Itt írjon a(z) Depression_immun-ról/ről

Immunology of Depression

Introduction
Relationship between the brain and the immune system and its on mental health
Structural changes in the brain with MDD
The relationship between the Blood-brain barrier and MDD
CRH & Cortisol and MDD
Serotonin and depression
Inflammatory state and MDD
Behavioural effect of cytokines
Treatment of depression (Antidepressant and Anti-inflammatory)
Conclusion
References

Introduction:

This essay will discuss the immunology of depression. The link between Psychology and Immunology are two sciences that hold a close & salient relationship. Depressive disorders are mental illnesses housing a spectrum of variants, this essay will mainly focus on major depression (MD). Five (or more) of the listed symptoms must be present during a two-week (consecutive) period and a deviation from previous behavior must be observed for diagnosis. It is compulsory that at least one of the symptoms is either a low mood or/and a loss of interest (American Psychiatric Association [APA], 2013).

Risk factors for depression include various life events, external environmental stress, cognitive impairment, depressed parents/caretakers, social dysfunction, and being female (Hammen, 2018).

People with malignant tumors, diabetes, chronic physical pain, or cardiovascular and cerebrovascular diseases also had higher rates of depression than healthy controls (Dai et al, 2019)

Figure 1 - Major Depressive Disorder Symptoms

Depression is one of the most prevalent mental health issues in the world, according to the World Health Organization (WHO) (reference). Depression can greatly influence an individual's quality of life & their social environment extremely negatively.

It is well known that the immune system is the human body’s defense system against harmful pathogens. The immune system is a complex system with many role players, the ones with specific relevance are the following:

Figure 2 - Relevant role players of the Immune

Other important molecules are going to play a role in the processes to be described, some of the important ones are as follows:

Figure 3 - Other relevant molecules

The blood-brain barrier (BBB), CRH, stress & cortisol, inflammatory state & its effect on behavior, the relationship between cytokines and serotonin and serotonin as a mood regulator will be discussed.

Relationship between the brain and the immune system and its effects on mental health

For many years there has been the belief in the scientific community that the immune system is almost independent, later it was discovered that the central nervous system has an effect in the immunology due to the sympathetic connections it has with lymphatic tissue, but there wasn’t an understanding regarding the connection between the effects of the immune system in the brain; now we know that this relationship is bilateral. The immune system and the central nervous system (CNS) are intertwined with one another, these two vital systems are in close communication via molecules like cytokines and neurotransmitters and they have an effect on both the systems.

We can see the production and the utilization of immune factors by the central nervous system and at the same time, there is also a production and utilization of neuroendocrine mediators by the immune system. From the simple interaction of immune cells and the peripheral nerve endings that innervate immune organs to the effect of cytokines in some neurotransmitter metabolism or the development of the CNS.

They support each other, the immune system will use the neural elements in order to organize its best defense mechanism, and at the same time, the nervous system will be influenced by immune cells in the process of neuronal plasticity of the synapses, especially during the development stage. This communication can be an advantage when the system is in equilibrium, but it can be a disadvantage when there is any type of important imbalance in the biochemistry of any of the two systems. When these two systems fail to communicate, there will be different types of pathologies that will appear and are commonly diagnosed as local organ dysfunction.

The intricate role that they have on each other will be essential for the balance between disease and health. The Immune system will have a great effect on neuronal functions and the nervous system will be a key factor in the positive and negative coordination of the immunological defense mechanism against any type of injury or dysfunction. (Dantzer, 2018)

Figure 4.0 - Bilateral connection between the nervous system and the immune system Central nervous system Relationship between neurons and the immune cells that circulate the central nervous system. Neuroendocrine system Relationship between neuroendocrine cells and immune cells that circulate the neuroendocrine system Vessels of lymphoid organs Effects of the central nervous system in the vessels that carry immune cells Communication via mediators of the neuroendocrine system, the central nervous system, and the mediators of the immune cells.

Structural changes in the brain with MDD

Neuroimaging studies have provided proof that psychological symptoms and behavioral deficits in patients with depression are related to structural and functional alterations in specific areas of the brain.

Morphological changes in several brain regions, including the frontal lobe, temporal lobe, and limbic system, in people with depression, compared to people without depression.

The volume of gray matter in the brain is associated with many physiological senses and higher functions, including muscle control, vision and hearing, memory, emotion, language, decision-making, and self-control (Rogers & De Brito, 2016; Zatorre, Fields & Johansen-Berg, 2012). The reduction of grey matter mass will affect all of these functions.

Impaired white matter connectivity and mass can lead to reduced information delivery, which may cause deficits in attention, declarative memory, executive function, and intelligence (Fields, 2008; Reddick et al., 2006).

Depression can cause the reduced volume of the brain on multiple levels and this can impact multiple facets of the patient’s life negatively.

