Das Stresskonzept von Allostase und Allostatic Load: Einordnung psychoneuroimmunologischer Forschungsbefunde an Beispielen zur Autoimmunität und Onkologie

Zusammenfassung

Klassische Theorien definieren Stress als Reaktion auf eine Bedrohung der Homöostase eines Organismus, welche eine Anpassungsreaktion erfordert. Langfristige Konsequenzen in Bezug auf die Entwicklung von Erkrankungen zu postulieren ist auf der Grundlage solcher Konzepte jedoch problematisch. Das Konzept von Allostatic Load ermöglicht Aussagen über Reaktionssequenzen von Stressmediatoren und von diesen initiierten Effekten und pathogenen Folgen. Stressmediatoren werden kurzfristig und in geringen Konzentrationen adaptiv sezeniert, können aber langfristig zu schädigenden Effekten führen. Dieses Konzept erlaubt die Formulierung von Ursache-Wirkungs-Kaskaden, um den Zusammenhang einer Dysregulation von Stressmediatoren wie Glukokortikoiden und Katecholaminen und der Anfälligkeit für Erkrankungen zu beschreiben. In der vorliegenden Arbeit beschreiben wir zunächst den theoretischen Hintergrund des Konzeptes von Allostatic Load. Anschließend übertragen wir dieses Konzept auf Forschungsergebnisse, welche darauf hinweisen, dass eine Dysregulation der Stressreaktionssysteme bei multipler Sklerose und Brustkrebs für die Pathogenese oder die Krankheitsentwicklung bedeutsam sein könnte. Stressmediatoren und ihre Folgen in der Reaktionskaskade sind jedoch in einem nicht-linearen Netzwerk miteinander verbunden.

Abstract

Classical theories have conceptualized stress as a reaction to threat to the homeostasis within the organism requiring an adaptive response. However, postulating mechanisms that could link such responses to long-term detrimental health outcomes remains difficult. The allostatic load concept enables us to think about how mediators can be protective in the short run but may have damaging effects when overused and/or not shut off. It further facilitates the formulation of cause-effects cascades to explain the link of dysregulations in stress mediators such as glucocorticoids and catecholamines and increased susceptibility for certain diseases. In the first section, we briefly summarize the theoretical background. We then employ the concept to integrate findings from basic and clinical research on dysregulations of the stress response systems in multiple sclerosis and breast cancer. Based on this model, it seems likely that such dysregulations are implicated in progression and possibly pathogenesis of these diseases. When using allostatic load as a heuristic model, one needs to consider that stress mediators and outcomes are interconnected in a non-linear network.

