Tracking stress

Stress, depression and immune defense are closely related. Stress makes you sick! This statement is simple and complicated at the same time.

Stress, depression and immune response are closely related. Stress makes you sick! This statement is simple and complicated at the same time. Simple, because surely many people can confirm this statement. It becomes complicated, however, when one wants to explore the causes for this statement. To do this, one must first understand how stress affects the body. In physical stress, cause (i.e., the stressor) and effect are directly related: At high temperatures, for example, the body starts to sweat. In the case of psychological stress, this connection is often indirect. Between the cause and the stress response is an individual assessment of the situation. This classification largely determines the physical stress response.

Since this varies from individual to individual and depends on personal experiences, assessments and resources, the same stress situation can trigger quite different responses in two people. For example, a stage performance in front of many spectators can be a pure nightmare for one person, but a moment of happiness for another person. This makes the study of stress responses much more complicated, as the same stressor does not always trigger the same response. This helps explain why different studies find different effects of stress on the immune system.

An old legacy of evolution

A basic distinction is made between acute and chronic stress. The response to acute stress can often be explained by the evolutionarily very old fight-or-flight response: The body is faced with a dangerous situation and responds by releasing stress hormones. These put the body on alert in preparation for a possible fight or flight. The immune system also reacts and prepares for injuries and associated infections. Thus, one can explain that acute stress often has a stimulating effect on the immune system – the number and function of various immune cells in the blood may be increased. This could be one reason why, despite being stressed before important events such as an exam, you are often protected from infection – only to fall ill after the event.

This illustrates that acute stress does boost the immune system – but also that this stimulation cannot continue indefinitely. In fact, the positive effects on the immune system are reversed in chronic stress: the number of different immune cells in the blood decreases, their activity is restricted and the defense reactions to pathogens no longer function as well. In addition, in studies of chronically stressed individuals, physicians often report finding elevated inflammatory parameters in the blood of the subjects.

The role of adrenaline and cortisol

How can the nervous system, which is responsible for assessing the stress response and thus also for the stress response, influence the immune system?? Scientists know best the connection between stress hormones and immune cells. Among other things, acute stress leads to a release of adrenaline. Different immune cells can respond directly to adrenaline and change the way they react. In addition, stress leads to the release of the stress hormone cortisol. Cortisol also has direct effects on immune cells. Among other things, it can lead to a weakening of the immune response. Through these and other mechanisms stress affects the immune system and reduces immune responses under chronic stress. This, in turn, results in an increased incidence of infections and other diseases during chronic stress.

Chronic stress affects the mood

However, the connection between the nervous system and the immune system is not a one-way street. Increased release of inflammatory messengers such as interleukin-6 by immune cells during chronic stress can also have effects in the brain: For example, they can negatively affect cognitive performance. Depression can also be caused by chronic stress, among other factors. In affected patients with this combination, doctors discuss that increased levels of inflammatory messengers can also affect patient behavior. Thus, immunological effects would even be the cause of changes in the nervous system. In rheumatoid arthritis, too, it is known that stress can have an influence on disease activity and symptoms.

Several studies have been able to show that repeated stress can have effects on disease activity, fatigue symptoms and joint pain. Stress and personal problems can also increase levels of inflammatory messengers such as interleukin-1-beta and interferon-gamma. However, concentrations of interleukin-1-beta, interferon- gamma, or the stress hormone cortisol are not sufficient to reliably predict disease progression. This illustrates that there must be additional mechanisms by which the nervous system can influence arthritis disease progression during stress and problem management.

Messenger substances mediate stress responses

In recent years, researchers have discovered that cells in the joints also have receptors for neurotransmitters, i.e. docking sites for messenger substances of the nervous system. Through these receptors, the nervous system can also influence inflammation in the joints by releasing neurotransmitters. An example is the so-called substance P, a messenger of the sensory nerves that conduct sensory stimuli to the brain. Stimulation of docking sites of this neurotransmitter can intensify an inflammatory reaction by attracting more immune cells to the joint. But there are also inhibitory players in this system, for example docking sites for the neurotransmitter acetylcholine from the so-called parasympathetic nervous system. Acetylcholine can suppress inflammatory processes, at least in the early phase of the disease.

Unfortunately, parasympathetic nervous system activity is often suppressed in the early phase of the disease, so anti-inflammatory activity is also absent. There are other receptors for neurotransmitters of the sympathetic nervous system that play an important role in joint inflammation. These include adrenaline, noradrenaline and dopamine. The docking sites for epinephrine and norepinephrine are called adrenergic receptors (ARs) and are divided into alpha and beta ARs. While stimulation of alpha-AR can enhance inflammatory responses, beta-AR have the opposite effect. However, in the course of chronic joint inflammation, alpha-ARs dominate, which can further exacerbate inflammatory processes.

Another player: dopamine

In recent years, work by our research groups has shown that cells in the joint of arthritis sufferers also carry receptors for dopamine. Stimulation of these receptors causes increased release of inflammatory messengers and is thus involved in joint damage. We are currently investigating the role of dopamine in bone resorption, as dopamine receptors are also increased in the bone of arthritis patients.

Our findings to date suggest that dopamine also plays a role in the development of osteoporosis in arthritis. These examples illustrate that the nervous system can influence the immune system in several ways. The presence of receptors for neurotransmitters in the joints of arthritis patients suggests a direct influence of the nervous system on the course of the disease. Therefore, it will be important for the future to understand how the different neurotransmitters can change the course of the disease. It is possible that this will lead to novel therapeutic approaches in the future.


Parasympathetic and sympathetic nervous system

The parasympathetic nervous system belongs to the autonomic nervous system and is responsible for the involuntary control of most internal organs and the blood circulation. Its activity serves, among other things, to recover. Its counterpart is the sympathetic nervous system, whose role is to activate many bodily functions.

To the authors

The biologist PROF. CARSTEN WATZL heads the Immunology Research Department at the Technical University of Dortmund, Germany.
DR. SILVIA CAPELLINO heads the Neuroimmunology Junior Research Group there,
DR. MAREN CLAUS is a research associate there.

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