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Aktuelle Rheumatologie 2021; 46(03): 267-280
DOI: 10.1055/a-1322-9936
Übersichtsarbeit

Wechselwirkungen zwischen neuroendokrinem System und Immunsystem bei chronisch-entzündlichen Systemerkrankungen

Crosstalk between the Neuroendocrine and Immune Systems in Chronic Inflammatory Systemic Diseases
Florian Günther
1   Klinik und Poliklinik für Rheumatologie/Klinische Immunologie, Asklepios Klinikum, Bad Abbach, Deutschland
,
Martin Fleck
1   Klinik und Poliklinik für Rheumatologie/Klinische Immunologie, Asklepios Klinikum, Bad Abbach, Deutschland
,
Rainer Straub
2   Internal Medicine, University Hospital Regensburg, Regensburg, Deutschland
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Zusammenfassung

Hormonelle und neuronale Signalwege können die Manifestation einer chronisch-entzündlichen Systemerkrankung entweder begünstigen oder verhindern. Bei bereits manifester Erkrankung modulieren Hormone und Neurotransmitter den Krankheitsverlauf, in dem sie die Krankheitsaktivität erhöhen oder abschwächen. Beispiele hierfür sind der entzündungshemmende Einfluss der körpereigenen und exogenen Glukokortikoide und die entzündungsfördernden Effekte von Stress bei chronisch-entzündlichen Systemerkrankungen. Bei chronisch-entzündlichen Systemerkrankungen ringt das aktivierte Immunsystem mit dem Gehirn und anderen Organsystemen um Energie, was zu vielfältigen Erkrankungsfolgen und Folgeerkrankungen führt: „sickness behaviour“ mit Fatigue-Symptomatik und depressiven Symptomen, Schlafstörungen, Anorexie, Fehl- und Mangelernährung, Knochenabbau, Muskelabbau und kachektische Fettsucht, Insulinresistenz mit Hyperinsulinämie (begleitet von einer Resistenz gegenüber dem Insulin-like growth factor 1), Dyslipidämie, Veränderungen der Steroidhormonachsen, Störungen der Hypothalamus-Hypophysen-Gonaden-Achse, erhöhter Sympathikotonus, herabgesetzte Aktivität des parasympathischen Nervensystems, arterielle Hypertonie und Volumenbelastung, Entzündungsanämie und zirkadiane Rhythmik der Symptomausprägung. Diese für die Patienten gravierenden Folgeerkrankungen, welche den chronisch-entzündlichen Systemerkrankungen inhärent sind, sollten konsequent therapiert werden.

Abstract

Hormonal and neuronal pathways either support or inhibit the manifestation of chronic inflammatory systemic diseases before the onset of the disease. After the onset of the disease, hormones and neurotransmitters may stimulate or inhibit the disease. Hormones and neurotransmitters modulate the course of the disease after disease onset. Examples are: 1) cortisol inhibits systemic chronic inflammatory disease, and 2) stress stimulates systemic chronic inflammatory disease. The active immune system in systemic chronic inflammatory diseases competes with the brain and other organ systems for energy-rich fuels, which leads to several disease sequelae. Chronic disease sequelae are sickness behaviour/fatigue/depressive symptoms, sleep disturbances, anorexia and malnutrition, bone loss, muscle wasting and cachectic obesity, insulin resistance with hyperinsulinaemia (accompanied by resistance to insulin-like growth factor–1), dyslipidaemia, alterations in the steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal (HPG) axis, elevated sympathetic tone, hypertension and volume overload, decreased parasympathetic tone, inflammation–related anaemia, and circadian rhythms of the symptoms. Disease sequelae are inherent to the disease and must be consistently treated.

Schlüsselwörter

Chronische Entzündungskrankheit - Hormone - Nervensysteme - Immunsystem - Energiehaushalt

Key words

Chronic inflammatory disease - hormones - nervous systems - immune system - energy regulation


