Medical Hypothesis (1996) 46: 551-555

Stress-induced suppression of the cellular immune reactions.
A contribution on the neuroendocrine control of the immune system.

A. HASSIG, LIANG WEN-XI AND K. STAMPFLI

The task of the immune system is to maintain the genetically determined individuality of the organism. This task covers two fields: Firstly the elimination of exogenous "not-self" structures and secondly the processing of endogenous "altered-self" structures, such as occur in large amounts with the constant restructuring of the cellular elements of the organism.(1) According to the latest opinions, the elimination of exogenous "not-self" structures is the primary task of the humoral immune reactions associated with the B cells. The processing of endogenous "altered-self" structures, on the other hand, is the primary task of the cellular immune reactions associated with cytotoxic T cells and natural killer cells. Immunological health depends on harmonious collaboration between the humoral and cellular immune reactions.

Immune competence as a state of eauilibrium between humoral and cellular immunity

In the search for documentary evidence for the duality of these reactions one first comes upon the studies of Glaser and Kiecolt-Glaser.(2) In comprehensive investigations they have shown that psychic stress reactions raise the titer of humoral antibodies against viruses such as EBV, CMV and HSV-1, whereby they at the same time impair the cellular immune reactions. They explained their findings with the release of latent viruses due to impairment of the cellular defence mechanisms and the secondary stimulation of the production of humoral antibodies. This interpretation is supported by the observation that in stress reactions the antipoliomyelitis-antibody titer is not changed. Poliomyelitis viruses are completely eliminated by the immune reaction following their spread throughout the body, which is not the case with the three herpes viruses mentioned.

The opposite behaviour of the humoral and the cellular immune reactions observed in these studies receives strong support from the reports of Mosmann and Coffmann on the functionally opposite cytokine profiles of the CD4 helper lymphocytes.(3) They showed that with the CD4 helper cells two groups of cells can be identified, which are known as Th-1 and Th-2 cells. The Th-1 cells secrete mainly IL-2, IL-12 and IFN-y, which stimulate the cellular reactions. The Th-2 cells, on the other hand, produce mainly IL-4, IL-6 and IL-10 and through them they stimulate the humoral reactions. In recent years these studies have aroused great interest and the results are today widely supported.

Neuroendocrine control of the balance between humoral and cellular immunity

At the present time the question is asked, among others, how the Th-1/Th-2 balance of the cytokine production by CD4 lymphocytes can be related to the neuroendocrine control mechanisms of the immune system in stress reactions. The essence of the concept of stress established by Selye in 1936 states that the organism responds in a uniform manner to the manifold somatic and psychic demands placed upon it. Here the central role is played by the activation of the stress axis, hypothalamus-pituitary-adrenals. The increased release of catecholamines and glucocorticoids from the adrenals causes a centralisation of the metabolism to the provision of rapidly available energy sources, especially glucose, in view of the increased muscular activity in a "fight or flight" situation. The physiological function of the glucocorticoids obviously consists mainly of limiting of the life-threatening acutephase reactions by endogenous mediators of inflammation.(4) Thereby a raised cortisol content leads to permanent suppression of the cellular immune reactions associated with the T cells and thus to an increased susceptibility to infection by opportunistic germs.

In regard to the relationship of the Th-1 and Th-2 cytokine profile of the CD4 lymphocytes to the neuroendocrine processes in stress reactions, it firstly has to be stated that before the Th-1 and Th-2 cytokine profile of the CD4 lymphocytes were described it was already known to how great an extent glucocorticoids inhibit the production of IL-2 and IFN-y (4). We have to thank the working-group of Daynesfor the important step they took towards clarification of the mechanism involved in the formation of these lymphocytic cytokine profiles.(5,6) These investigators firstly showed that the cytokine production of activated lymphocytes is controlled from the periphery. Mitogen- or antigen-stimulated lymphocytes from lymphoid organs in the area of the mucous membranes produce mainly IL-4. Lymphocytes from other organs produce mainly IL 2 Decisive for the type of peripheral control of the lymphocytic cytokine production is probably the production of steroid hormones, which develop locally from inactive precursors. In this process, the dehydroepiandosterone (DHEA) produced in the adrenal cortex plays a central role as an antagonist to cortisol. DHEA is the adrenocortical hormone which of all the steroidal hormones is contained in the blood in the highest concentration. It is sulphated (DHEAS) and is inactive in this form. DHEAS is desulphated in the periphery by steroid sulphatase and in this way is transformed into the active form. In the lymphocytes, the active DHEA is responsible for the increased production of IL-2 and IFN-y, but not of IL-4. These findings show that the different content of steroid sulphatase in different tissues is of great importance in the transformation of the pro-hormone DHEAS into active DHEA in the production of Th-1 and Th-2 lymphocytes. In the lymphatic tissue, macrophages are the only cells that contain a noteworthy amount of DHEAS sulphatase. Moreover, the large amount of circulating DHEAS serves as a reservoir for the production of androgenic and, to a lesser extent, of oestrogenic hormones.

