (4, 5) complemented these studies.

Furthermore, Solomon & Moos correctly recognized that the responses of RA patients may be due to “actual limitations [editor: by the inflammatory disease], to the effects of hospitalization, or to a changed physical-social reality, and may, therefore, not reflect pathological personality dynamics” (1). In other words, the results are not dependent on a “rheumatic personality” but are a consequence of the chronic inflammatory disease. This was very far-sighted because most other psychoanalytically driven investigators at the time were propelled by the idea of an a priori existing personality that stimulated a given disease.

Today, we well know that chronic inflammatory diseases can have a strong influence on the brain, which most obviously can be seen as chronic fatigue, anxiety, and major depression (7). The concept of a “rheumatic personality” did not stand the test of time but the highly relevant influence of inflammation on brain function in patients with RA – suggested by Solomon and Moos – did. Furthermore, preceding trauma in childhood and adolescence was clearly associated with a higher risk of RA (8). The latter findings link Solomon’s psychoimmunology to the direct stimulation of RA (summarized in a recent book, 9).

The journal Neuroimmunomodulation published several papers on the link between damaged brain and RA (10-15).

References

  1. Moos RH, Solomon GF. Minnesota multiphasic personality inventory response patterns in patients with rheumatoid arthritis. J Psychosom Res. 1964;8:17-28
  2. Cohen D. Psychological concomitants of chronic illness: A study of emotional correlates of pulmonary tuberculosis, peptic ulcer, the arthritides, and cardiac disease. Doctoral dissertation, University of Pittsburgh (1949).
  3. Wiener DN. Personality characteristics of selected disability groups. J Clin Psychol. 1948;4:285-90
  4. Moos RH, Solomon GF. Psychologic comparisons between women with rheumatoid arthritis and their nonarthritic sisters. I. Personality test and interview rating data. Psychosom Med. 1965;27:135-149
  5. Moos RH, Solomon GF. Psychologic comparisons between women with rheumatoid arthritis and their nonarthritic sisters. II. Content analysis of interviews. Psychosom Med. 1965;27:150-164
  6. Solomon GF, Moos RH. The relationship of personality to the presence of rheumatoid factor in asymptomatic relatives of patients with rheumatoid arthritis. Psychosom Med. 1965;27:350-360
  7. Fatigue in Rheumatic Arthritis. Issue Supplement to Rheumatology. https://academic.oup.com/rheumatology/issue/58/Supplement_5
  8. Dube SR, Fairweather D, Pearson WS, Felitti VJ, Anda RF, Croft JB. Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med. 2009;71:243-250
  9. Straub RH. Early trauma as the origin of chronic inflammation. Springer, Heidelberg, 2023
  10. Philipp J, Baerwald CG, Seifert O. Association between the Ile164 β2 Adrenergic Receptor Polymorphism and Fatigue in Patients with Rheumatoid Arthritis. Neuroimmunomodulation. 2023;30:93-101
  11. Straub RH, Detert J, Dziurla R, Fietze I, Loeschmann PA, Burmester GR, Buttgereit F. Inflammation Is an Important Covariate for the Crosstalk of Sleep and the HPA Axis in Rheumatoid Arthritis. Neuroimmunomodulation. 2017;24:11-20
  12. Petersen LE, Grassi-Oliveira R, Siara T, dos Santos SG, Ilha M, de Nardi T, Keisermann M, Bauer ME. Premature immunosenescence is associated with memory dysfunction in rheumatoid arthritis. Neuroimmunomodulation. 2015;22:130-137
  13. Silverman MN, Sternberg EM. Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation. 2008;15:19-28
  14. Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, Bellinger DL. Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation. 2006;13:357-374
  15. Cutolo M, Straub RH. Stress as a risk factor in the pathogenesis of rheumatoid arthritis. Neuroimmunomodulation. 2006;13:277-282

Rainer H. Straub

Professor Rainer H. Straub, MD, is a Professor of Experimental Medicine and a rheumatologist at the Department of Internal Medicine, University Hospital Regensburg where he heads the Laboratory of Experimental Rheumatology and Neuroendocrine Immunology. His research primarily focuses on the role of interactions between the nervous system, endocrine system, and immune system in the development and maintenance of chronic inflammatory diseases such as rheumatoid arthritis. In complement to his own impactful contribution to unveiling the fascinating connections between brain, immunity, and health he is the Editor-in-Chief for the journal Neuroimmunomodulation.

