Dear reader of ADxS.org, please excuse the disruption.

ADxS.org needs about $63500 in 2024. In 2023 we received donations of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 23,000 times a week, but only 75 people donate. If you find ADxS.org useful, please take a minute and support ADxS.org with your donation. Thank you!

Since 01.06.2021 ADxS.org is supported by the non-profit ADxS e.V..

$21963 of $63500 - as of 2024-05-31
34%
Header Image
The immune system

Sitemap

The immune system

The immune system consists of various elements: The cellular and humoral immune system, the complement system, the innate non-specific immune response and the adaptive specific (formerly: acquired) immune response.
The cellular immune system consists of cells such as macrophages, dendritic cells and natural killer cells, while the humoral immune system consists of non-cellular components of body fluids.
The complement system consists of proteins in the blood that help fight pathogens.
The innate immune response is rapid and non-specific and is mediated by cells such as macrophages and natural killer cells.
The acquired immune response is specific and is mediated by B and T lymphocytes.

Glucocorticoids can influence the immune response by modulating the production of cytokines. In this way, severe or prolonged stress can lead to an imbalance in the immune response and increase susceptibility to certain diseases. Glucocorticoids are also thought to influence the TH1/TH2 shift, which is important for the balance between inflammatory responses and immune defense.
A high or low cortisol stress response can have different effects on cytokine responses in the body. A higher cortisol stress response has been associated with a lower cytokine response in some cases and a higher cytokine response in others.

1. The immune system

The following brief description of the immune system is essentially based on Wolf.1

The immune system consists of several different elements that complement and overlap each other, just like the stress systems do in relation to stress.

1.1. Cellular / humoral immune response

The cellular immune response is the part of the immune response of the adaptive immune system mediated by cytotoxic cells. These include macrophages, granulocytes, dendritic cells and natural killer cells.
The cellular immune system primarily mediates TH-1 immune responses, which are active during acute inflammation.2

The humoral immune response (humor = moisture, sap, fluid) is the immune response mediated by non-cellular components of body fluids. These include cytokines, chemokines and the complement system.
The humoral immune system primarily mediates TH-2 immune responses, which are active in chronic inflammation and allergies.2

1.2. Complement system

The complement system consists of around 30 glycoproteins that are found in the blood. When one of these binds to a pathogen, a cascade of enzyme reactions occurs, through which the proteins activate each other, which can help to combat the pathogen.3

The complement system consists of plasma proteins and proteolytic enzymes and can inactivate and destroy bacteria and viruses by means of lysis, opsonization or local inflammatory reactions.

Positive regulators:

  • C1 to C9
  • Mannose-binding lectin (MBL)
  • Serine proteases C1r, C1s, MASP-1 to 3

Many other proteins and protein complexes are formed from parts of C1 to C5 and (by means of protease-mediated cleavage) and assemblies with C6 to C9, e.g:

  • C3a
  • C5a
  • C4a
  • Membrane attack complex

Negative regulators:

  • C1 inhibitor
  • Factor H
  • Factor I
  • C4bp
  • CD35
  • CD46
  • CD55
  • CD59
  • Vitronectin

Activators:

  • Properdin
  • Cobra Venom Factor.

1.3. Innate immune response

The innate immune response (macrophages, dendritic cells, natural killer cells, neutrophil, basophil and eosinophil granulocytes) is rapid and non-specific.
Macrophages recognize pathogens based on the proteins on their surface and break them down by phagocytosis. The macrophages then present the resulting antigens on their surface, which activates cells of the acquired immune defense. The activated macrophages release cytokines. Cytokines are chemical messengers that trigger local inflammatory reactions.
Like macrophages, dendritic cells represent antigens and mediate between innate and acquired immune defense via activated B and T lymphocytes.
Natural killer cells (NK) can recognize virus-infected or degenerated cells. NK are activated by a complex receptor system and cause apoptosis (cell death) of the target cell by releasing various cytotoxins.

1.4. Adaptive (specific, acquired) immune response

The adaptive immune response (B and T lymphocytes and the resulting TH cells) is slower, but more effective. The adaptive immune response uses antigen-specific effector cells and memory cells to store successfully formed immune responses so that they can be called up more quickly when they are needed again. Vaccination makes use of this principle.