Publication History

Article published online:
02 March 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 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
    PubMedGoogle Scholar
  • 2 Hench PS, Slocumb CH, Holley HF. et al. Effect of cortisone and pituitary adrenocorticotropic hormone (ACTH) on rheumatic diseases. J Am Med Assoc 1950; 1327-1335
    CrossrefPubMedGoogle Scholar
  • 3 Labrie F. Intracrinology. Mol Cell Endocrinol 1991; 78: C113-C118
    CrossrefPubMedGoogle Scholar
  • 4 Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007; 28: 521-574
    CrossrefPubMedGoogle Scholar
  • 5 Cutolo M, Straub RH. Sex steroids and autoimmune rheumatic diseases: state of the art. Nat Rev Rheumatol 2020; 16: 628-644
    CrossrefPubMedGoogle Scholar
  • 6 Whitacre CC. Sex differences in autoimmune disease. Nat Immunol 2001; 2: 777-780
    CrossrefPubMedGoogle Scholar
  • 7 Cohen-Solal JF, Jeganathan V, Hill L. et al. Hormonal regulation of B-cell function and systemic lupus erythematosus. Lupus 2008; 17: 528-532
    CrossrefPubMedGoogle Scholar
  • 8 Trigunaite A, Dimo J, Jorgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol 2015; 294: 87-94
    CrossrefPubMedGoogle Scholar
  • 9 Kissick HT, Sanda MG, Dunn LK. et al. Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation. Proc Natl Acad Sci U S A 2014; 111: 9887-9892
    CrossrefPubMedGoogle Scholar
  • 10 Carlsten H, Nilsson N, Jonsson R. et al. Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice. Cell Immunol 1992; 144: 190-202
    CrossrefPubMedGoogle Scholar
  • 11 Stark K, Straub RH, Rovensky J. et al. CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women. Arthritis Res Ther 2015; 17: 56
    CrossrefPubMedGoogle Scholar
  • 12 Uthman I, Senecal JL. Onset of rheumatoid arthritis after surgical treatment of Cushing’s disease. J Rheumatol 1995; 22: 1964-1966
    PubMedGoogle Scholar
  • 13 Sternberg EM, Young WS, Bernardini R. et al. A central nervous system defect in biosynthesis of corticotropin- releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc Natl Acad Sci U S A 1989; 86: 4771-4775
    CrossrefPubMedGoogle Scholar
  • 14 Straub RH, Bijlsma JW, Masi A. et al. Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases-The 10-year update. Semin Arthritis Rheum 2013; 43: 392-404
    CrossrefPubMedGoogle Scholar
  • 15 Carsin-Vu A, Oubaya N, Mulé S. et al. MDCT Linear and Volumetric Analysis of Adrenal Glands: Normative Data and Multiparametric Assessment. Eur Radiol 2016; 26: 2494-2501
    CrossrefPubMedGoogle Scholar
  • 16 Thompson M, Bywaters EGL. Unilateral rheumatoid arthritis following hemiplegia. Ann Rheum Dis 1962; 21: 370-370
    CrossrefPubMedGoogle Scholar
  • 17 Dolan AL. Asymmetric rheumatoid vasculitis in a hemiplegic patient. Ann Rheum Dis 1995; 54: 532
    CrossrefPubMedGoogle Scholar
  • 18 Glynn JJ, Clayton ML. Sparing effect of hemiplegia on tophaceous gout. Ann Rheum Dis 1976; 35: 534-535
    CrossrefPubMedGoogle Scholar
  • 19 Sethi S, Sequeira W. Sparing effect of hemiplegia on scleroderma. Ann Rheum Dis 1990; 49: 999-1000
    CrossrefPubMedGoogle Scholar
  • 20 Pongratz G, Straub RH. Role of peripheral nerve fibres in acute and chronic inflammation in arthritis. Nat Rev Rheumatol 2013; 9: 117-126
    CrossrefPubMedGoogle Scholar
  • 21 Neufeld KM, Karunanayake CP, Maenz LY. et al. Stressful life events antedating chronic childhood arthritis. J Rheumatol 2013; 40: 1756-1765
    CrossrefPubMedGoogle Scholar
  • 22 Straub RH. The origin of chronic inflammatory systemic diseases and their sequelae. Hrsg San Diego: Academic Press; 2015
    Google Scholar
  • 23 Lee YC, Agnew-Blais J, Malspeis S. et al. Post-Traumatic Stress Disorder and Risk for Incident Rheumatoid Arthritis. Arthritis Care Res 2016; 68: 292-298
    CrossrefPubMedGoogle Scholar
  • 24 Buttgereit F. Views on glucocorticoid therapy in rheumatology: the age of convergence. Nat Rev Rheumatol 2020; 16: 239-246
    CrossrefPubMedGoogle Scholar
  • 25 Saldanha C, Tougas G, Grace E. Evidence for anti-inflammatory effect of normal circulating plasma cortisol. Clin Exp Rheumatol 1986; 4: 365-366