Pillar Articles Series: Stress and Susceptibility to Infection

Viewpoint On

Rasmussen AF Jr, Marsh JT, Brill NQ. Increased susceptibility to herpes simplex in mice subjected to avoidance-learning stress or restraint. Proc Soc Exp Biol Med. 1957;96:183-189

Aaron Frederick Rasmussen Jr. (1915-1984) was an American microbiologist and immunologist, a physician. He graduated in 1940 with an M.S., in 1941 with a Ph.D. and in 1944 with an M.D. from the University of Wisconsin, Madison. At the University of California’s (UCLA) School of Medicine (now named the David Geffen School of Medicine at UCLA), he was appointed in 1952 a full professor in the Department of Infectious Diseases (which became the Department of Microbiology and Immunology).

Together with Dr. Norman Brill, Professor of Psychiatry at the UCLA, and Dr. James Marsh, an experimental psychologist, he used the Miller shuttle box to study avoidance learning. The box had two chambers, one with a grid on the floor to apply electrical footshocks and one without grid and footshocks. Through a barrier, the animal can easily shuttle from one chamber to the other. Mice soon learned to avoid the electric shock and were, thus, exposed primarily to the stress of anticipation of pain and fear (1). In 1970, Rasmussen wrote (1):

“The readily observable bodily changes induced by repeated applications of the avoidance learning situation were hypertrophy of the adrenals, ’leukopenia, primarily due to reduction in lymphocytes,’ hypotrophy of the spleen, hypotrophy of the thymus, persistent pseudo estrous without ovulation in female, and suppression of granuloma formation. The responses to experimental infections in mice exposed repeatedly to this stressful situation were an increased susceptibility to herpes simplex (2), poliomyelitis (3), Coxsackie B (4), and polyoma virus infections (unpublished).”

This increased susceptibility to viruses was not always observed such as with influenza, respiratory viruses or Rauscher leukemia virus (1). The figure shows the percentage of dead animals after herpes simplex virus infection with or without additional avoidance learning stress (Fig. 1).

Fig. 1 Influence of avoidance learning stress on death by herpes simplex virus infection in mice.

Fig 1. Influence of avoidance learning stress on death by herpes simplex virus infection in mice.

The figure was created by the blogger and is based on tabular data published in Rasmussen AF Jr et al. (1957).

Today, we well know that stress can have a strong influence on infection. This can have unfavorable but sometimes also favorable effects depending on the type of infection and the investigated species (2 vs. 5).

The journal Neuroimmunomodulation published several papers on psychological stress and infection (6-11).

References

  1. Rasmussen AF Jr. Emotions and immunity. Ann N Y Acad Sci. 1969;164:458-462
  2. Rasmussen AF Jr, Marsh JT, Brill NQ. Increased susceptibility to herpes simplex in mice subjected to avoidance-learning stress or restraint. Proc Soc Exp Biol Med. 1957;96:183-189
  3. Johnsson T, Rasmussen AF Jr. Emotional stress and susceptibility to poliomyelitis virus infection in mice. Arch Gesamte Virusforsch. 1965;17:392-397
  4. Johnsson T, Lavender JF, Hultin E, Rasmussen AF Jr. The influence of avoidance-learning stress on resistance to coxsackie B virus in mice. J Immunol. 1963;91:569-575
  5. Marsh JT, Lavender JF, Chang SS, Rasmussen AF. Poliomyelitis in monkeys: decreased susceptibility after avoidance stress. Science. 1963;140(3574):1414-1415
  6. Deak T, Nguyen KT, Fleshner M, Watkins LR, Maier SF. Acute stress may facilitate recovery from a subcutaneous bacterial challenge. Neuroimmunomodulation. 1999;6:344-354
  7. Stowe RP, Pierson DL, Feeback DL, Barrett AD. Stress-induced reactivation of Epstein-Barr virus in astronauts. Neuroimmunomodulation. 2000;8:51-58
  8. Rodriguez-Galán MC, Correa SG, Cejas H, Sotomayor CE. Impaired activity of phagocytic cells in Candida albicans infection after exposure to chronic varied stress. Neuroimmunomodulation. 2001;9:193-202
  9. Gomez-Merino D, Drogou C, Chennaoui M, Tiollier E, Mathieu J, Guezennec CY. Effects of combined stress during intense training on cellular immunity, hormones and respiratory infections. Neuroimmunomodulation. 2005;12:164-172
  10. Welsh CJ, Steelman AJ, Mi W, Young CR, Dean DD, Storts R, Welsh TH Jr, Meagher MW. Effects of stress on the immune response to Theiler’s virus-implications for virus-induced autoimmunity. Neuroimmunomodulation. 2010;17:169-172
  11. Brook MJ, Christian LM, Hade EM, Ruffin MT. The Effect of Perceived Stress on Epstein-Barr Virus Antibody Titers in Appalachian Ohio Women. Neuroimmunomodulation. 2017;24:67-73