What has been said up till now shows that the Th-1/Th-2 balance of the CD4 lymphocytes is substantially determined by the local balance of the steroidal hormones, cortisol and DHEA, at the site of the activation, whereby DHEA is the local antagonist of the systemically-acting cortisol. In stress reactions there is a shift of the Th-1 profile of the CD4 lymphocytes to the Th-2 profile, apparently due to the fact that through the sympathicotonic adrenergic-corticoid displacement of the metabolism the cortisol-DHEA balance is shifted in favour of cortisol, as a result of which the concentration of the cytokine profiles of the CD4 lymphocytes is shifted more into the area of the mucous membranes. According to this hypothesis, in stress situations the humoral immune reactions, which are directed against exogenic "not self" structures, are potentiated, while at the same time the cellular immune reactions, directed against endogenous "altered self"' structures, are weakened.

With regard to the direct effect of a hypercortisolism on the lymphocytes, it has to be noted that immature CD4+/CD8+ thymocytes represent the most cortisol-sensitive element of the lymphatic tissue. They are reduced by increased apoptosis, so that the number of immunological precursor cells decreases. Peripheral mature CD4+/CD8- and CD4-/CD8+ lymphocytes are relatively cortisol-resistant.(7,8) The decrease in the number of CD4 lymphocytes in the blood,with a practically constant number of CD8 lymphocytes, which is characteristic for stress reactions, is due primarily to a sequestration of the CD4 cells in the bone marrow.(9)

With regard to the effect of a deficiency of IL-2 and IFN-y, the following has to be considered: IL-2 is produced in activated T cells. It activates the clonal expansion of the T and B cells and the natural killer cells. In the case of an IL-2 deficiency the function of the idiotypic network is impaired, as its polyclonality is regraded to oligoclonality. IFN-y is produced by activated T cells. Its main effect is the activation of the macrophages in regard to their phagocytic function, particularly the degradation or the intracellular immobilisation of bacteria, viruses and tumour cells.

Direct and indirect activation of the neuroendocrine stress axis

The stress-induced suppression of cellular immune reactions can be divided into two pathogenetic groups. The one group comprises conditions with direct activation of the neuroendocrine stress axis due to increased production of corticotropin-releasing hormone (CRH) in the hypothalamus. Psychic and toxic stress states belong to this group. The second group comprises conditions with indirect activation of the neuroendocrine stress axis due to acute-phase reactions following injuries and infections and conditions of severely protein-deficient diet.

In the course of the last decade, under the term "psychoneuroimmunology." introduced by Ader, the field of the psychic influencing of immune reactions has grown into a separate, independent science.(10,11)

Of the toxic stress reactions, the immunosuppressive effect of opiates has been best researched up till now. In animal experiments in mice the chronic administration of morphine causes a severe involution of the thymus, characterised by increased apoptosis, especially of immature CD4+/CD8+ thymocytes. This is due to the fact that morphine increases the production of CRH in the hypothalamus, as a result of which the production of ACTH in the pituitary and of cortisol in the adrenal cortex is activated.(13,14)

Numerically most important, however, is the indirect activation of the neuroendocrine stress axis due to the increased production of CRH in the hypothalamus as a result of a persistently raised release of monokines, particularly IL-1 and TNFa, from macrophages activated by inflammation.(15) The increased release of monokines is coupled with an increased release of O2 radicals. (16) The production of these radicals within the phagocytes is essential to the orderly degradation of structures taken up from outside. Under physiological conditions, antioxidative enzymes and low-molecular antioxidants ensure that released O2 radicals cause no damage. Excessive production of O2 radicals and/or deficient antioxidative defence lead to radical-induced damage to normal cell structures, especially DNA, proteins and lipids. The most important radicals involved here are the highly active hydroxy radicals (HO.), whose production is catalysed by Fe2+. The accumulation of radicals is thus increased by an iron-overloading of the macrophages.(17) Within the framework of any inflammatory acute-phase reaction a considerable part of the serum iron is shifted into macrophages, where it is bound to ferritin. This displacement of iron has the useful effect of reducing the amount of iron available for the multiplication of extracellular pathogens. For these reasons it is important, in stress situations, to counteract both iron overloading and antioxidant depletion of the organism.