B lymphocytes (bone) develop from hematopoietic stem cells of the bone marrow. They develop into memory cells or antibody-producing plasma cells. They produce antigen-specific antibodies (= immunoglobulins, Ig) with or without contact with T helper cells (Th cells).
Regulatory B cells suppress the immune system.

T lymphocytes develop in the fetal liver and bone marrow and migrate with the blood to the thymus, where they mature. Through recombination of gene segments, they form specific receptors for various antigens.
Lymphocytes produce cellular glycoproteins, the “clusters of differentiation”, on their surface. Depending on the type of these glycoproteins, T lymphocytes develop into different types of T helper cells (Th cells).
The mature (still antigen-naïve = not yet specialized in certain antigens) TH cells migrate from the thymus into the lymphatic tissue (lymph follicles, lymph nodes, spleen) where they are presented with antigens by B lymphocytes, dendritic cells or macrophages, causing them to specialize in these antigens (differentiation).

1.5. Surface marker

The cells of the immune system differ according to surface markers:4

  • CD4+: TH-1 (T inducer cells)
  • CD8+: TH-2 (T-suppressor cells)
  • CD14+: monocytes, macrophages
  • CD16+, CD56+: NK cells
  • CD5+, CD19+: B lymphocytes
  • CD3+: T lymphocytes
  • CD45+: T memory cells

1.6. Receptor classes

In order to protect the body’s own cells from the immune response, the antigen-presenting cells use different classes of receptors for antigen presentation to the TH cells. There are 3 receptor classes: CD4+ TH cells only bind to antigens presented by MHC-II, CD8+ TCH cells only bind to antigens presented by MHC I. The MHC III complexes include the complement factors C2, C4 and Bf, as well as various cytokines, e.g. tumor necrosis factor (TNF). MHC III are plasma proteins that are involved in the non-specific immune defense.

1.7. T helper cells (TH cells)

TH-0 cells are TH cells that have not yet had antigen contact. Depending on the type of antigen presented to them by the antigen-presenting cells, they develop (primarily) into TH-1 or TH-2 cells.

TH-1 cells are activated during acute inflammation42 and secrete cytokines such as IFN-γ, IL-2 and TNF-α, which activates and differentiates macrophages. Macrophages (and dendritic cells) release IL-12, which in turn promotes the formation of TH-1 cells from naïve TH-0 cells.
IL-12 and IFN-γ inhibit TH-2 cell formation.

TH-2-CD4-positive cells are activated during chronic inflammation and allergic reactions42 and interact with B lymphocytes by means of cytokines and cell-bound molecules. The B lymphocytes then produce antibodies.
Type 2 CD4-positive cells thereby promote the production of IL-4, IL-5, IL-6, IL-10, IL-13 and lymphotoxin-α.
IL-4 and IL-10 inhibit macrophage activation and thus TH-1 cell formation.

TH-1 cells and TH-2 cells therefore inhibit each other.
The immune system is normally in a functional balance between a TH-1 and a TH-2 emphasis.42 Cortisol inhibits TH-1 and promotes TH-2, while growth hormone oppositely promotes TH-2 and inhibits TH-1. Cortisol and growth hormone are subject to a staggered daily rhythm and are thus likely to modulate the regular TH-1/TH-2 alternation. If the stress systems constantly release too much or too little cortisol, this stress imbalance causes disorders of the immune system.15

TH-17 cells develop from T helper cells after their activation by antigen contact using IL-6 and TGF-β. TH-17 cells need IL-23 to survive. IL-23 is involved in the development of autoimmune diseases.
TH17 cells produce IL-17A to IL17F, TNF-α and IL-6 and inhibit TH-1 cells.

Natural regulatory T cells (nTreg) account for up to 10 % of peripheral CD4-positive T lymphocytes. They have pronounced immunomodulatory properties and support the maintenance of self-tolerance by limiting excessive attacks on intact body cells. They inhibit dendritic cells, natural killer cells, CD4+, CD8+ cells and B lymphocytes. They are involved in various autoimmune diseases.
nTreg promote the production of CD25.