A Wikipedia site reports on the life of Aaron Frederick Rasmussen Jr.

Pillar Articles Series: The Role of Glucocorticoids in Human Chronic Inflammatory Disease

Viewpoint On

  • Hench PS. The analgesic effect of hepatitis and jaundice in chronic arthritis, fibrositis, and sciatic pain, Ann Internal Med. 1934:7:1278-1294.
  • Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious, rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis, Proc Staff Meetings Mayo Clinic 1938;13:161-167.
  • Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-II-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis (Preliminary Report). Proc Staff Meetings Mayo Clinic 1949;24:181-197; more officially and international: Ann Rheum Dis. 1949;8:97-104.

Philip Showalter Hench (1896-1965) was an American rheumatologist. Together with his colleague Edward C Kendall and the Swiss chemist Tadeus Reichstein, he was awarded the Nobel Prize for Medicine in the year 1950 for the discoveries on steroid hormones and their favorable effects in rheumatoid arthritis (RA). Philip Hench received his MD degree from the University of Pittsburgh in 1922 and started his career in 1923 at the Mayo Clinic, Rochester, Minnesota.

Already in the late 1920s, he observed the extremely favorable effects of jaundice in a patient with RA. At the time, this was a great surprise because RA remission was a medical curiosity. Between 1929 and 1934, he collected data of 16 patients with RA who developed jaundice that ameliorated the crippling disease (1). Today we know that in the bile, some biliary acids with the typical steroid hormone structure can have anti-inflammatory activities (2). However, many therapeutic approaches with bile or compound thereof – he expected the healing “substance X” in the bile – were not successful.

At the same time, he observed the ameliorating effect of pregnancy in women with RA, and he speculated on a “common denominator substance X” favorable in jaundice and pregnancy (3). He wrote: “It does not seem illogical to suppose that the agents responsible for both these phenomena are closely related, perhaps identical, and if the agent were a chemical substance, it would appear that it is neither bilirubin nor a strictly female sex hormone.”

During the hunt for “substance X”, Philip Hench also recognized that other inflammatory diseases like psoriasis arthritis, asthma, hay fever, Addison’s disease, and even migraine were sometimes relieved during pregnancy and/or jaundice. Substance X was unspecific and bisexual.

In the early 1940s he started a collaboration with Edward Kendall “in a laboratory [at Mayo Clinic] a few yards away”. Edward Kendall and colleagues –biochemists – already isolated several adrenal steroid hormones in the late 1930 (4), but administration of them lasted years because the substance was difficult to isolate from extracts. In the year 1948, in a collaboration of Edward Kendall and the American company of Merck & Co., Inc., enough compound E was available to treat a woman “badly crippled with RA” (5). More patients followed with highly favorable results (figure) (5). The similar effects of adrenocor-ticotropic hormone (ACTH) were correctly linked to the ACTH-induced secretion of adrenal glucocorticoids. This was the breakthrough! In Switzerland, concurrently, Tadeus Reichstein also discovered the different adrenal hormones.

