Psychoneuroimmunology
and HIV
Doug MacDonald
PSY 760 April 7, 2005
Psychoneuroimmunology and HIV
• “Immunology 101” -- overview of the
Immune System
• HIV – overview
• Psychoneuroimmunology
– Background
– Mechanisms
– Research
– Methodological Issues
Doug MacDonald
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The Immune System
•The immune system is made up of a complex
network of cells, organs and chemicals that protect
the body from infection.
•Its purpose: keep infectious microorganisms, such as
certain bacteria, viruses, and fungi, out of the body,
and to destroy any infectious microorganisms that do
invade the body.
•The cells in the immune system have the ability to
recognize something as either self or invader, and
they try to get rid of anything that is invader.
Doug MacDonald
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Organs of the Immune System
Tonsils and adenoids
Lymph nodes
Lymphatic vessels
Thymus
Lymph nodes
Spleen
Peyer’s patches
Appendix
Lymph nodes
Bone marrow Lymphatic vessels
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Lymphatic System
http://www.herbalhouse.co.nz/images/Immune%2520System.jpg
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Natural and Acquired Immunity
• Natural immunity: created by the body's natural
barriers, such as the skin, and protective
substances in the mouth, the urinary tract, and on
the eye surface.
• Acquired immunity: develops through exposure to
specific foreign microorganisms, toxins, and/or
foreign tissues, which are "remembered" by the
body's immune system. When that antigen enters
the body again, the immune system "remembers"
exactly how to respond to it.
Doug MacDonald
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The immune system: two components
Non-Specific:
• They are generally able to distinguish foreign
antigens, but are unable to recognize specific
invaders. They will respond to a foreign antigen in
the same manner, despite repeated exposures.
• They do not adapt and improve their effectiveness
against previously encountered antigens.
• Include:
– Physical Barriers: skin, mucosa, stomach acid
– Chemical Agents: lysozymes, complement
– Effector Cells: macrophages, natural killer cells
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The immune system: two components
Specific:
• also referred to as acquired immunity or adaptive.
• able to distinguish foreign cells from self cells and
can distinguish one foreign antigen from another.
Acquired immunity cells have mechanisms for selecting a
precisely defined target and for remembering the specific antigen
so that subsequent exposures will result in a more effective and
efficient response.
• Components of the specific system are broken down
into 2 categories:
humoral (B-cells, antibodies)
cell mediated. (T-cells)
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Cells of the Immune System
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Phagocytes (“big eaters”) and Their Relatives
Monocyte
Eosinophil
Mast cell
Macrophage Dendritic cell
Neutrophil
Basophil
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B Cells
Antigen-specific Class II MHC and
B cell receptor processed antigen
are displayed
Antigen
B cell Antibodies
Lymphokines Plasma cell
Antigen-presenting Activated
bacteria helper T cell
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T Cells
Resting helper T cell Resting cytotoxic T cell
Activated helper T cell Activated killer cell
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Killer Cells: Cytotoxic Ts and NKs
Killer cell Target cell
Target-oriented
granules
Surface contact
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Cytokines
Lymphokines Monokines
Mature helper T cell Macrophage
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Mounting an Immune Response
www.healingdaily.com/ conditions/colostrum.htm
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Mounting an Immune Response
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Activation of T Cells
http://ag.ansc.purdue.edu/nielsen/www495/third%20line%20of%20defense2.jpg
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Mounting an Immune Response
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Mounting an Immune Response
Doug MacDonald
http://academic.brooklyn.cuny.edu/biology/bio4fv/page/aviruses/helperTcells.html 19
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Mounting an Immune Response: video
Macrophage Attacking E.coli (SEM x8,800). This image is copyright Dennis Kunkel at www.DennisKunkel.com
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Disorders of the Immune System: AIDS
Virus protein
Virus RNA
Virus DNA
Cell DNA
New virus
particle
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Disorders of the Immune System: AIDS -- VIDEO
Human T-lymphocyte (SEM x12,080). This image is copyright Dennis Kunkel at www.DennisKunkel.com
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Psychoneuroimmunology (PNI)
"Psychoneuroimmunology"
a field that studies the
interactions between the
central nervous system, the
endocrine system and the
immune system; the impact of
behavior/stress on these
interactions; and the
implications for health of
these interactions.
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Psychoneuroimmunology - background
• The term was first used in 1974 by Robert Ader.
• In his classical conditioning experiment, Ader
paired a conditioned stimulus (saccharin
solution) with an unconditioned stimulus, a drug
called Cytotaxan, which is known to decrease the
number of T-lymphocytes in rats.
• After several pairings, the rats were presented
with the saccharin solution (CS) in the absence of
Cytotaxan (US), and a blood sample was taken so
the rat’s T-lymphocytes could be counted.
• The result was a decline in the T-lymphocyte
count, indicating that conditioned
immunosuppression had occurred.
Doug MacDonald
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Psychoneuroimmunology - background
George F. Solomon, M.D., of the University of
California in Los Angeles, defines
psychoneuroimmunology as having "to do
with the complex bidirectional interactions
between the central nervous system and the
immune system and their clinical
implications. Psychoneuroimmunology
attempts to unravel biological mechanisms
by which emotions, attitudes, and coping
mechanisms affect the course of disease."
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Background - additional suggestive evidence:
1970s, Guillemin: endorphins, neuropeptides that bind
to opioid receptors in the brain and also appear to
have receptors on lymphocytes, suggesting a
relationship between the brain and the immune
system.
