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The link between stress and the immune system
MENTAL DISORDERS THROUGH PERMANENT STRESS
Activated through permanent stress, immune cells will have a damaging effect on and cause changes to the
brain. This might result in mental disorders.
The search for causes of mental disorders has been keeping researchers busy for a long time. Various hypotheses
have been postulated; in the 1960s, for example, scientists assumed the underlying cause to be a chemical
imbalance in the brain. Is the balance of messenger substances disrupted? Do hormones play a key role?
Later, researchers discovered the so-called neuroplasticity, the brain's ability to adapt. Contact points between
neurons, namely synapses, can be regrown, but they can also disappear, new neurons form, but they also die. Such
processes occur during learning and training and are perfectly normal. But they also play a role in mental disorders.
As it turned out, therapies had a demonstrable impact on those processes.
A small and very recent research field is so-called psychoneuroimmunology. It focuses on the immune system’s
significance in the evolution of mental disorders, and strives to use all previous approaches in combination with each
other.
"Originally, the brain and the immune system were considered two separate systems," explains Prof Dr Georg
Juckel, Medical Director at the RUB's LWL university clinic for psychiatry, psychotherapy and preventive medicine. "It
was assumed that the brain operates independently from the immune system and has hardly anything to do with it.
This, however, is not true." Direct neural connections from the brain to organs of the immune system, such as the
spleen, do exist. And vice versa, immune cells migrate to the brain, and local immune cells carry out various tasks
there, including disposing of damaged synapses. There is yet more evidence supporting the theory that the immune
system is involved in brain processes: in patients suffering from certain mental conditions, the immune parameters
present characteristic mutations. A treatment with immune system mediators such as Interferon alpha, which is
deployed in e.g. hepatitis C treatment, leads to depressions in 20 to 30 per cent of the patients.
Dr Astrid Friebe's work group in the LWL clinic lab researches into the mechanisms involved in these processes.
The researchers are mainly interested in microglial cells. These immune-competent cells, which belong to the
phagocyte family, are typically responsible for repairing synaptic links, removing damaged synapses and encouraging
the growth of new neurons in the brain. Moreover, they carry out various metabolic processes, some of which have
not yet been fully understood. In case of a threat, microglial cells are activated and switch into the destructive mode.
In this active mode, they trigger inflammation and release messengers that damage nerve cells. "We see this very
clearly in patients suffering from multiple sclerosis or Alzheimer's. The brain areas affected by inflammation or
neurodegeneration are surrounded by a circle of microglial cells," describes Georg Juckel. In schizophrenia patients,
the number of microglial cells is considerably higher than in healthy individuals. Here, the cells cause synaptic links
between neurons to degenerate. Those links form the so-called grey matter, which in schizophrenia patients is
significantly decreased.
Microglial cells can also be activated via the peripheral immune system, i.e. outside the brain. This is where stress
comes into play: it is an important factor affecting the immune system. Acute stress stimulates the immune system.
"That makes sense," explains Astrid Friebe: "In stress situations, the body readies itself for fight or flight, prepares
itself for potential injuries, too." But what happens under permanent stress? "What is certain is that microglial cells
adapt to the new conditions, in a way. The more frequently they get triggered due to stress, the more they are
inclined to remain in that mode. This is when microglial cells start to pose a danger to the brain." Permanent stress is
thus a relevant risk factor in the development of mental disorders.
Why will some people develop a mental condition under permanent stress while others won't? "We suspect that
the origins of a schizophrenia predisposition go back to the embryonic phase," says Georg Juckel. This assumption is
backed by a large US study conducted in the 1950s. It showed that children born of mothers who contracted true
viral influenza during pregnancy were seven times as likely to suffer schizophrenia later in life. The researchers from
Bochum confirmed this result in animal models. They also discovered that particularly high numbers of activated
microglial cells are found in the brains of young adults, which is the age bracket where schizophrenia most
commonly breaks out. "We don't know what exactly happens in the embryo when his or her mother contracts
influenza," says Astrid Friebe. "But the embryo undergoes some kind of immune response which has far-reaching
consequences and presumably shapes the future immune system."
Currently, the work group is studying the damaging effects of activated microglial cells in detail. What kind of
molecules do they release that are harmful to nerve cells? "We suspect this has something to do with nitrogen
monoxide, because we have found evidence that more enzymes are formed that produce nitrogen-monoxide
bonds," says Astrid Friebe. In the next step, the researchers will have to substantiate this hypothesis in cell cultures.
At the same time, the scientists used the animal model to investigate depressions. Looking into this condition, the
immune and stress effects can be expressly brought together. "Depressions can – in mice and in humans – be
triggered not only through the addition of immune system mediators such as Interferon alpha, but also through
stress itself. In both cases, microglial cells are activated," explains Astrid Friebe. Currently, the research question is:
in which brain regions exactly do the cells have a damaging effect. "In conclusion one can say: stress is a risk factor
for activating a predisposed immune system," says Georg Juckel.
Meike Drießen
Info
Schizophrenia
Schizophrenia is a severe mental disorder that occurs quite frequently. The likelihood for developing this
condition at some point in one's life is one per cent. Multiple relapses typically characterise the course of this
disorder, which most commonly breaks out in young adults. Typical symptoms include exaggeration of and delusions
regarding everyday experiences, up to and including hallucinations (positive symptoms), lack of motivation, cognitive
and motor deficits (negative symptoms).