 

Picture Influence of compound E (17-hydroxy-11-dehydrocorticosterone) on erythrocyte sedimentation rate of the first 14 patients with RA treated. Graph created by the blogger combining the tabular data pub-lished in Hench PS et al. (1949).

Fig 1. Influence of compound E (17-hydroxy-11-dehydrocorticosterone) on erythrocyte sedimentation rate of the first 14 patients with RA treated. Graph created by the blogger combining the tabular data published in Hench PS et al. (1949).

Today, we well know that therapeutic glucocorticoids ameliorate inflammation in autoimmune diseases and other inflammatory diseases. The anti-inflammatory effects of glucocorticoids stood the test of time. However, we also know that glucocorticoids must be administered at low doses up to 5 mg prednisolone per day to avoid side effects (6-8).

The journal Neuroimmunomodulation published several papers on glucocorticoids (6-10). In 2015, a special issue appeared in the journal.

References

  1. Hench PS. The analgesic effect of hepatitis and jaundice in chronic arthritis, fibrositis, and sciatic pain, Ann.Internal Med. 1934:7:1278-1294.
  2. Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol. 2012;36(Suppl 1):S3-S12.
  3. Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious, rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis, Proc. Staff Meetings Mayo Clinic 1938;13:161-167.
  4. Mason HL, Hoehn WM, Kendal EC. Chemical studies of the suprarenal cortex: IV. Structures of compounds C, D, E, F, AND G. J Biol Chem. 1938;124:459-474.
  5. Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-II-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis (Preliminary Report). Proc. Staff Meetings Mayo Clinic 1949;24:181-197; Ann Rheum Dis. 1949;8:97-104.
  6. Pincus T, Sokka T, Cutolo M. The past versus the present, 1980-2004: reduction of mean initial low-dose, long-term glucocorticoid therapy in rheumatoid arthritis from 10.3 to 3.6 mg/day, con-comitant with early methotrexate, with long-term effectiveness and safety of less than 5 mg/day. Neuroimmunomodulation. 2015;22:89-103.
  7. Hwang YG, Saag K. The safety of low-dose glucocorticoids in rheumatic diseases: results from observational studies. Neuroimmunomodulation. 2015;22:72-82.
  8. Santiago T, da Silva JA. Safety of glucocorticoids in rheumatoid arthritis: evidence from recent clinical trials. Neuroimmunomodulation. 2015;22:57-65.
  9. Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015;22:20-32.
  10. Silverman MN, Sternberg EM. Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation. 2008;15:19-28.

Special Topic Issue: Stress, the Stress System and the Role of Glucocorticoids, Neuroimmunomodulation, Volume 22, Issue 1-2 (September 2014).

Pillar Articles Series: The Influence of Adrenaline and Emotional Excitement on Phagocytosis of Tubercle Bacilli

Viewpoint On

Ishigami T. The influence of psychic acts on the progress of pulmonary tuberculosis. Am. Rev. Tuberc. 1919;2:470-484.

Tohru Ishigami (1857–1919) was the “discoverer of emotional effects on tuberculosis progression related to adrenaline”. After several educational stays at different research institutes (in Adelaide, Berlin with Shibasaburo Kitasato, Hongkong with the same Kitasato), he founded a tuberculosis sanatorium in Osaka in 1902. His own work on patients with tuberculosis, the role of Ivan Pavlov (conditioning of gastric secretion), and the contemporaneous publications of Walter Cannon from Harvard University (adrenal secretion and physical excitation) inspired him to explore the relationship between mental excitement and tuberculosis phagocytosis. He wrote: “It has long been recognized that the mental state of a patient has a great deal to do with his reaction to disease. I have noted this relationship in the treatment of tuberculosis.”

He used the opsonic index, which is a numerical measure of potency of a patient’s serum to opsonize bacteria in the process of phagocytosis (2). Today we know that opsonins can be specific antibodies to bacteria but also unspecific complement factors, which was unknown at the time of Ishigami. The lower the opsonic index, the lower is the capacity to phagocyte bacteria.

