Elements of the immune system: cytokines and co

• 1. Cytokines
  • 1.1. Areas of action of cytokines
  • 1.2. Types of cytokines
    • 1.2.1. Hematopoietins
    • 1.2.2. Tumor necrosis factor (TNF)
    • 1.2.3. Interferons
    • 1.2.4. Chemokines
  • 1.3. Differentiation according to TH-1 and TH-2 affiliation
    • 1.3.1. TH-1 cytokines
    • 1.3.2. TH-2 cytokines
    • 1.3.3. TH-17
    • 1.3.4. TH-reg
• 2. Other inflammatory biomarkers
  • 2.1. Acute phase proteins
    • 2.1.1. C-reactive protein (CRP)
  • 2.2. Microglia
• 3. Cytokines in the brain: migration and development
  • 3.1. Migration of cytokines into the brain
  • 3.2. Development of cytokines in the brain
• 4. Measurement of cytokines: CSF / serum

1. Cytokines¶

Cytokines are proteins that are released by body cells in response to an activating stimulus. They bind to specific receptors and thus have a variety of effects. Over 50 cytokines are currently known.

1.1. Areas of action of cytokines¶

Cytokines have various effects:

• Activation of the immune system in inflammatory processes
• Regulation of the blood-brain barrier
• Regulation of the HPA axis hormones
• Excitatory and inhibitory effects on neurotransmitter systems
  • Dopamine
  • Serotonin
  • Noradrenaline
  • Acetylcholine

1.2. Types of cytokines¶

Cytokines differ in

1.2.1. Hematopoietins¶

• Interleukins (IL, also known as lymphokines) are cytokines released by lymphocytes
  • IL-2
  • IL-3
  • IL-4
  • IL-5
  • IL-6
    (Former names: Interferon-β2 (IFNB2), B-cell stimulating factor, B-cell differentiation factor, liver cell stimulating factor)
    Release increased approx. 100-fold in response to heavy and prolonged muscle strain (6 hours). Maximum release at the end of muscle strain, followed by a rapid decline. Release partly from muscle cells themselves. Prolonged training causes a reduction in IL-6 release during exercise. IL-6 probably regulates immunological and metabolic responses to exercise via the liver, adipose tissue, the HPA axis and leukocytes. ¹
    • Receptors:
    • IL-6R, only on liver cells and leukocytes
    • SIL-6R, soluble IL-6 receptor. Via this binding to binds to the glycoprotein gp130 in cell membranes of many cell types.
  • IL-7
  • IL-9
  • IL-11
  • IL-12
  • IL-13
  • IL-15
  • Erythropoietin (EPO)
  • Thrombopoietin (TPO)
  • Leukemia inhibitory factor (LIF)
  • G-CSF
  • GM-CSF

1.2.2. Tumor necrosis factor (TNF)¶

• TNF-α
  • Effects:
    • Hypothalamus:
      • Increases CRH
      • Inhibits appetite
      • Regulates fever
    • Liver:
      • Forms acute phase proteins
        e.g.
        • C-reactive protein (CRP).
    • Macrophages:
      • Stimulates phagocytosis.
    • Neutrophil granulocytes
      • Promoting migration.
    • In general:
      • Increases insulin resistance
      • Increases cyclooxygenase-2 activity
      • Local increase causes inflammation
        • Heat
        • Redness
        • Swelling
        • Pain
      • Extreme increase causes shock
  • Bupropion reduces the TNF-alpha level.²

1.2.3. Interferons¶

Interferons are antiviral proteins that are produced by cells in response to a viral infection. They inhibit the replication of viruses.

• Alpha interferon (IFN-α) (formerly: type I)
• Beta-interferon (IFN-β)
• Gamma interferon (IFN-γ)
  • Activates macrophages by improving the fusion of phagosomes with lysosomes and promoting the production of bactericidal nitric oxide and reactive oxygen radicals
  • Induces antimicrobial peptides
  • Induces 1α-hydroxylase in macrophages
  • Converts 25(OH) vitamin D3 into 1,25(OH)2 vitamin D3 without product inhibition of 1α-hydroxylase
• Tau interferon

1.2.4. Chemokines¶

Chemokines are released by various cells in response to bacteria or viruses. They can chemically direct leukocytes (chemoattractants). There are 4 groups: CC, CXC. C3 and C. A comprehensive list can be found on Wikipedia.³. Many chemokines have several names. IL-8 is another name for CXC-8.

1.3. Differentiation according to TH-1 and TH-2 affiliation¶

1.3.1. TH-1 cytokines¶

TH-1 cytokines are pro-inflammatory cytokines that are primarily promoted by stress hormones of the first two stages of the HPA axis (CRH and ACTH) and are inhibited by cortisol.

• TNF-α⁴⁵
• TNF-β,⁵
• IFN-α⁶⁵
• IFN-γ⁴⁵
• IL-1α⁵
• IL-1β⁴⁵
• IL-2⁴
• IL-6⁴⁵
• IL-8⁴⁵
• IL-12⁶
• IL-18⁷
• Macrophage inhibitory protein-1⁵

Disease patterns with a shift of the immune system towards TH-1 are, for example

• Rheumatoid arthritis⁶
• Multiple sclerosis⁶
• Type 1 diabetes mellitus⁶
• Autoimmune thyroid disease⁶
• Collagen- and adjuvant-induced arthritis⁶
• Experimental allergic/autoimmune encephalomyelitis⁶

1.3.2. TH-2 cytokines¶

TH-2 cytokines are anti-inflammatory cytokines that are primarily promoted by stress hormones of the third stage of the HPA axis (cortisol).