A further large group of stress-induced suppressions of the cellular immunity is represented by the so-called protein calorie malnutrition in children with kwashiorkor or marasmus. Beisel fittingly described this group of diseases as "nutritionally acquired immunodeficiency syndromes" (NAIDS) and drew attention to the fact that worldwide about 40,000 children under the age of five years die from these diseases every day.(18) These children show atrophy of the thymus, associated with a severe deficiency of T lymphocytes in the lymph nodes and the spleen. As in AIDS, they die from infections caused by intracellular opportunist pathogens, such as Pneumocystis carinii and Herpes simplex, or from anergic miliary tuberculosis.(19)

Also in AIDS, failure of the cellular immune reactions is the central factor in the pathological process. In regard to the importance of the human immunodeficiency viruses (HIV) in the development of AIDS, it is now known that patients with a healthy immune system with the Th-1 cytokine profile of the CD4 lymphocytes are as a rule able to bring an HIV infection under control through cellular immune reactions, without the production of anti-HIV antibodies. A positive result in the anti-HIV-antibody test in HIV infection is an indication of a previous impairment of the cellular immune reactions. This is presumably attributable to the stress situation existing in the risk-groups for AIDS, namely homosexuals, drug addicts, haemophiliacs and blood recipients.(20)

Moreover, it has to be borne in mind that the sepsis syndrome, with multiple organ failure, which is often to be observed in multiple in;uries, severe burns and serious surgical interventions, is also due to excessive, persistent inflammation in the whole organism. In these cases the massive release of inflammation mediators overrides the an/inflammatory action of the glucocorticoids, so that the whole humoral and cellular immune defence breaks down and otherwise harmless nosocomial germs spread throughout the organism. That excessive macrophage activity plays a central role in this process can also be seen from the fact that, as in AIDS, the extent of the release of neopterin from the macrophages is closely linked to the outcome - survival or death - for the patient (21).

According to what has been said so far, it has to be accepted that the Th-2 profile of the CD4 lymphocytes corresponds to a stress situation with an excess of cortisol and a deficiency of DHEA. This causes a deficiency of IL-2, IL-12 and IFN-y throughout the organism, with a simultaneous excess of IL-4, IL-6 and IL-10.

Possibilities for diagnosis of a stress-induced immunosuppression

The Th-2 profile of the CD4 lymphocytes can be determined directly by demonstrating the impairment of the cellular immunity by means of the cutaneous energy against infectious antigens. Delayed skin reactions require intact humoral and cellular immunity. Indirect indications of a Th-2 profile are the increased acute-phase proteins, especially C-reactive proteins, associated with an increased amount of IL 6. The simplest indication for the presence of an acute-phase reaction is acceleration of the erythrocyte sedimentation rate.

Possibilities for the prevention and treatment of a stress-induced immunosuppression

How can a persisting Th-2 profile, with its neuroendocrine suppression of the cellular immune reaction, be transformed into the Th-1 profile, with its homeostatic state of eguilibrium between cellular and humoral immunity?

According to what has been said up till now, the recovery of the neuroendocrine suppression with adrenergic-corticoid adjustment of the total metabolism is central to this process. The administration of individual cytokines such as IL-2, IL-12 and IFN-y has, at best, a short-term symptomatic effect. With direct activation of the stress axis, elimination of situations of mental conflict and freedom from drugs seem to us to be decisive. In the case of indirect activation of the stress axis through infectious and nutritional stress mechanisms, the central, decisive factor is correction of the persisting activation of the phagocytes with continuous release of O2 radicals and inflammation mediators, through an adequate and balanced diet.

With regard to the pharmacological treatment of these conditions, the most interesting possibility at the present time is the administration of two endogenous hormones, namely DHEA and melatonin (22-24). DHEA as a cortisol antagonist is at present the subject of an extensive pharmacological and clinical investigation. Melatonin is the most powerful antioxidant known at the present time and in this respect it is many times stronger than the antioxidative vitamins E, C and beta-carotene. This hormone, too, is at present the subject of great scientific interest.

In our opinion, however, adjustment of the way of life and the diet is in the long term decisive for the prevention of permanent impairment of the cellular immunity with its presumed conseguences in regard to the diseases of Western civilisation, such as arteriosclerosis and cancer. As far as way of life is concerned, attention should be paid the balance between work and leisure. With regard to diet, the most important aspect is the balanced intake of macro-nutrients (protein, fats, carbohydrates) and micro-nutrients (vitamins, trace elements, minerals). However, according to present-day knowledge an adequate intake of vegetable-based antioxidants, namely polyphenols such as flavonoids and tannins, is also essential (25).