IL-12 - together with IL-18 - enhance the production of IFN-γ by natural killer (NK) cells. IL-12 together with IL-18, IFN-α and IFN-γ promote the differentiation of naïve TH cells into TH-1 cells.5

Stress and glucocorticoids have direct reciprocal effects on the immune system. Stress influences certain cytokines, cytokines influence glucocorticoids and glucocorticoids influence cytokines.

2. Stress and the immune system

2.1. Cytokine reactions and cortisol stress response in healthy individuals

One study found that healthy people with a low cortisol stress response to mild stress showed higher stress responses of IL-6 and IL-1ra in the blood than those with a high cortisol stress response. At the same time, subjects with a low cortisol stress response showed lower heart rate variability, indicating poorer stress processing by the autonomic nervous system.6 This correlates with the results of another study in healthy subjects, according to which a lower cortisol stress response correlated with a prolonged IL-6 stress response.7 In contrast, a further study on healthy individuals found a tendency for an increased IL-6 stress response to be associated with an increased cortisol stress response.3

2.2. Cytokine reactions and cortisol stress response in mental disorders

A smaller study on depressed people found a positive correlation between IL-6 stress response and cortisol stress response and no correlation in healthy people.8
In fatigue, a reduction in IL-6 and TNF-alpha was found in response to stress, while healthy people showed an increase as a stress response. In fatigue, ACTH and salivary cortisol levels were also lower overall, while blood cortisol was only basally lower. This showed a negative correlation of the IL-6 and TNF-alpha stress response to the cortisol stress response in fatigue, compared to a positive correlation in healthy individuals.9

A study on psoriasis sufferers found a correlation between the immune and cytokine stress response (lymphocytes, granulocytes, CD3+, CD8+, CD16+/CD56+, CD3+/HLA-DR+) and the cortisol stress response to the TSST.10

Increased ACTH and cortisol stress responses correlated positively with increased granulocytes and natural killer cells and negatively with B lymphocytes. Furthermore, the response to TSST in psoriasis sufferers and healthy individuals showed10

  • CD4+ cells increased
    • CD4+ cells typically trigger elevated levels of
      • IL-2
      • IFN-gamma
      • TNF-alpha from.
  • CD25+ cells reduced, but only in psoriasis sufferers, not in healthy people
  • IFN-gamma significantly increased
  • IL-2 significantly increased
  • IL-10 significantly reduced
  • IL-4 significantly reduced

In acutely depressed people (unlike healthy people), there was a positive correlation between the stress responses of cortisol and IL-6 and between the stress responses of adrenaline, TNF-α and CRP. Healthy individuals only showed a significant correlation between ACTH and CRP stress responses.8
In contrast, no correlation was found between the stress responses of cortisol on the one hand and cytokines on the other (IL-6, TNF-α, IL-10) in both non-depressed and remitted (healthy former) depressives.3

Increased chronic stress levels correlated with increased basal blood levels of IL-6 and IL-10, but not with TNF-α, in both remitted depressives and healthy individuals. Remitted depressives had higher chronic stress levels and consequently higher basal IL-6 and IL-10 levels than non-depressives.3

The subjective perception of acute stress correlated with elevated basal blood levels of IL-6, but not of TNF-α and IL-10.3 IL-10 levels were significantly elevated during the anticipation of a stress test (TSST) in subjects with a high cortisol stress response.3

TNF-α did not differ in the stress anticipation phase or in the stress response between subjects with a high and a low cortisol stress response.3

Chronic and prolonged elevation of cortisol levels can lead to decreased HPA axis activity as a result of persistent negative feedback from the HPA axis, which triggers increased neuroinflammation and impaired cognitive function.11

While the magnitude of the cortisol stress response to an emotionally stressful movie showed no correlation to subsequent cognitive control/performance in the Stroop test, this was more strongly affected by higher stress-induced increases in the proinflammatory cytokines IL-1β, IL-6, and IL-8 than by weaker increases.12

Adrenaline and noradrenaline (which are also part of the endocrine stress response) also cause a TH1/TH-2 shift.1314

2.3. Glucocorticoids and the immune system

The reaction to glucocorticoids is only part of the stress response. Moreover, glucocorticoids are essentially only released at the end of the stress response by the 3rd stage of the HPA axis.