The relationship between the Blood-brain barrier and MDD

The blood-brain barrier consists of highly specialized endothelial cells maintaining the homeostasis of the central nervous system (CNS). This membrane prevents the movement of pathogens and inflammation from the peripheral blood circulation into the parenchyma of the CNS. This continuous basement membrane provides a very selective semi-permeable membrane. To ensure selectivity, endothelial cells express specific transporters to move materials and waste across the membrane, with the help of tight junctions between the endothelial cells (Daneman and Prat, 2015). A healthy blood-brain barrier has very low levels of leukocyte adhesion molecules which limit the mode of transport through which the immune cells would enter the CNS. This level is elevated in neuroinflammatory diseases, such as multiple sclerosis (MS). At the sites of MS lesions, an elevated level of T cells, B cells, neutrophils, and macrophages can be found. In a healthy brain, macrophages and microglia provide the first line of innate immunity and are able to cross the blood-brain barrier. These neuroinflammatory diseases have been found to have a high correlation to major depression symptoms (Lee and Giuliani, 2019).

Injury and disease in the brain is known to increase the permeability of the blood-brain barrier, making it easier for immune cells to enter the parenchyma. Tumor necrosis factor-alpha (an inflammatory cytokine produced during inflammation) has shown to increase the blood-brain barrier permeability along with increasing the size of the extracellular gaps. This allows cytokines and immune cells to enter the brain, increasing the inflammation in the parenchyma, along with making the blood-brain barrier more vulnerable. This inflammation is related to an increased rate of depression (Jansen et al, 2016). In EAE studies, the inflammation of the brain’s parenchyma was seen prior to the depressive symptoms, leading to the conclusion that the inflammation may lead to major depression (Lee and Giuliani, 2019).

CRH & Cortisol and MDD

Corticotropin-Releasing hormone (CRH) is released by the paraventricular nucleus in the anterior pituitary gland. Secondary stimuli for the release of CRH include stress, fever & hypoglycemia. When CRH is released, it stimulates corticotrophs & breaks Proopiomelanocortin (POMC) into alpha Melanocyte-stimulating hormone (a-MSH) & Adreno-corticotropic hormone (ACTH). ACTH is of greater relevance in this topic. ACTH facilitates the production of cortisol, made by the adrenal glands above the kidneys. Cortisol can also be released by the effect of the sympathetic nervous system (not only the pituitary gland). Cortisol is the “main” stress hormone produced by the body. It is often described as the “fight or flight” hormone. Cortisol has numerous functions in the human body: facilitating stress response metabolism regulation inflammatory response immunological function

While this hormone is fundamental to human life, overproduction or extended periods of exposure to cortisol can have detrimental effects, possibly leading to depression. (Oakley, Cidlowski, 2013)

It has been suggested that stress may present as a predisposing contributor for MD. Impaired reduced ability of stress coping/management has frequently been observed in patients with MD, even prior to the initial progression of the disorder, and psychosocial stress factors frequently pave the way for the onset of MD (Paykel et al, 1969). The hypothalamic-pituitary-adrenal axis (HPA axis) describes the relationship between the hypophysis (pituitary gland), hypothalamus & adrenal glands.

It has been found that an altered HPA axis functioning and dysfunctions of the extrahypothalamic CRH complex have been consistently found in patients with MD (Hasler et al, 2004) Stimulation of the HPA axis is one of the best-studied changes in MD (Roy et al, 1987). Several studies prove that MD patients show increased baseline cortisol levels, or much higher cortisol levels during the recuperation period following stress (psychological) (Burke et al, 2005).

When stress levels are high, more CRH is released, thus more ACTH is produced & released by the pituitary gland, and in turn more cortisol will be produced (hypercortisolemia). Hypercortisolemia leads to decreased T-cell & natural killer cell functioning. (Herbert & Cohen, 1993) & (Zorilla et al, 2001) both observed that natural killer & T-cells have an impaired function in subjects diagnosed with major depression, further linking immunology to depression.

CRH also activates the sympathetic nervous system as mentioned earlier. This increases the release of another hormone, norepinephrine. Norepinephrine is released when a stressful situation is being perceived. Norepinephrine is produced in the adrenal medulla (kidney) and postganglionic neurons of the sympathetic nervous system.

Increased production of CRH can also activate microglia. Microglia are types of glial cells (neuroglia) found in the brain and spinal cord. Microglia acts as the initial & main form of immune defense in the central nervous system (CNS). Norepinephrine also activates microglia.

Microglial cells initiate the activation of macrophages. An increase in macrophage activation will lead to an increase in cytokines (Tumor necrotic factor a (TNF) & Interleukins (IL) 1,2 & 6). The effect of cytokines is discussed earlier in the essay.

In conclusion, major depression can reduce immune system function. Immune system dysfunction can lead to depression. With the increasingly stressful environment humans have evolved to survive in, stress management is becoming increasingly important.

Serotonin and depression

Serotonin (5-Hydroxytryptamine) is a neurotransmitter and can also act as a hormone when it’s in the peripheral arterial system, it can have an effect on the gastrointestinal system as well as the central nervous system serotonin and the effects that it has.