As the conclusion to be drawn from the foregoing, we would like to state the following: Stress situations improve the survival rate in "fight or flight" situations. The organism tolerates these states for only a short time. If they persist they lead to far-reaching damage, the most serious being impairment of the thymus-dependent functions of the T cells. For this reason it is crucial, in the prevention and treatment of the diseases of Western civilisation and in diseases of the elderly, to pay special attention to maintenance of the functions of the thymus.(26,27) *

We thank the Hans Eggenberger Foundation in Zurich for the support given to this study.

References

1. H.U. Lutz: Erythrocyte Clearance Blood Cell Biochemistry. Vol. I. Erythroid Cells. Chapter 4. Ed. J.R. Harris, Plenum Press, New York, London

2. R. Glaser, J.K. Kiecolt-Glaser: Stress associated Immuno Modulation and its Implication for Reactivation of latent Herpesviruses. Herpes Virus Infections R. Glaser, J.E. Jones (Eds) Marcel Dekker Inc. N.Y. (1994)

 3. T.R. Mosmann, R.L. Coffman: Thl and Th2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties. Ann.Rev. Immunol. 7, 145 (1989)

4. A. Munck, P.M. Guyre, N.J. Holbrook: Physiological Funktions of Glucocorticoids in Stress and their relation to Pharmacological Actions. Endocrine Reviews 5, 25 (1984)

5. R.A. Daynes, B.A. Araneo et al.: Regulation of Murine Lymphokine production in vivo III. The Lymphoid Tissue Microenvirement exerts Regulatory Influence over T Helper Cell functions. J.exp.Med. 171,979 (1990)

6. J.D. Hennebold, R.A. Daynes: Regulation of Macrophage Dehydroepiandrosteron; Sulfate Metabolism by Inflammatory Cytokins. Endocrinology 135, 67 (1994)

7. J.J. Cohen: Glucocorticoid-induced apoptosis in the thymus. Sem. Immunol. 4, 363 (1982)

8. J. Gruber, R. Sgonc et al.: Thymocyte apoptosis induced by elevated endogenous corticosterone levels. Europ.J. Immunol.24, 1115 (1994)

9. B.F. Haynes, A.S. Fauci: The differential effect of in vivo hydrocortisone on the kinetics of subpopulations of human peripheral blood thymus-derived lymphocytes. J .cl in. Invest. 61 703 (1978)

10. R. Ader, D.L. Felten, N. Cohen: Psychoneuroimmunology 2nd ed. Academic Press San Diego (1991)

11. B.E. Leonard, K. Miller (Eds): Stress, the Immune System and Psychiatry. J. Wiley, Chichester (1994)

13. H.U. Bryant, E.W. Berton et al.: Role of Adrenal Cortisoh Activation in the Immunosuppressive Effects of Chronic Morphine Treatment Endocrinology 128, 3253 (1991)

14. B.A. Fuchs, S.B. Pruett: Morphine produces Apoptosis in Murine Xhymocytes in Vivo but not in Vitro. J. Pharmacol.-expl.Therapeutics 266, 417 (1993)

15. H. Besedovsky, A.E. del Rey, E. Sorkin, C.A. Dinarello: Immunoregulatory feed back between interleukin-1 and glucocorticoid hormones. Science, 233, 652 (1986)

16. J.M.C. Gutteridge, B. Halliwell: Antioxidants in Nutrition, Health and Disease. Oxford University Pres (1994)

17. E.D. Weinberg: The Iron-with-holding-Defence-System. Ann.Soc. Microbiol. News 59, 559 (1993)

18. W.R.Beilel: History of Nutritional Immuology: Introduction an Overview. J. Nutr. 122, 591 (1992)

19. D.R. Purtilo, D.H. Connor: Fatal infections in protein-calorie malnourished children with thymolymphatic atrophy. Archives of Diseases in Childhood 50, 149 (1975)

20. A. Hassig, Liang Wen-Xi, K. Stampfli: Can we find a solution of the HIV/AIDS Controversy, Medital Hypothesis, in print

21. D. Nast-Kolb, M. Jochum et al.: Die klinische Wertigkeit biochemischer Faktoren beim Polytrauma. Hefte Unfaliheilkd. (Suppl) 215 (1991)

22. A.J. Morales, J.J. Nolan, J.C. Nelson, S.S.C. Yen: Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J. Clin. Endocrinol. Metab. 78, 1360-1367 (1994)

23. B. Araneo, R. Daynes: Dehydroepiandrosterone Functions as More Than an Antiglucocorticoid in Preserving Immuncompetence after Thermal Injury. Endocrinology 136, 393-401 (1995)