The stress response of some cytokines correlates with the level of the cortisol stress response, while others do not. ADHD-HI is often associated with a flattened cortisol stress response, ADHD-I very often with an excessive cortisol stress response.

In the response to antigens, the highest increase in antibodies coincides with a simultaneous increase in glucocorticoids (by a factor of 2 to 3) and the highest activity of the stress hormone-producing cells of the hypothalamus.4 IL-1 causes an immediate release of ACTH and cortisol (unlike IL-2, INF-gamma and TNF-alpha). Cortisol in turn inhibits IL-1 synthesis.15 The immune response thus appears to differ from the stress response, in which glucocorticoids are only released with a time delay at the end of the HPA axis.
In addition, lymphocytes directly produce endocrine hormones such as ACTH, beta-endorphins, TSH, GH and prolactin.4

2.1.1. Activating effect of glucocorticoids

Glucocorticoids increase the production or release of

  • IL-
    • Even small amounts of dexamethasone increase the endotoxin-induced amount of IL-1β by macrophages16
  • IL-4
    • By inhibiting IL-12, which reduces its IL-4-inhibiting effect1718 Against this background, the authors warn against the long-term use of glucocorticoids for allergies, as they exacerbate allergy problems.
    • By stimulating the production of IL-4 by TH-2 cells19
    • Study results are contradictory, see below
  • IL-10
    • By stimulating the production of IL-10 by TH-2 cells19
  • IL-13
    • By stimulating the production of IL-13 by TH-2 cells19
  • IL-18
    • Cushing’s patients with high cortisol levels also have high IL-18 levels5

2.1.2. Inhibitory effect of glucocorticoids

Glucocorticoids reduce the production or release of

  • IFN-α by 50 to 60 %5
  • IFN-γ5
    • By suppressing IL-12 production in antigen-presenting cells
    • By reducing the IL-12 receptor sensitivity of natural killer cells and TH-1 cells
  • IL-1-Beta
    • By reducing the transcription rate of the genes of these interleukins and reducing the stability of their mRNA20
  • IL-25
  • IL-421 (study results are contradictory, see above)
  • IL-521
  • IL-620
    • On the other hand, maternal stress, which causes damage to the unborn child, is mediated by IL-6. The defective development of GABAergic cells in the unborn child caused by prenatal stress in the mother can be prevented by IL-6 antagonists.22
    • Cortisol can increase the expression of IL-6 receptors in liver cells and induce IL-6-mediated production of acute phase proteins (APP).23
    • Noradrenaline, which (like cortisol) is part of the endocrine stress response, stimulates the expression of IL-6 mRNA and the production of IL-6 in astrocytes via β2 and α1 adrenoceptors in a dose-dependent manner.24 Since the release of noradrenaline occurs before the activation of the HPA axis, the inhibition of IL-6 by cortisol could represent a negative feedback loop, comparable to the inhibition of the HPA axis after a stress response.
  • IL-1217
    • Which increases IL-10 production5
    • Catecholamines also mediate a reduction in IL-12 over several days via β2-adrenoceptors.25
    • Asthma therapy with glucocorticoid and / or β2-AR agonists probably reduces
      • The ability of the antigen-presenting cells to17
        • To produce IL-12
        • Suppress type 2 cytokine synthesis in activated TH cells and
        • To combat eosinophilia.
      • As a result, these antigen-presenting cells activate naive (non-cytokine-bound) T cells, whereby
        • IL-4 is increased
        • IFN-γ is restricted
      • As a result, glucocorticoids and β2-AR agonists are only beneficial for asthma in the short term. In the long term, they can increase susceptibility to allergic diseases. This is confirmed by the fact that glucocorticoids such as β2-AR agonists potentiate IgE production. 52627
  • The expression of IL-12 receptors on T cells and NK28
  • IL-1321
  • IL-18, even if not complete5
  • TNF5
  • TGF-β-1 in glial cells (on dexamethasone)29
  • Histamine
    • The histamine production of mast cells is reduced by means of β2-adrenoceptors. Catecholamines have the same effect.5
      It is assumed that reduced cortisol levels due to increased histamine levels cause asthmatics to wheeze at night.
      Histamine enhances the TH-1/TH-2 shift via H2 receptors.5
  • GM-CSF (granulocyte macrophage colony-stimulating factor)21