Key words

Stress - psychoneuroimmunology - oncology - multiple sclerosis

Literatur

• 1 Cannon W B. Emotional stimulation of adrenal secretion.  Am J Physiol. 1911;  28 64-70
• 2 Cannon W B. The emergency function of the adrenal medulla in pain and major emotions.  Am J Physiol. 1914;  33 356-372
• 3 Selye H. A syndrome produced by diverse noxious agents.  Nature. 1936;  138 32
• 4 Selye H. The general adaptation syndrome and the diseases of adaptation.  J Clin Endocrinol. 1946;  6 117-230
• 5 Mason J W. A re-evaluation of the concept of „non-specificity” in stress theory.  J Psychiatr Res. 1971;  8 323-333
• 6 Dimsdale J E, Moss J. Plasma catecholamines in stress and exercise.  JAMA. 1980;  243 340-342
• 7 Chrousos G P, Gold P W. The concept of stress and stress system disorders. Overview of physical and behavioral homeostasis.  JAMA. 1992;  267 1244-1252
• 8 Chrousos G P. Syndromes of glucocorticoid resistance.  Ann Int Med. 1993;  119 1113-1124
• 9 Besedovsky H O, Sorkin E. Network of immune-endocrine interactions.  Clin Exp Immunol. 1977;  27 1-12
• 10 Ader R, Felten D L, Cohen N (eds). Psychoneuroimmunology. San Diego; Academic Press 2001
• 11 Sterling P, Eyer J. Allostasis: A new paradigm to explain arousal pathology. In: Fisher S, Reason J (eds) Handbook of life stress, cognition and health. New York; Wiley 1988: 629-649
• 12 McEwen B S. Protection and damage from acute and chronic stress. Allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders.  Ann N Y Acad Sci. 2004;  1032 1-7
• 13 Schulkin J. Corticotropin-releasing hormone signals adversity in both the placenta and the brain: regulation by glucocorticoids and allostatic overload.  J Endocrinol. 1999;  161 349-356
• 14 McEwen B S. Protective and damaging effects of stress mediators.  N Engl J Med. 1998;  338 171-179
• 15 Koob G F, LeMoal M. Drug addiction, dysregulation of reward, and allostasis.  Neuropsychopharmacology. 2001;  24 97-129
• 16 McEwen B S, Seeman T. Protective and damaging effects of mediators of stress. Elaborating and testing the concepts of allostasis and allostatic load.  Ann NY Acad Sci. 1999;  896 30-47
• 17 McEwen B S, Wingfield J C. The concept of allostasis in biology and biomedicine.  Hormones and Behavior. 2003;  43 2-15
• 18 McEwen B S, Wingfield J C. Response to commentaries on the concept of allostasis.  Hormones and Behavior. 2003;  43 28-30
• 19 Kaplan J R, Petterson K, Manuck S B, Olsson G. Role of sympatho-adrenal medullary activation in the initiation and progression of atheriosclerosis.  Circulation. 1991;  84, Suppl VI VI23-VI32
• 20 Lupien S J, McEwen B S. The acute effects of corticosteroids on cognition: Integration of animal and human model studies.  Brain Res Rev. 1997;  24 1-27
• 21 Haddad J J, Saade N E, Safieh-Garabedian B. Cytokines and neuro-immune-endocrine interactions: A role for the hypothalamic-pituitary-adrenal revolving axis.  J Neuroimmunol. 2002;  133 1-19
• 22 Sapolsky R M, Romero L M, Munck A U. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.  Endocr Rev. 2000;  21 55-89
• 23 Webster J I, Tonelli L, Sternberg E M. Neuroendocrine regulation of immunity.  Ann Rev Immunol. 2002;  20 125-163
• 24 McEwen B S, Biron C A, Brunson K. et al . Neural-endocrine-immune interactions: The role of adrenocorticoids as modulators of immune function in health and disease.  Brain Res Rev. 1997;  23 79-133
• 25 McEwen B S. Interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging.  Metabolism. 2003;  52 (Suppl 2) 10-16
• 26 Seeman T, McEwen B, Rowe J, Singer B H. Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging.  Proc Natl Acad Sci U S A. 2001;  98 4770-4775
• 27 Yamada K, Duong D T, Scott D K. et al . CCAAT/Enhancer-binding protein is an accessory factor for the glucocorticoid response from the cAMP response element in the rat phosphoenolpyruvate carboxykinase gene promoter.  J Biol Chem. 1999;  274 5880-5887
• 28 McEwen B S. Plasticity of the hippocampus: Adaptation to chronic stress and allostatic load.  Ann NY Acad Sci. 2001;  933 265-277
• 29 Cohen S, Hamrick N, Rodriguez M S. et al . Reactivity and vulnerability to stress-associated risk for upper respiratory illness.  Psychosom Med. 2002;  64 302-310
• 30 Wilder R L. Neuroendocrine-immune system interactions and autoimmunity.  Annu Rev Immunol. 1995;  13 307-338
• 31 Schorr E C, Arnason B G. Interactions between the sympathetic nervous system and the immune system.  Brain Behav Immun. 1999;  13 271-278
• 32 Sternberg E M, Glowa J R, Smith M A. et al . Corticotropin releasing hormone related behavioural and neuroendocrine response to stress in Lewis and Fischer rats.  Brain Res. 1992;  570 54-60
• 33 Mason D, MacPhee I, Antoni F. The role of the neuroendocrine system in determining genetic susceptibility to experimental allergic encephalomyelitis in the rat.  Immunol. 1990;  70 1-5