• IL-1ra (receptor antagonist)⁴⁵
• IL-4⁴
• IL-5⁴
• IL-9⁶
• IL-10⁴
• IL-11⁷
• IL-13⁶
• IL-25
• Soluble IL-1 Receptor⁵
• TNF-α binding protein⁵
• IL-1 binding protein⁵

In addition, TH-2 dominance of the immune system is associated with increased histamine⁶ and IgE production.⁸

1.3.3. TH-17¶

• IL-17

1.3.4. TH-reg¶

2. Other inflammatory biomarkers¶

2.1. Acute phase proteins¶

2.1.1. C-reactive protein (CRP)¶

CRP is an acute-phase protein that becomes measurable 12 to 24 hours after the onset of an infection. It activates the complement immune system. CRP is an important indicator for the activation of the immune system.

2.2. Microglia¶

Microglia are certain glial cells with the function of tissue macrophages. Unlike most cells, they do not develop from the bone marrow, but from yolk sac cells.

There are two types of macrophage activation: M1 and M2.
The activation of microglial cells is triggered by the M1 phenotype, which is associated with an increase in IL-1β and TNF-α. In contrast, the M2 phenotype is associated with the release of anti-inflammatory cytokines.⁹

3. Cytokines in the brain: migration and development¶

3.1. Migration of cytokines into the brain¶

Peripheral cytokines can enter the brain or be produced there via various routes:¹⁰

• Direct or carrier-mediated passage of the blood-brain barrier
• Activation of endothelial cells and perivascular macrophages in the blood vessels of the brain
• Local activation of peripheral nerves (e.g. vagus), which then transmit cytokine signals to relevant brain regions, e.g. to the solitary nucleus or hypothalamus
• Peripherally recruited activated immune cells (e.g. monocytes, macrophages, T cells) into the brain

Cytokines such as IFN-a, IFN-c, IL-2, IL-10, IL-1, IL-6 and TNF-a can cross the blood-brain barrier, bind to receptors of vagal sensory nerves and stimulate the HPA axis.¹¹

Disorders of the blood-brain barrier are found in 20 to 30 % of psychiatric patients. This is usually accompanied by activation of the astrocytes. It is assumed that the disruption of the blood-brain barrier is the result of mild chronic inflammation.¹²

3.2. Development of cytokines in the brain¶

Cytokines are produced in the brain by¹⁰

• Microglia (mainly)
• Astrocytes
• Nerve cells
• Oligodendrocytes

Endothelial cells and perivascular macrophages are stimulated by cytokines to express the prostaglandin-producing enzymes cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PGES).¹⁰

4. Measurement of cytokines: CSF / serum¶

Pro-inflammatory cytokines are detectable in the brain and in the blood. The measurement of cytokines in the blood is primarily related to their immunological effects. Cytokines that are present in the blood also reach the brain. Conversely, this is not always the case. Since the neuropsychological effects, i.e. the change in behavior, are mediated in the brain and cytokines that are present in the brain are not detectable to the same extent in the blood, measuring cytokines in the blood makes little sense in terms of determining neuropsychological influences.¹³

Examples:

• Peripherally administered IFN-α reduces the L-tryptophan level in the blood, but not the L-tryptophan level in the cerebrospinal fluid.¹⁴
• A single administration of endotoxin in mice immediately increases TNF-α levels. While peripheral TNF-α decreased in serum after 9 h and in the liver after 1 week, it remained elevated in the brain for 10 months.¹⁵
• Cytokines are partly transported through the blood-brain barrier, but are also synthesized in astrocytes and microglia directly in the brain.¹²
• IL-2 in the blood does not represent the symptoms mediated by IL-2 in the brain. Thus, only CSF IL-2, but not blood IL-2, has a prognostic value in relation to schizophrenia.¹²
• The effects of IL-1-beta on IL-6 changes in the blood differ from the effects on IL-6 in the cerebrospinal fluid.¹⁶
• Quinolinic acid, which mediates considerable behavioral deficits, showed no correlation between blood values and cerebrospinal fluid values in a study despite significantly increased values in the brain.¹⁷

This also applies to neurotransmitters and hormones.

The DHEA values in the brain are on average 6.5 times the blood value, but the DHEA values in the cerebrospinal fluid are only 1/20 of the blood values.¹⁸

While acute and severe neuroinflammation of the brain is not easy to measure and diagnose, chronic or low-threshold neuroinflammation is even more difficult to detect and assess. Measurements of cerebrospinal fluid are characteristic of acute meningoencephalitis, more difficult in acute encephalitis without meningitis and very difficult in low-threshold neuroinflammation and can only be evaluated with a high level of expertise. Measurements should always include pairs of cerebrospinal fluid and serum samples taken simultaneously in order to recognize the dynamics of the exchange between the blood and cerebrospinal fluid. All immunoglobulin subclasses should always be examined and the respective quotients compared with Q-albumin. The final classification is based on the complete set of all parameters of serum, cerebrospinal fluid and cells in order to detect outliers and errors in the data set more quickly. Even this approach cannot completely rule out acute encephalitis, as CSF obtained lumbally (= from the back) may have little significance with regard to the cerebral cortex or CSF from subarachnoid spaces of the brain.¹⁹