    PubMedGoogle Scholar
  • 26 Doria A, Iaccarino L, Arienti S. et al. Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases. Reprod Toxicol 2006; 22: 234-241
    CrossrefPubMedGoogle Scholar
  • 27 Dhabhar FS. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 2014; 58: 193-210
    CrossrefPubMedGoogle Scholar
  • 28 Buttgereit F, Burmester GR, Straub RH. et al. Exogenous and endogenous glucocorticoids in rheumatic diseases. Arthritis Rheum 2011; 63: 1-9
    CrossrefPubMedGoogle Scholar
  • 29 Huong DL, Wechsler B, Vauthier-Brouzes D. et al. Importance of planning ovulation induction therapy in systemic lupus erythematosus and antiphospholipid syndrome: a single center retrospective study of 21 cases and 114 cycles. Semin Arthritis Rheum 2002; 32: 174-188
    CrossrefPubMedGoogle Scholar
  • 30 Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum 2007; 56: 399-408
    CrossrefPubMedGoogle Scholar
  • 31 Buttgereit F, Doering G, Schaeffler A. et al. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet 2008; 371: 205-214
    CrossrefPubMedGoogle Scholar
  • 32 Buttgereit F, Mehta D, Kirwan J. et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis 2013; 72: 204-210
    CrossrefPubMedGoogle Scholar
  • 33 Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008; 4: 80-90
    CrossrefPubMedGoogle Scholar
  • 34 Cutolo M, Plebani M, Shoenfeld Y. et al. Vitamin D endocrine system and the immune response in rheumatic diseases. Vitam Horm 2011; 86: 327-351
    CrossrefPubMedGoogle Scholar
  • 35 Cutolo M, Otsa K, Laas K. et al. Circannual vitamin d serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin Exp Rheumatol 2006; 24: 702-704
    PubMedGoogle Scholar
  • 36 Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med 2010; 88: 441-450
    CrossrefPubMedGoogle Scholar
  • 37 Smith RD. Effect of hemiparesis on rheumatoid arthritis. Arthritis Rheum 1979; 22: 1419-1420
    CrossrefPubMedGoogle Scholar
  • 38 Keyszer G, Langer T, Kornhuber M. et al. Neurovascular mechanisms as a possible cause of remission of rheumatoid arthritis in hemiparetic limbs. Ann Rheum Dis 2004; 63: 1349-1351
    CrossrefPubMedGoogle Scholar
  • 39 Kane D, Lockhart JC, Balint PV. et al. Protective effect of sensory denervation in inflammatory arthritis (evidence of regulatory neuroimmune pathways in the arthritic joint). Ann Rheum Dis 2005; 64: 325-327
    CrossrefPubMedGoogle Scholar
  • 40 Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun 2007; 21: 901-912
    CrossrefPubMedGoogle Scholar
  • 41 Bierhaus A, Wolf J, Andrassy M. et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci U S A 2003; 100: 1920-1925
    CrossrefPubMedGoogle Scholar
  • 42 Straub RH. Rheumatoid arthritis: Stress in RA: a trigger of proinflammatory pathways?. Nat Rev Rheumatol 2014; 10: 516-518
    CrossrefPubMedGoogle Scholar
  • 43 Vasamsetti SB, Florentin J, Coppin E. et al. Sympathetic Neuronal Activation Triggers Myeloid Progenitor Proliferation and Differentiation. Immunity 2018; 49: 93-106
    CrossrefPubMedGoogle Scholar
  • 44 Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 2005; 5: 243-251
    CrossrefPubMedGoogle Scholar
  • 45 de Brouwer SJ, Van MH, Stormink C. et al. Immune responses to stress in rheumatoid arthritis and psoriasis. Rheumatology (Oxford) 2014; 53: 1844-1848
    CrossrefPubMedGoogle Scholar
  • 46 Okada Y, Wu D, Trynka G. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014; 506: 376-381
    CrossrefPubMedGoogle Scholar
  • 47 Vereecke L, Beyaert R, van Loo G. The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol 2009; 30: 383-391
    CrossrefPubMedGoogle Scholar
  • 48 Straub RH, Cutolo M, Buttgereit F. et al. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 2010; 267: 543-560
    CrossrefPubMedGoogle Scholar
  • 49 Straub RH. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Res Ther 2014; 16: S4 (pages 1–15)
    CrossrefPubMedGoogle Scholar
  • 50 Straub RH. The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat Rev Rheumatol 2017; 13: 743-751
    CrossrefPubMedGoogle Scholar