  1. Wolf (2012): Die regulatorische Rolle von Cortisol und Wachstumshormon auf die Zytokinproduktion humaner T-Lymphozyten und die TH-1/TH2-Balance; Dissertation

  2. Müller, Schwarz (2007): Immunologische Aspekte bei depressiven Störungen, Nervenarzt 2007 · 78:1261–1273 DOI 10.1007/s00115-007-2311-3

  3. Poidinger (2015): Immunparameter bei remittiert depressiven und gesunden Probanden unter Berücksichtigung der Reaktion auf die Exposition mit psychosozialen Stressoren. Dissertation, n = 71

  4. Müller: Psychoneuroimmunologische Grundlagen psychischer Erkrankungen, in: Möller, Laux, Kapfhammer (Hrsg.) (2017): Psychiatrie, Psychosomatik, Psychotherapie, Band 1, 5. Auflage, Kapitel 11, S. 291 – 310

  5. Elenkov (2004): Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004 Jun;1024:138-46.

  6. Kunz-Ebrecht, Mohamed-Ali, Feldman, Kirschbaum, Steptoe (2003): Cortisol responses to mild psychological stress are inversely associated with proinflammatory cytokines, Brain, Behavior, and Immunity, Volume 17, Issue 5, 2003, Pages 373-383, ISSN 0889-1591, https://doi.org/10.1016/S0889-1591(03)00029-1. n = 199

  7. Izawa, Sugaya, Kimura, Ogawa, Yamada, Shirotsuki, Mikami, Hirata, Nagano, Nomura (2013): An increase in salivary interleukin-6 level following acute psychosocial stress and its biological correlates in healthy young adults, Biological Psychology, Volume 94, Issue 2, 2013, Pages 249-254, ISSN 0301-0511, https://doi.org/10.1016/j.biopsycho.2013.06.006. n = 50

  8. Weinstein, Deuster, Francis, Bonsall, Tracy, Kop (2010): Neurohormonal and inflammatory hyper-responsiveness to acute mental stress in depression, Biological Psychology, Volume 84, Issue 2, 2010, Pages 228-234, ISSN 0301-0511, https://doi.org/10.1016/j.biopsycho.2010.01.016. n = 28

  9. Gaab, Rohleder, Heitz, Engert, Schad, Schürmeyer, Ehlert (2005): Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome, Psychoneuroendocrinology, Volume 30, Issue 2, 2005, Pages 188-198, ISSN 0306-4530, https://doi.org/10.1016/j.psyneuen.2004.06.008.

  10. Buske-Kirschbaum, Kern, Ebrecht, Hellhammer (2007): Altered distribution of leukocyte subsets and cytokine production in response to acute psychosocial stress in patients with psoriasis vulgaris, Brain, Behavior, and Immunity, Volume 21, Issue 1, 2007, Pages 92-99, ISSN 0889-1591, https://doi.org/10.1016/j.bbi.2006.03.006. n = 48

  11. Verlaet, Noriega, Hermans, Savelkoul (2014): Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014 Jul;23(7):519-29. doi: 10.1007/s00787-014-0522-2.

  12. Shields, Kuchenbecker, Pressman, Sumida, Slavich (2016): Better cognitive control of emotional information is associated with reduced pro-inflammatory cytokine reactivity to emotional stress. Stress. 2016;19(1):63-8. doi: 10.3109/10253890.2015.1121983.

  13. Elenkov, Chrousos (1999): Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease, Trends in Endocrinology & Metabolism, Volume 10, Issue 9, 1999, Pages 359-368, ISSN 1043-2760, https://doi.org/10.1016/S1043-2760(99)00188-5.