Serotonin is synthesized from Tryptophan, which is an Amino Acid. It has an effect on mood, emotions, sleep, memory, temperature regulation, and appetite. It is a central neurotransmitter, therefore it has major implications for many mental disorders that will show behavioral changes in the individual. Therefore Serotonin levels in the body will be the main factor that will be related to Anxiety, Obsessive Compulsive Disorder and Depression.

It is believed that the decreased activity of serotonin pathways is the cause of the physiological factors that lead to depression, this theory is 50 years old, but we still don’t have a full understanding of the bigger picture that leads to Major Depressive Disorder.

The tryptophan levels will have an impact on the synthesis of serotonin due to the fact that tryptophan is the precursor amino acid for serotonin. Even if they lack of tryptophan will not cause depression by itself unless the person already had episodes of depression before. This is why serotonin is believed to have a role in the recovery process that your brain has after depression, but it is not one of the direct causes.

Some of the factors that need to be present for serotonin to be a leading factor in depression can be the severity of the disorder itself (pre-diagnosed), a family history that has persisted through several generations.

Nonetheless, antidepressants that modulate serotonin levels are still commonly used against MDD and other types of mental disorders.

Healthy and unhealthy patients that receive serotonin-based antidepressants present positive changes, making them regulate in a better way their emotions. It switches their automatic response to different stimuli, this learned behavior is driven by negative bias that the individual might have developed over traumatic or abusive circumstances.

Serotonin will not change the mood of the people but it will not have an effect on the mood directly, but it will help to mitigate the secondary responses to emotional mechanisms, this might help to create positive biases over time. Changing the way the patient processes their thoughts and giving a more level ground for the patient to choose a proper response that doesn’t generate anxiety or lead to a deeper depression state (Cowen and Browning, 2015).

Inflammatory state and MDD

When the body enters an inflammatory state, it often leads to major depressive symptoms such as fatigue.

In response to pathogens, the cytokine activity often leads to the body reserving energy to focus on the inflammatory response, making one feel fatigued. Fatigue is a very common symptom of major depression (Lee and Giuliani, 2019).

As for endotoxins, MRI scans have produced evidence of the changes in connections within the brain and reduced ventral striatal response to reward cues. This means the dopamine that would normally get released when one is expecting a reward is inhibited. Endotoxins were also noticed to lead to depressive symptoms such as anhedonia, which is reduced interest in things people once used to enjoy (Eisenberger et al, 2010).

Interferon type I has also been studied to cause defects in long-term potentiation through the interferon receptor chain 1 pathway, which has been observed to lead to depressive behaviors (Eisenberger et al, 2016).

Furthermore, higher rates of depression have been found in conditions associated with immune system activation. For example, people with allergies, autoimmune diseases like MS, or septic infections have a much higher chance of having major depression (Lee and Giuliani, 2019). People who have Rheumatoid arthritis are seventy-four percent more likely to be diagnosed with major depression than others (Matcham et al, 2013). Higher tumor necrosis factor-alpha in asthmatic patients is connected to higher rates of depression. Finally, among people with immune conditions, those with higher inflammatory serum levels (for example TNFalpha) have a more severe level of depression (Lee and Giuliani, 2019). These examples show how inflammatory responses are closely linked with symptoms of major depression.

Behavioural effect of cytokines

Pro-inflammatory cytokines are released in the body during an infection, they are released all throughout the organism and have multiple effects on other cells and in their metabolism.

Some of the most common pro-inflammatory cytokines are interleukin-1, interleukin 6 (IL-1, IL-6) and tumor necrosis factor (TNF) these ones are

These cytokines will come from the periphery of the body by the accessory immune cells and arrive at the brain where the brain will process such information and act accordingly, this will lead to the sickness feeling through the neuronal pathway that causes the stimulation of peripheral sensory nerves. (Dantzer et al, 2006)

Treatment of depression:Antidepressant and Anti-inflammatory

The use of inflammatory medicines in depressive conditions has been successful in some experiments, pointing to the potential inflammatory pathway of depression With animal sepsis patients, immunosuppression studies on animal models showed that by applying dexamethasone (a corticosteroid reducing inflammation in the immune system) it is possible to inhibit the NF-κB pathway and by doing so, they were able to reduce depressive symptoms (Cassol et al, 2010).

Antidepressant medications such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors also lead to a decrease in inflammation. Administration of these antidepressants leads to increased levels of cytokine synthesis inhibitory factor (IL10) in order to cease the inflammatory response. Also, inflammatory cytokines all showed a decrease (Lee and Giuliani, 2019). It has been shown that anti-inflammatory effects are more important with some antidepressants than others. For example, SSRIs produced a greater treatment response for individuals with lower baseline levels of proinflammatory cytokines than with other types of antidepressants (Lee and Giuliani, 2019). This proves that to some extent inflammation plays a role in depression and may play a role in the treatment.

Conclusion:

There are many immunological factors that lead to major depression. It is important to understand the correlation between these two important topics. Understanding the relationship between the two can help with managing the effects of major depression on the patient & the people surrounding them. Understanding and further research of this relationship can lead to the improvement of the overall physical and mental health of society.

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