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Lecture 5 ; Sept 24, 2013

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Immune system

What is sickness?
The behavior and physiology of sick people
(and animals) changes dramatically. They
tend to:

Ignore food and beverages.


Lose interest in social interaction.
Have excess or fragmented sleep.
Feel depressed and irritable.
Have impaired attention and memory.

The behavioral and cognitive changes that


accompany physical illness have been
termed sickness behavior.
Sickness behavior may represent a
motivational state responsible for helping
individuals cope with infection.
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What is psychoneuroimmunology
Psychoneuroimmunology is the study
of the interaction between the mind,
brain, and immune system.
As we will see, ones psychological
state can interact with the immune
system and vice versa. These
interactions are important for
everything from the common cold to
cancer.
This field of study constitutes a major
advance from earlier viewpoints that
saw infectious diseases as strictly
physical phenomena.
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Rationale of psychoneuroimmunology
Given that physical illness causes changes in
behavior, it is reasonable to expect that the
immune system has some way of
communicating with the brain in order to bring
about this behavioral change.
On the other hand, emerging evidence
suggests that our emotional state can influence
immune function.
The communication between the brain and
immune system is therefore bi-directional.
Disorders such as depression have symptoms
that somewhat resemble sickness behavior
(anhedonia, excess sleep, social withdrawal,
etc.,). The immune system may be involved in
these symptoms.

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What is the immune system?


The human body is a warm, moist and
nutritive environment a climate perfectly
suited for microorganisms of all kinds.
The immune system is responsible for
protecting your body from microbial
overgrowth. The immune system
monitors the internal environment for
signs of invasion by bacteria or viruses, as
well as evidence of tissue damage.
The immune system is extremely
powerful, and is highly regulated in order
to maintain optimal levels of function.
The immune system is able to
distinguish self from non-self so that it
only attacks enemy cells.
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Macrophages are immune cells


that are able to seek out and
engulf bacterial invaders.

How does the immune system work?


Unlike the nervous system, the
immune system is decentralized.
Immune cells circulate throughout
the blood stream and act directly
where they are needed.

Thymus!
Lymph nodes!

Organs such as the spleen, lymph


nodes, thymus, and bone
marrow act as factories and
repositories for immune cells.
Like the nervous and endocrine
systems, the immune system
relies on chemical communication
to organize its functions.
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Spleen!

Bone marrow!

The immune system, in brief


The immune system has two basic
divisions:
Innate immune system.
Adaptive immune system.

Innate immune
system

Cell-mediated immunity (T cells)


Antibody-mediated immunity (B cells)

The immune response is a


coordinated eort between all three
systems that typically follows the
same progression (see figure).
The various branches of the
immune system communicate with
each other using chemical
messengers called cytokines
cell + movement (G.).
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Cell-mediated
immunity

Antibodymediated
immunity

Adaptive immune system

The innate immune system


The innate immune system is used for
general purpose immunity, and is
sensitive to molecules that are universally
present on bacteria.
Cells such as macrophages have
receptors on their membranes that bind
to pathogens and trigger phagocytosis.

A macrophage attacking bacteria

In phagocytosis, the macrophage


destroys the pathogen by eating it.

When activated, cells of the innate


immune system (such as
macrophages) release cytokines into
circulation.
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A macrophage reaching out to


engulf two particles.

The adaptive immune system


The adaptive immune system underlies
two dierent types of immune response.
Cell-mediated immunity involves T cells
(named because they develop in the
thymus).
T cells are activated by cytokine signals
and interaction with macrophages. Once
activated, T cells proliferate and develop
into a form that attacks body cells that
have been infected.

Antibody-mediated immunity involves B


cells (named because they develop in
bone marrow).
B cells (plasma cells) produce antibodies
that bind to antigens on pathogens to kill
or deactivate them.
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A cytotoxic T cell attacking an


infected body cell.

Cytokines and the immune response


After ingesting pathogens, macrophages
release cytokines such as interleukin-1
(IL-1) (inter between, leukos white).

Macrophage!

IL-1 stimulates T helper cells to release IL-2.


IL-1!

IL-2 induces the proliferation and


development of antibody producing B cells
(plasma cells) and cytotoxic T cells.

T helper
cell

Cytokines also:
Trigger an inflammatory response (redness,
fever, aches, etc.)
Attract more innate immune cells.
Activate the adaptive immune system.

So in general, cytokines are molecules that


coordinate the immune response, and tell
the body that it is under attack.
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IL-2!
Plasma
(B) cell!

Cytotoxic
T cell!

Cytokines in the brain


IL-1 can aect the brain through a
variety of mechanisms:
The vagus nerve connecting the brain
to the abdominal organs.
Receptors on blood vessels in the
brain detect circulating IL-1 or
pathogens and stimulate cytokine
production in the brain.
Circulating IL-1 can be actively
transported into the brain.

Cytokines in the brain are linked to


sickness behavior. This informs the
brain of infection, and allows it to
adjust the animals behavior
accordingly.

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IL-1!

Cytokines and depression


Sickness behavior is quite similar to depressed
behavior. Could cytokines play a role in
depression? Three pieces of evidence in favor of
this view:
1. Giving people cytokine treatment can produce
depressive symptoms.
Example: AIDS and cancer patients treated with
cytokines often develop depression & suicidality.

2. Depression is more common among people


suering from inflammatory diseases.

Example: Cardiovascular disease, type 2 diabetes,


rheumatoid arthritis.