  • 51 Dantzer R, O'Connor JC, Freund GG. et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56
    CrossrefPubMedGoogle Scholar
  • 52 Detert J, Dziurla R, Hoff P. et al. Effects of treatment with etanercept versus methotrexate on sleep quality, fatigue and selected immune parameters in patients with active rheumatoid arthritis. Clin Exp Rheumatol 2016; 34: 848-856
    PubMedGoogle Scholar
  • 53 Straub RH, Cutolo M, Pacifici M. Evolutionary medicine and bone loss in chronic inflammatory diseases – a theory of inflammation-related osteopenia. Semin Arthritis Rheum 2015; 45: 220-228
    CrossrefPubMedGoogle Scholar
  • 54 Roubenoff R. Rheumatoid cachexia: a complication of rheumatoid arthritis moves into the 21st century. Arthritis Res Ther 2009; 11: 108
    CrossrefPubMedGoogle Scholar
  • 55 Hahn BH, Grossman J, Ansell BJ. et al. Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther 2008; 10: 213
    CrossrefPubMedGoogle Scholar
  • 56 Tsigos C, Papanicolaou DA, Defensor R. et al. Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology 1997; 66: 54-62
    CrossrefPubMedGoogle Scholar
  • 57 Cutolo M, Foppiani L, Prete C. et al. Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids. J Rheumatol 1999; 26: 282-288
    PubMedGoogle Scholar
  • 58 Kanik KS, Chrousos GP, Schumacher HR. et al. Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset synovitis/rheumatoid arthritis: relations with indices of inflammation. J Clin Endocrinol Metab 2000; 85: 1461-1466
    PubMedGoogle Scholar
  • 59 Straub RH, Paimela L, Peltomaa R. et al. Inadequately low serum levels of steroid hormones in relation to IL-6 and TNF in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum 2002; 46: 654-662
    CrossrefPubMedGoogle Scholar
  • 60 Wolff C, Krinner K, Schroeder JA. et al. Inadequate corticosterone levels relative to arthritic inflammation are accompanied by altered mitochondria/cholesterol breakdown in adrenal cortex: a steroid-inhibiting role of IL-1beta in rats. Ann Rheum Dis 2015; 74: 1890-1897
    CrossrefPubMedGoogle Scholar
  • 61 Stangl H, Krammetsvogl A, Lesiak M. et al. MHC/class-II-positive cells inhibit corticosterone of adrenal gland cells in experimental arthritis: a role for IL-1β, IL-18, and the inflammasome. Sci Rep 2020; 10: 17071 doi: 17010.11038/s41598-17020-74309-17070
    CrossrefPubMedGoogle Scholar
  • 62 Weidler C, Struharova S, Schmidt M. et al. Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency. Arthritis Rheum 2005; 52: 1721-1729
    CrossrefPubMedGoogle Scholar
  • 63 Schmidt M, Hartung R, Capellino S. et al. Estrone/17beta-estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis. Arthritis Rheum 2009; 60: 2913-2922
    CrossrefPubMedGoogle Scholar
  • 64 Straub RH. Evolutionary medicine and chronic inflammatory state – known and new concepts in pathophysiology. J Mol Med 2012; 90: 523-534
    CrossrefPubMedGoogle Scholar
  • 65 Straub RH, Ehrenstein B, Gunther F. et al. Increased extracellular water measured by bioimpedance and by increased serum levels of atrial natriuretic peptide in RA patients-signs of volume overload. Clin Rheumatol 2017; 36: 1041-1051
    CrossrefPubMedGoogle Scholar
  • 66 Günther F, Ehrenstein B, Hartung W. et al. Increased extracellular water measured by bioimpedance analysis and increased serum levels of atrial natriuretic peptide in polymyalgia rheumatica patients : Signs of volume overload. Z Rheumatol 2020; DOI: 10.1007/s00393-00020-00845-00399.
    CrossrefPubMedGoogle Scholar
  • 67 Sloan RP, McCreath H, Tracey KJ. et al. RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol Med 2007; 13: 178-184
    CrossrefPubMedGoogle Scholar
  • 68 Weinberg ED. Iron availability and infection. Biochim Biophys Acta 2009; 1790: 600-605
    CrossrefPubMedGoogle Scholar
  • 69 Schaible UE, Kaufmann SH. Iron and microbial infection. Nat Rev Microbiol 2004; 2: 946-953
    CrossrefPubMedGoogle Scholar
  • 70 Crofford LJ, Kalogeras KT, Mastorakos G. et al. Circadian relationships between interleukin (IL)-6 and hypothalamic- pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab 1997; 82: 1279-1283
    CrossrefPubMedGoogle Scholar