In Ishigami’s famous paper (1), he investigated the opsonic index in cell cultures with phagocytes by adding tubercle bacilli, adrenaline, and serum of a healthy person with phagocytes of guinea pigs. With increasing concentrations of adrenaline phagocytosis decreased (Fig. A). Using the same technique but this time with material from patients with tuberculosis, he observed a clear inhibitory effect of adrenaline on phagocytosis (Fig. B). In the third experiment, he observed in patients with tuberculosis that emotional excitement inhibited phagocytosis (Fig. C). In the paper, he did not describe how and why patients were emotionally excited.

 

Three plots depicting disease progression at different stages.

Figure 1. Influence of adrenaline in the test tube (A, B) and of emotional excitement on phagocytosis of tubercle bacilli. The figures were created using the original data from the publication of Ishigami presented in tabular form

Today we well know that phagocytosis can be blocked through beta2-adrenergic pathways (e.g., 3-5) or by increasing intracellular cyclic adenosine monophosphate (e.g., 6). The experiments of Tohru Ishigami stood the test of time and some similar experiments have also been published in Neuroimmunomodulation (7–9).

References

  1. Ishigami T. The influence of psychic acts on the progress of pulmonary tuberculosis. Am. Rev. Tuberc. 1919;2:470-484.
  2. Wright AE, Douglas SR. An experimental investigation of the bole of the blood fluids. Roy Soc Proc 1902;71:357-370.
  3. Abrass CK, O’Connor SW, Scarpace PJ, et al: Characterization of the beta-adrenergic receptor of the rat peritoneal macrophage. J Immunol 1985;135:1338-1341.
  4. Mitra S, Ghosh L, Chakrabarty P, et al: Effect of bioamines on uptake of promastigotes of Leishmania donovani by hamster peritoneal macrophages. J Med Microbiol 1992;36:283-287.
  5. Steininger TS, Stutz H, Kerschbaum HH. Beta-adrenergic stimulation suppresses phagocytosis via Epac activation in murine microglial cells. Brain Res. 2011;1407:1-12.
  6. Rossi AG, McCutcheon JC, Roy N, et al: Regulation of macrophage phagocytosis of apoptotic cells by cAMP. J Immunol 1998;160:3562-3568.
  7. Margatho RO, Massoco CO, Calefi AS, Cruz DSG, Sandini TM, Alves GJ, Florio JC, Palermo-Neto J. Beta-adrenergic blockade decreases the neuroimmune changes in mice induced by cohabitation with an Ehrlich tumorbearing cage mate. Neuroimmunomodulation. 2017;24:40-53.
  8. Alves GJ, Palermo-Neto J. Odor cues released by Ehrlich tumorbearing mice are aversive and induce psychological stress. Neuroimmunomodulation. 2015;22:121-9.
  9. Rodriguez-Galán MC, Correa SG, Cejas H, Sotomayor CE. Impaired activity of phagocytic cells in Candida albicans infection after exposure to chronic varied stress. Neuroimmunomodulation. 2001;9:193-202.

Pillar Articles Series: Severe Stress Contracts Lymphoid Organs and Changes Leukocyte Blood Count

Viewpoint On

  • Selye H. Thymus and adrenals in the response of the organism to injuries and intoxications. Brit J Exper Path. 1936;17:234-248
  • Selye H. Studies on adaptation. Endocrinology 1937;21:169-188
  • Harlow CM, Selye H. The blood picture in the alarm reaction. Proc Soc Exp Biol Med. 1937;36;141-144

Hans Selye (1907-1982) is the “Founder of Stress Theory” (1). He defined “the general adaptation syndrome”, which is the sum of all non-specific, systemic reactions of the body, which ensue upon long continued exposure to stress. In order to induce stress in rats, he exposed animals to many different nocuous alarm signals such as, e.g., toxins like formaldehyde. He recognized three different phases of the general adaptation syndrome: 1) a short-lived alarm reaction (including shock and counter-shock), 2) resistance, and 3) exhaustion (death). In these studies, he described the non-specific, systemic stress reactions of the body. He looked on body weight, weight of adrenal glands, blood pressure, body temperature, heart rate, blood sugar concentration, blood levels of chloride, histological changes of organs, and many more.