• 34 Kuroda Y, Mori T, Hori T. Restraint stress suppresses experimental allergic encephalomyelitis in Lewis rats.  Brain Res Bull. 1994;  34 15-17
• 35 Bartolomucci A, Sacerdote P, Panerai A E. et al . Chronic psychosocial stress-induced down-regulation of immunity depends upon individual factors.  J-Neuroimmunol. 2003;  141 (1 - 2) 58-64
• 36 MacPhee I, Antoni F A, Mason D W. Spontaneous recovery from rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids.  J Exp Med. 1989;  169 431-445
• 37 Bolton C, Flower R J. The effect of anti-glukokortikoid RU 38 486 on steroid-mediated suppression of experimental allergic encephalomyelitis (EAE) in the Lewis rat.  Life Sci. 1989;  45 97-104
• 38 Michelson D, Stone L, Galliven E. et al . Multiple sclerosis is accociated with alterations in hypothalamic-pituitary-axis function.  J Clin Endocrinol Metab. 1994;  79 848-853
• 39 Grasser A, Möller A, Backmund A. et al . Heterogeneity of hypothalamic-pituitary-adrenal system response to a combined dexamethasone-CRH test in multiple sclerosis.  Exp Clin Endocrinol Diabetes. 1996;  104 31-37
• 40 Wei T, Lightman S L. The neuroendocrine axis in patients with multiple sclerosis.  Brain. 1997;  120 1067-1076
• 41 Purba J S, Raadsheer F, Hofman M A. et al . Increased number of corticotropin releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of patients with multiple sclerosis.  Neuroendocrinol. 1995;  62 62-70
• 42 Reder A T, Lowy M T, Meltzer H Y, Antel J P. Dexamethasone suppression test abnormalities in multiple sclerosis: relation to ACTH therapy.  Neurology. 1987;  37 849-853
• 43 Limone P, Ferrero B, Calvelli P. et al . Hypothalamo-pituitary-adrenal axis function and cytokine production in multiple sclerosis with or without interferon-β treatment.  Acta Neurol Scand. 2002;  105 372-377
• 44 Then Bergh F, Kümpfel T, Trenkwalder C. et al . Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS.  Neurology. 1999;  53 772-777
• 45 Heesen C, Gold S M, Raji A. et al . Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis.  Psychoneuroendocrinol. 2002;  27 505-517
• 46 Schumann E M, Kümpfel T, Then Bergh F. et al . Activity of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: correlations with gadolinium-enhancing lesions and ventricular volume.  Ann Neurol. 2002;  51 763-767
• 47 Frohman E M, Monson N L, Lovett-Racke A E, Racke M K. Autonomic regulation of neuroimmunological responses: implications for multiple sclerosis.  J Clin Immunol. 2001;  21 61-73
• 48 Cosentino M, Zaffaroni M, Marino F. et al . Catecholamine production and tyrosine hydroxylase expression in peripheral blood mononuclear cells from multiple sclerosis patients: effect of cell stimulation and possible relevance for activation-induced apoptosis.  J Neuroimmunol. 2002;  133 (1 - 2) 233-240
• 49 Flachenecker P, Reiners K H, Krauser M. et al . Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability.  Mult Scler. 2001;  7 324-327
• 50 Huitinga I, Erkut Z A, Beurden D Van, Swaab D F. The hypothalamo-pituitary-adrenal axis in multiple sclerosis.  Ann NY Acad Sci. 2003;  992 118-128
• 51 Then Bergh F, Grasser A, Trenkwalder C. et al . Binding characteristics of the glucocorticoid receptor in peripheral blood lymphocytes in multiple sclerosis.  J Neurol. 1999;  246 292-298
• 52 Correale J, Gilmore W, Li S. et al . Resistance to glucocorticoid-induced apoptosis in PLP peptide-specific T cell clones from patients with progressive MS.  J Neuroimmunol. 2000;  109 197-210
• 53 Winsen L van, Muris D, Dijkstra C, Polman C. Glucocorticoid sensitivity in patients with multiple sclerosis. Mult Scler ECTRIMS 2002 Poster P274
• 54 DeRijk R H, Eskandari F, Sternberg E M. Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production.  J Neuroimmunol. 2004;  151 (1 - 2) 180-188
• 55 Karaszewski J W, Reder A T, Maselli R. et al . Sympathetic skin responses are decreased and lymphocyte beta-adrenergic receptors are increased in progressive multiple sclerosis.  Ann Neurol. 1990;  27 366-372
• 56 Zoukos Y, Kidd D, Woodroofe M N. et al . Increased expression of high affinity IL-2 receptors and beta-adrenoceptors on peripheral blood mononuclear cells is associated with clinical and MRI activity in multiple sclerosis.  Brain. 1994;  117 (Pt 2) 307-315
• 57 Zoukos Y, Thomaides T N, Kidd D. et al . Expression of beta2 adrenoreceptors on peripheral blood mononuclear cells in patients with primary and secondary progressive multiple sclerosis: a longitudinal six month study.  J Neurol Neurosurg Psychiatry. 2003;  74 197-202
• 58 Heesen C, Gold S M, Sondermann J. et al . Oral terbutaline differentially affects cytokine (IL-10, IL-12, TNF, IFNγ) release in multiple sclerosis patients and controls.  J Neuroimmunol. 2002;  132 189-195
• 59 Giorelli M, Livrea P, Trojano M. Post-receptorial mechanisms underlie functional disregulation of beta2-adrenergic receptors in lymphocytes from Multiple Sclerosis patients.  J Neuroimmunol. 2004;  155 143-149