3. Anti-depressant treatment improves certain


components of sickness behavior in mice.

Example: Sick mice show reduced preference for


sugar water and social exploration, but these
symptoms are improved by anti-depressants.

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The birth of psychoneuroimmunology


Robert Ader (1932-2011) was one of the
fathers of psychoneuroimmunology.
Until the mid-1970s, it was assumed that
the nervous and immune systems
operated independently. Aders
experiments changed this belief.
In his seminal study, he showed that the
immune system in rats could be
suppressed by classical conditioning.

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Robert Ader (1932-2011)

The birth of psychoneuroimmunology


In the first phase of Aders study, rats were
fed a mixture of sweet tasting saccharin and
an immunosuppressant drug.
As expected, rats fed this way showed
evidence of suppressed immune function.

In the second phase, rats were fed just


saccharin by itself. Surprisingly, these rats
also showed evidence of suppressed
immune function.
The rats had formed an association
between the sweet taste of saccharin and
the physiological eect of
immunosuppression.
This showed for the first time that strictly
neurological and psychological processes
could influence in the immune system!

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Stress and the immune system


It is becoming clear that the HPA axis can aect the function
of the immune system.
This fits into our view that the stress response is designed
to help the body deal with short-term challenges.
For a short-term challenge, the body can save a lot of energy by
shutting down then immune system. This energy can be used to
cope with enemy attacks, survive starvation, etc.,

Problems arise when the HPA axis is over- or understimulated.


Chronic stress can lead to disease, and the interaction between
the stress response and the immune system can explain why this
happens.
On the other hand, having a weak HPA axis can lead to the
immune system getting out of control.
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Too much CRH can be a problem


Melancholic depression resembles a
state of organized anxiety. Because
the anxiety is not directed at anything in
particular, patients feel helpless and
vulnerable.
Melancholic depression is associated
with several symptoms of physiological
arousal:

Hypothalamus!

Ant.
pituitary!

Insomnia
Inhibited eating, sexual activity, and
menstruation
Hypersecretion of cortisol

Patients suering from melancholic


depression seem to have stress
responses that are perpetually stuck in
the on position.
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ACTH!

CRH!

Cortisol!

Too much CRH can be a problem


Normally, the brain detects elevated
blood levels of CRH and cortisol and
shuts down the stress response.
This process is called negative
feedback.
It seems that in many depression
patients, this feedback loop no longer
functions correctly, leading to
inappropriately elevated CRH and
cortisol.
Administration of tricyclic
antidepressant drugs seems to reverse
this defect.

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Hypothalamus!

Ant.
pituitary!

ACTH!

CRH!

Cortisol!

Cortisol suppresses the immune system


The stress response is designed to
re-direct energy toward dealing with
a stressor.
Part of this response means putting
the immune system on the back
burner.
Cortisol is a potent antiinflammatory agent and
immunoregulator.
This helps the immune system avoid
over-reacting to injuries.
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Hypothalamus!

Ant.
pituitary!

ACTH!

CRH!

Cortisol!

Too little CRH can be a problem


People who suer from diseases that
cause lethargy and fatigue often have
reduced levels of CRH in their blood.
Chronic fatigue syndrome, seasonal
aective disorder (SAD), and atypical
depression have all been linked to
impaired HPA axis function, and
reduced CRH secretion.
These disorders lead to increased
fatigue, sleep, and eating. Patients also
report feverishness, aches and pains,
and allergic symptoms.
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Hypothalamus!

Ant.
pituitary!

ACTH!

CRH!

Cortisol!

CRH can suppress the immune system


CRH inhibits the immune system
indirectly by stimulating the release of
cortisol.
CRH also acts on brainstem nuclei that
are connected to the sympathetic
nervous system (SNS). The SNS is
connected to the immune organs and
also inhibits the immune system.
So, a disorder characterized by too little
CRH can result in over-activation of the
immune system (and cytokine release).
This leads to excessive inflammation,
and sickness behaviors.
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Stress and disease


Folk wisdom suggests that stress
makes people more susceptible to
illness. There may be some truth to
this
Chronic stress suppresses the
immune system, but acute stress
often enhances the immune system.

Stressed mice get sicker when
exposed to influenza. This eect
depends on the SNS and HPA axis.

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The human rhinovirus (common cold)

Stress and disease


Laboratory experiments that have exposed human
volunteers to the common cold find that stress plays a
role in getting sick.
Specifically, they found that the odds of getting sick were
directly related to how much stress the person had
experienced during the past year.

A positive and optimistic cognitive style seems to


protect against developing a cold.
Exam periods at university are stressors that seem to
produce increased rates of upper respiratory tract
infection (common cold, influenza, etc.,)
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Stress and disease


Other diseases show evidence of being aected
by stress. For example, genital herpes.
Genital herpes is a chronic viral infection that spends
most of its time in a dormant, asymptomatic state.

Herpes flare-ups happen periodically usually


about four times a year.
Stress-control procedures such as relaxation
seem to decrease the frequency and duration
herpes flare-ups.
This effect likely works through the positive effects of
relaxation on the immune system.

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Social stress and disease


Chronic social stress increases susceptibility
to the common cold.
On the other hand, having more and better
friends seems to reduce the odds of getting
sick.

Immune responses of long-term caregivers
of Alzheimers patients are blunted.
Marital conflict also reduces immune
responses.
On the other hand, positive social support
seems to support the immune system. This
may explain the success of holistic medical
treatments that incorporate social support.
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Bullying is a form of social stress

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