The “immunological idea” of Selye

Although Selye was not an immunologist, he recognized two important aspects after severe stress, which he incorporated into his theory of the general adaptation syndrome:

  1. Shrinkage of lymphoid organs such as thymus, spleen, and lymph nodes
  2. Increase of neutrophils and decrease of lymhocytes

Many different stress reactions can stimulate both events. Importantly, prior adrenalectomy partly inhibited the effects (Fig. 1). Other authors later added the fact that stress hormones induce immunoglobulin secretion (2) etc.

 

Picture Scheme of classical conditioning on the example of Pavlov's dog

Figure 1. Stress reactions induce shrinkage of the thymus (and other lymphoid organs, not shown) and a marked increase in blood leukocyte count. Graph created by the blogger combining the tabular data published in the three above-mentioned original works.

Today we recognize that reactions through stress axes such as the sympathetic nervous system and the adrenal glands can stimulate the immune system at early time points during stress. A typical reaction is the mobilization and extravasation of blood immune cells (high monocytes/neutrophils, low lymphocytes). In the long term, stress responses inhibit the immune system, particularly when they are strong.

In one form or the other, stress-stimulated immediate changes of blood immune cells stood the test of time, and some of the experiments have also been published in Neuroimmunomodulation (3-10).

References

  1. Tan SY, Yip A. Hans Selye (1907-1982): Founder of the stress theory. Singapore Med J. 2018;59:170-171
  2. Dougherty TF, Chase JH, White A. Pituitary-adrenal cortical control of antibody release from lymphocytes. An explanation of the anamnestic response. Proc Soc Exp Biol Med. 1945;58:135-140
  3. Tarcic N, Levitan G, Ben-Yosef D, Prous D, Ovadia H, Weiss DW. Restraint stress-induced changes in lymphocyte subsets and the expression of adhesion molecules. Neuroimmunomodulation. 1995;2:249-257
  4. Nakata A, Araki S, Tanigawa T, Sakurai S, Yokoyama M. Effects of uncontrollable and controllable electric shocks on T lymphocyte subpopulations in the peripheral blood, spleen, and thymus of rats. Neuroimmunomodulation. 1996;3:336-341
  5. Sudo N, Yu XN, Sogawa H, Kubo C. Restraint stress causes tissue-specific changes in the immune cell distribution. Neuroimmunomodulation. 1997;4:113-119
  6. Sudo N, Oyama N, Yu XN, Kubo C. Restraint stress-induced elevation of endogenous glucocorticoids decreases Peyer’s patch cell numbers via mechanisms that are either dependent or independent on apoptotic cell death. Neuroimmunomodulation. 2001;9:333-339
  7. Kumlien Georén S, Olgart Hoglund C, Tcacencu I, Wikstrom AC, Stierna P. Timing-dependent effects of restraint stress on eosinophilic airway inflammation in mice. Neuroimmunomodulation. 2008;15:157-164
  8. Martínez-Carrillo BE, Godinez-Victoria M, Jarillo-Luna A, Oros-Pantoja R, Abarca-Rojano E, Rivera-Aguilar V, Yépez JP, Sánchez-Torres LE, Campos-Rodríguez R. Repeated restraint stress reduces the number of IgA-producing cells in Peyer’s patches. Neuroimmunomodulation. 2011;18:131-141
  9. Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation. 2009;16:300-317
  10. Haake P, Krueger TH, Goebel MU, Heberling KM, Hartmann U, Schedlowski M. Effects of sexual arousal on lymphocyte subset circulation and cytokine production in man. Neuroimmunomodulation. 2004;11:293-298

Pillar Articles Series: The Transformation of Pavlov’s Theory into Immunology

Viewpoint On

  • Metalnikov S, Chorine V. Role des reflexes conditionnels dans l’immunite. Ann Inst Pasteur (Paris) 1926;40:893–900
  • Metalnikov S, Chorine V. Role des reflexes conditionnels dans la formation des anticorps. CR Soc Biol 1928:1:142–145

What was Pavlov’s Theory?

