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The immune system

The immune system

1. The immune system

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

The immune system is made up of several different elements that complement and overlap each other, just as 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 mediates primarily TH-1 immune responses, which is active during acute inflammation.2

The humoral immune response (humor = moisture, juice, 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 mediates primarily TH-2 immune responses, which is active in chronic inflammation and allergy.2

1.2. Complement system

The complement system consists of about 30 glycoproteins found in the blood. When one of them binds to a pathogen, a cascade of enzymatic 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

From parts of C1 to C5 and (by means of protease-mediated cleavage) and intercalations with C6 to C9, many other proteins and protein complexes are formed, 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, neutrophils, basophils, and eosinophils granulocytes) is rapid and nonspecific.
Macrophages recognize pathogens by the proteins on their surface and break them down by phagocytosis. Afterwards, the macrophages 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.
Dendritic cells, like macrophages, represent antigens and mediate between innate and acquired immune defenses via activated B and T lymphocytes.
Natural killer (NK) cells can recognize cells infected with viruses 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. Acquired (adaptive) immune response

The adaptive (acquired, specific) immune response (B and T lymphocytes and the resulting TH cells) is slower but more effective. The adaptive immune response stores once successfully formed immune responses via antigen-specific effector cells and memory cells, so that they can be recalled more quickly when needed again. This principle is used by vaccination.

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

T lymphocytes originate in the fetal liver and bone marrow and migrate with the blood to the thymus, where they mature. By recombination of gene segments, they form specific receptors for various antigens.
Lymphocytes produce cellular glycoproteins on their surface, the “clusters of differentiation”. Depending on the type of these glycoproteins, T lymphocytes develop into different types of T helper cells (Th cells).
The mature (still antigen-naive = not yet specialized for certain antigens) TH cells migrate from the thymus to the lymphoid tissues (lymphoid 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 differentiate 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+: memory T cells

1.6. Receptor classes

To protect endogenous cells from the immune response, antigen-presenting cells use different receptor classes for antigen presentation to TH cells. There are 3 receptor classes: CD4+ TH cells bind only to antigens presented by MHC-II, CD8+ TH cells bind only to antigens presented by MHC I. MHC III complexes include complement factors C2, C4, and Bf, as well as various cytokines, e.g., tumor necrosis factor (TNF). MHC III are plasma proteins involved in nonspecific 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) secrete IL-12, which in turn promotes TH-1 cells to form from naive 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-derived molecules. The B lymphocytes thereby produce antibodies.
Type2 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 thus 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 an offset diurnal rhythm and in this way are likely to modulate the regular TH-1/TH-2 alternation. If the stress systems permanently 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 require 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 naive TH cells into TH-1 cells.5

Stress and glucocorticoids have direct mutual 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 responses and cortisol stress response in healthy individuals

One study found that on mild stress, healthy subjects with a low cortisol stress response 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, which found that a lower cortisol stress response correlated with a prolonged IL-6 stress response.7 In contrast, another study in healthy subjects found a tendency for an increased IL-6 stress response to be accompanied by an increased cortisol stress response.3

2.2. Cytokine responses and cortisol stress response in mental disorders

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

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

Increased ACTH and cortisol stress responses correlated positively with increased granulocytes and natural killer cells and negatively with B lymphocytes. Furthermore, in response to TSST in psoriatic patients as well as healthy individuals, the following were observed10

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

Acutely depressed individuals (unlike healthy individuals) showed a positive correlation of the stress responses of cortisol and IL-6 and between the stress responses of epinephrine, TNF-α, and CRP. Healthy subjects showed only a significant correlation between ACTH and CRP stress responses.8
In contrast, in nondepressed as well as in remitted (recovered formerly) depressed individuals, no correlation was found between stress responses of cortisol on the one hand and cytokines on the other (IL-6, TNF-α, IL-10).3

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

Subjective perception of acute stress correlated with elevated basal blood levels of IL-6, but not TNF-α and IL-10.3 In this regard, IL-10 levels were significantly elevated during anticipation of stress test (TSST) in those subjects who exhibited a high cortisol stress response.3

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

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

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

Epinephrine and norepinephrine (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 response to glucocorticoids represents only part of the stress response. Glucocorticoids are also essentially released only 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 that of others does not. ADHD-HI is often associated with a flattened cortisol stress response, ADHD-I very often with an exaggerated cortisol stress response.

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

2.1.1. Activating effect of glucocorticoids

Glucocorticoids increase the production or secretion of

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

2.1.2. Inhibitory effect of glucocorticoids

Glucocorticoids reduce the production or secretion of

  • IFN-α by 50 to 605
  • IFN-γ5
    • By suppression of 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 decreasing the rate of gene expression of these interleukins and decreasing the stability of their mRNA20
  • IL-25
  • IL-421 (study results are conflicting, see above)
  • IL-521
  • IL-620
    • On the other hand, maternal stress causing damage to the unborn is mediated by IL-6. The deficient development of GABAergic cells in the unborn child caused by prenatal stress of the mother can be prevented by IL-6 antagonists.22
    • Cortisol can enhance IL-6 receptor expression in liver cells and induce IL-6-mediated acute phase protein (APP) production.23
    • Norepinephrine, which (like cortisol) is part of the endocrine stress response, stimulates IL-6 mRNA expression and IL-6 production in astrocytes via β2- and α1-adrenoceptors in a dose-dependent manner.24 Because norepinephrine release occurs temporally before activation of the HPA axis, inhibition of IL-6 by cortisol could represent a negative feedback loop, comparable to inhibition of the HPA axis after the stress response has occurred.
  • IL-1217
    • Which increases IL-10 production5
    • Catecholamines also mediate IL-12 reduction over several days via β2-adrenoceptors.25
    • Asthma therapy with glucocorticoid and/or β2-AR agonists probably reduces
      • The ability of antigen-presenting cells to17
        • IL-12 to produce
        • Suppress type 2 cytokine synthesis in activated TH cells and
        • To combat the eosinophilia.
      • Subsequently, these antigen-presenting cells activate naive (non-cytokine-bound) T cells, causing
        • IL-4 is increased
        • IFN-γ is restricted
      • In conclusion, glucocorticoids and β2-AR agonists are beneficial in asthma only in the short term. In the long term, they may increase susceptibility to allergic disease. This is confirmed by the fact that glucocorticoids like β2-AR agonists potentiate IgE production 52627
  • The expression of IL-12 receptors on T cells and NK28
  • IL-1321
  • IL-18, although not completely5
  • TNF5
  • TGF-β-1 in glial cells (on dexamethasone)29
  • Histamine
    • By means of β2-adrenoceptors, histamine production by mast cells is reduced. Catecholamines have the same effect.5
      Decreased cortisol levels are thought to cause the nocturnal wheezing of asthmatics due to increased histamine levels.
      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

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