• 60 Frohman E M, Vayuvegula B, Noort S van den, Gupta S. Norepinephrine inhibits gamma-interferon-induced MHC class II (Ia) antigen expression on cultured brain astrocytes.  J Neuroimmunol. 1988;  17 89-101
• 61 Keyser J De, Wilczak N, Leta R, Streetland C. Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors.  Neurology. 1999;  53 1628-1633
• 62 Heesen C, Gold S M, Hartmann S. et al . Endocrine and cytokine response to standardized physical stress in patients with multiple sclerosis and healthy controls.  Brain Behav Immun. 2003;  17 473-481
• 63 Heesen C, Köhler G, Gross R. et al . Fatigue in multiple sclerosis: altered cardiovascular and cytokine responses to cognitive stress.  Mult Scler. 2005;  11 51-57
• 64 Heesen C, Schulz H, Schmidt M. et al . Endocrine and cytokine response to acute psychological stress in multiple sclerosis.  Brain Behav Immun. 2002;  16 282-287
• 65 Ackerman K D, Martino M, Heyman R. et al . Stressor-induced alteration of cytokine production in multiple sclerosis patients and controls.  Psychosom Med. 1998;  60 484-491
• 66 Fassbender K, Schmidt R, Mossner R. et al . Mood disorders and dysfunction of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: association with cerebral inflammation.  Arch Neurol. 1998;  55 66-72
• 67 Keyser J De, Zeinstra E, Wilczak N. Astrocytic beta2-adrenergic receptors and multiple sclerosis.  Neurobiol Dis. 2004;  15 331-339
• 68 Keyser J De, Zeinstra E, Mostert J, Wilczak N. Beta 2-adrenoceptor involvement in inflammatory demyelination and axonal degeneration in multiple sclerosis.  Trends Pharmacol Sci. 2004;  25 67-71
• 69 Kümpfel T, Then Bergh F, Friess E. et al . Dehydroepiandrosterone response to the adrenocorticotropin test and the combined dexamethasone and corticotropin-releasing hormone test in patients with multiple sclerosis.  Neuroendocrinology. 1999;  70 431-438
• 70 Huitinga I, Erkut Z A, Beurden D van, Swaab D F. Impaired hypothalamus-pituitary-adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions.  Ann Neurol. 2004;  55 37-45
• 71 Gold S M, Raji A, Huitinga I. et al .Hypothalamo-pituitary-adrenal axis hyperactivity predicts disease progression in multiple sclerosis. (zur Publikation eingereicht)
• 72 Pharoah P DP, Day N E, Duffy S. et al . Family history and the risk of breast cancer: A systemic review and meta-analysis.  Int J Cancer. 1997;  71 800-809
• 73 Arver B, Du Q, Chen J. et al . Hereditary breast cancer: A review.  Cancer Biol. 2000;  10 271-288
• 74 Claus E B, Schildkraut J M, Thompson W D, Risch N J. The genetic attributable risk of breast cancer and ovarian cancer.  Cancer. 1996;  77 2318-2324
• 75 Bovbjerg D H, Valdimarsdottir H B. Interventions for healthy individuals at familial risk for cancer. In: Baum A, Anderson BL (eds) Psychosocial interventions for cancer. Washington; American Psychological Association 2001: 305-320
• 76 Cohen M, Klein E, Kuten A. et al . Increased emotional distress in daughters of breast cancer patients is associated with decreased natural killer cytotoxic activity, elevated levels of stress hormones and decreased secretion of TH1 cytokines.  Int J Cancer. 2002;  100 347-354
• 77 Gold S M, Zakowski S G, Valdimarsdottir H B, Bovbjerg D H. Stronger endocrine responses after brief psychological stress in women at familial risk of breast cancer.  Psychoneuroendocrinology. 2003;  28 584-593
• 78 Kirschbaum C, Pirke K M, Hellhammer D K. The „Trier Social Stress Test” - a tool for investigating psychobiological stress responses in a laboratory setting.  Neuropsychobiology. 1993;  28 76-81
• 79 James G D, Berge-Landry H van, Valdimarsdottir H B. et al . Urinary catecholamine levels in daily life are elevated in women at familial risk of breast cancer.  Psychoneuroendocrinology. 2004;  29 831-838
• 80 Dettenborn L, James G D, Berge-Landry H van. et al .Heightened cortisol responses to daily stress in working women at familial risk for breast cancer. Biological Psychology (in press)
• 81 Valdimarsdottir H B, Zakowski S G, Gerin W. et al . Heightened psychobiological reactivity to laboratory stressors in healthy women at familial risk of breast cancer.  J Behav Med. 2002;  25 51-65
• 82 Bovbjerg D H, Valdimarsdottir H B. Familial cancer, emotional distress, and low natural cytotoxic activity in healthy women.  Ann Oncol. 1993;  4 745-752
• 83 Imai K, Matsuyama S, Miyake S. et al . Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population.  Lancet. 2000;  356 1795-1799
• 84 Gold S M. Acute endocrine stress reactivity and recovery in women at familial risk of breast cancer. Dissertation. Universität Hamburg; 2003 erhältlich unter http://www.sub.uni-hamburg.de/opus/volltexte/2003/1023/
• 85 Dallman M F. Stress by any other name.  Horm Behav. 2003;  43 18-20