  1. Pavlov called a salivation response of a dog to a meal the unconditioned response and the meal itself was the unconditioned stimulus.
  2. Using a neutral stimulus such as a bell did not elicit a response, but…
  3. Association of the bell with the meal again lead to salivation. Repeating the association makes the neutral stimulus – the bell – to the conditioned stimulus.
  4. After repeated associations, the conditioned stimulus of the bell elicits salivation, which is now the conditioned response.

 

Picture Scheme of classical conditioning on the example of Pavlov's dog

Figures 1-4. Scheme of classical conditioning on the example of Pavlov’s dog. Image is modified from Pavlov’s dog.svg (Wikimedia Commons). This file is licensed under the Creative Creative Commons and Attribution-Share Alike 3.0 Unported license.

For this work and others, Ivan Petrovich Pavlov was awarded the Nobel Prize in Physiology or Medicine in 1904. Today, we recognize this form of conditioning as a learning mechanism, which involves our memory in the brain. Immune conditioning plays a role in placebo therapy of immunological diseases (1).

The Idea of Metalnikov and Chorine

In the 1920s, Metalnikov and his colleague Chorine at the Pasteur Institute in Paris, France demonstrated that a conditioned stimulus alone without the presence of an antigen could evoke an immune response (#4 in the picture). How did they show it? They applied intraperitoneal injections of various bacteria-derived compounds such as Bacillus anthracis, a Staphylococcus filtrate, or Vibrio cholera as unconditioned stimulus, and scratching or heating the skin with a warm metallic plate as conditioned stimulus in guinea pigs. After the association phase and a delay to allow the return to baseline levels, the conditioned stimulus alone yielded a significant and rapid influx of neutrophils. Using Vibrio cholera as unconditioned stimulus, unconditioned animals died 7 to 8 hours after the Vibrio cholera challenge one day following conditioned stimulus re-exposure, whereas the conditioned animals lived 36 hours. Some even survived and were re-challenged.

In one form or the other, immune conditioning stood the test of time (1), and some of the experiments have also been published in Neuroimmunomodulation (2-8).

References

  1. Hadamitzky M, Lückemann L, Pacheco-López G, Schedlowski M.: Pavlovian Conditioning of Immunological and Neuroendocrine Functions. Physiol Rev. 2020;100:357-405. doi: 10.1152/physrev.00033.2018
  2. Bauer D, Busch M, Pacheco-López G, Kasper M, Wildschütz L, Walscheid K, Bähler H, Schröder M, Thanos S, Schedlowski M, Heiligenhaus A.: Behavioral conditioning of immune responses with cyclosporine a in a murine model of experimental autoimmune uveitis. Neuroimmunomodulation. 2017;24:87-99. doi: 10.1159/000479185
  3. Vidal J, Chamizo VD.: The conditioned stimulus elicits taste aversion but not sickness behavior in conditioned mice. Neuroimmunomodulation. 2010;17:325-32. doi: 10.1159/000292021
  4. Pacheco-López G, Niemi MB, Kou W, Baum S, Hoffman M, Altenburger P, del Rey A, Besedovsky HO, Schedlowski M.: Central blockade of IL-1 does not impair taste-LPS associative learning. Neuroimmunomodulation. 2007;14:150-6. doi: 10.1159/000110639
  5. Haour F.: Mechanisms of the placebo effect and of conditioning. Neuroimmunomodulation. 2005;12:195-200. doi: 10.1159/000085651
  6. Mei L, Li L, Li Y, Deng Y, Sun C, Ding G, Fan S.: Conditioned immunosuppressive effect of cyclophosphamide on delayed-type hypersensitivity response and a preliminary analysis of its mechanism. Neuroimmunomodulation. 2000;8:45-50. doi: 10.1159/000026452
  7. Exton MS, von Hörsten S, Strubel T, Donath S, Schedlowski M, Westermann J.: Conditioned alterations of specific blood leukocyte subsets are reconditionable. Neuroimmunomodulation. 2000;7:106-14. doi: 10.1159/000026428
  8. Rogers CF, Ghanta VK, Demissie S, Hiramoto N, Hiramoto RN.: Lidocaine interrupts the conditioned natural killer cell response by interfering with the conditioned stimulus. Neuroimmunomodulation. 1994;1:278-83. doi: 10.1159/000097177
TOP