  14. Elenkov, Wilder, Chrousos, Vizi (2000): The Sympathetic Nerve – An Integrative Interface between Two Supersystems: The Brain and the Immune System. Pharmacological Reviews December 2000, 52 (4) 595-638

  15. Besedovsky, del Rey, Sorkin, Dinarello (1986): Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 08 Aug 1986: Vol. 233, Issue 4764, pp. 652-654, DOI: 10.1126/science.3014662

  16. Brough-Holub, Kraal (1996): Dose‐ and time‐dependent activation of rat alveolar macrophages by glucocorticoids. Clinical & Experimental Immunology, 104: 332-336. doi:10.1046/j.1365-2249.1996.29733.x

  17. DeKruyff, Fang, Umetsu (1998): Corticosteroids Enhance the Capacity of Macrophages to Induce Th2 Cytokine Synthesis in CD4+ Lymphocytes by Inhibiting IL-12 Production. J Immunol March 1, 1998, 160 (5) 2231-2237

  18. Blotta, DeKruyff, Umetsu (1997): Corticosteroids inhibit IL-12 production in human monocytes and enhance their capacity to induce IL-4 synthesis in CD4+ lymphocytes. J Immunol June 15, 1997, 158 (12) 5589-5595

  19. Ramírez, Fowell, Puklavec, Simmonds, Mason (1996): Glucocorticoids promote a TH2 cytokine response by CD4+ T cells in vitro. J Immunol April 1, 1996, 156 (7) 2406-2412

  20. Chrousos (1995): The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995 May 18;332(20):1351-62.

  21. Jee, Gilmour, Kelly, Bowen, Richards, Soh, Smith, Hawrylowicz, Cousins, Lee, Lavender (2005): Repression of Interleukin-5 Transcription by the Glucocorticoid Receptor Targets GATA3 Signaling and Involves Histone Deacetylase Recruitment. J. Biol. Chem. 2005 280: 23243-. doi:10.1074/jbc.M503659200

  22. Gumusoglu, Fine, Murray, Bittle, Stevens (1995): The role of IL-6 in neurodevelopment after prenatal stress. Brain Behav Immun. 2017 Oct;65:274-283. doi: 10.1016/j.bbi.2017.05.015.

  23. Jain, Gautam, Naseem (2011): Acute-phase proteins: As diagnostic tool. J Pharm Bioallied Sci. 2011 Jan-Mar; 3(1): 118–127. doi: 10.4103/0975-7406.76489 PMCID: PMC3053509 PMID: 21430962

  24. Norris, Benveniste (1993): Interleukin-6 production by astrocytes: Induction by the neurotransmitter norepinephrine, Journal of Neuroimmunology, Volume 45, Issues 1–2, 1993, Pages 137-145, ISSN 0165-5728, https://doi.org/10.1016/0165-5728(93)90174-W.

  25. Elenkov, Papanicolaou , Wilder, Chrousos (1996): Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proceedings of the Association of American Physicians, 01 Sep 1996, 108(5):374-381. PMID:8902882

  26. Zieg, Lack, Harbeck, Gelfand, Leung (1994): In vivo effects of glucocorticoids on IgE production. Journal of Allergy and Clinical Immunology, Volume 94, Issue 2, Part 1, 1994, Pages 222-230, ISSN 0091-6749, https://doi.org/10.1053/ai.1994.v94.a54936.

  27. Coqueret, Lagente, Frere, Braquet, Mencia-Huerta (1994): Regulation of IgE Production by β2‐Adrenoceptor Agonists. Annals of the New York Academy of Sciences, 725: 44-49. doi:10.1111/j.1749-6632.1994.tb39788.x

  28. Wu, Wang, McDyer, Seder (1998): Prostaglandin E2 and Dexamethasone Inhibit IL-12 Receptor Expression and IL-12 Responsiveness; J Immunol September 15, 1998, 161 (6) 2723-2730

  29. Batuman, Ferrero, Cupp, Jimenez, Khalili (1995): Differential regulation of transforming growth factor beta-1 gene expression by glucocorticoids in human T and glial cells. J Immunol November 1, 1995, 155 (9) 4397-4405

Diese Seite wurde am 15.02.2024 zuletzt aktualisiert.