• In 1988, Irwin, UCSD: emotional stress induces
release of corticotropin-releasing factor (CRF). This
triggers the release of NE from the SNS, which
appeared to reduce the ability of natural killer cells to
destroy cancer cells in vitro.
• Bovbjerg and Redd, chemotherapy patients seemed to
develop conditioned immune suppression as a result of
repeated hospital visits for chemotherapy.
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Background - Stress evidence
• Human studies suggest stressors such as
decreased sleep, tension, varied eating patterns
that occur during final exams can put stress on
the immune system and result in more students
becoming ill.
• It is possible that the immune system may
respond in a similar way during exams the next
year, even in the absence of physical stressors,
indicating that the perception of stress has
become a conditioned stimulus for
immunosuppression
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What is the mechanism?
• Evidence supports the existence of bi-directional pathways
connecting the brain and the immune system.
• Psychoneuroimmunology (a.k.a. Neuro-endocrino-
immunology) is a point of intersection.
– cells of immune system and inflammatory systems
communicate directly with the peripheral and/or central
nervous system.
– This communication is also mediated via the bloodstream,
and therefore involves hormonal communication.
– Thus, the brain and the nervous system are part of a
neuroimmuno-regulatory network in which each of the
various components not only communicate with each other,
but also regulate additional sites in the body.
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Tuesday’s class - Stress
The Brain's Response to Acute Stress
• Hypothalamic-pituitary-adrenal
(HPA) system is activated.
• Release of Steroid Hormones
—Glucocorticoids
—Cortisol
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Tuesday’s Class - HPA Axis
The Brain's Response to Acute Stress
• Activation of HPA Axis.
Thank you, Kate!
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HPA Axis
• HPA axis is a central link between the central
nervous system and the immune system.
• An increased expression of corticotropin-
releasing hormone (CRH) through the
hypothalamus results in the formation of
adrenocorticotropin hormone (ACTH), which
subsequently…
• signals the adrenal cortex to increase levels of
glucocorticoid hormones, which act to
downregulate parts of the immune response
Doug MacDonald
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Mechanisms
Tonsils and adenoids
Lymph nodes
Lymphatic vessels
Thymus
Lymph nodes
Spleen
Peyer’s patches
Appendix
Lymph nodes
Bone marrow Lymphatic vessels
Doug MacDonald
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NTs receptor found on Ts, Bs, monocytes
Thus, the nervous system is able to…
• Induce T cell function, including cytokine
secretion, proliferation, migration.
• Modify T cell membrane potential and
thereby affecting the gating of specific
voltage gated channels.
• Modulate antigen driven T cell function.
Doug MacDonald
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Direct and indirect effects
• Direct: synapsing of neurons with white blood cells in
lymphoid tissues.
• Indirect: through blood-borne neurotransmitters and
hormones, which activate receptors on white blood cell
surfaces.
• Also, the immune system acts upon the nervous system
through cytokines released by immune cells
– within the brain, immune-related information causes glia cells and
neurons to secrete cytokines such as interleukin (IL)-1, IL-2, and
IL-6, interferon gamma, and tumor necrosis factor, which
influence activation of the hypothalamic- pituitary-adrenal (HPA)
axis and are, in turn, influenced by glucocorticoid secretion.
– These cytokines are regulated by the presence of glucocorticoids.
– Recent research has revealed that glucocorticoids help inhibit the
production of cytokines, and thus minimize the behavioral effects
of cytokines (i.e. sickness behavior).
Doug MacDonald
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Bidirectional pathways
• Besedovsky: activation of the immune system is
accompanied by changes in hypothalamic, autonomic, and
endocrine processes.
• Immune system activation increases the firing rate of
neurons in the ventromedial nucleus of the hypothalamus
at the time of peak antibody production;
• sympathetic activity, indexed by noradrenaline turnover, is
increased in the spleen and the hypothalamus; and
• immune responses initiated by viral infections, are
associated with dramatic increases in blood levels of
adrenocorticotropic hormone (ACTH) and corticosterone
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PNI research
• Most PNI research is Stress research
• E.g. PNI and HIV:
– Stressful life experiences (loss, deaths of friends); bereavement
– Depression
– Coping style and Adaptation
– [Perceived] Social support
– CB stress reduction Therapy
– Exercise
• Results suggest that
expected links exist.
E.g. Robinson, et al. 2003,
8-wk. MBSR may have
improved immunity.
• Best evidence: Hypnosis and Conditioning (Miller, Cohen, 2001)
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Methodological issues
• Confounding factors:
– Health related behaviors
– CNS impairment – HIV infection in the brain?
– Physical Symptoms – e.g. swollen lymph glands
Change in immune status or a sign
of distress?
– Treatment effects – correlation
between distress and immune
status may be mediated by use
of immune altering
treatment regimens.
http://www.mushroomscience.com/msstore/images/immune_builder_90.jpg
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Design Issues
• Sample selection – such variety of participants that
“explaining variance” difficult. Age, sex, alcohol,
tobacco, other drugs, nutrition, sleep…
• Time period assessed – longer longitudinal studies
needed.
• Lack of agreement on how to measure
immune function –
what validly reflects
“immunocompetence?”
http://www.apihealth.com/images/immune-new%20.jpg
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Is there practical significance?
• Much evidence for stress-
related immune impairment in
humans, yet what remains
uncertain is the clinical
significance of the altered
immunity that accompanies
psychological stress.
• Yet, popular belief in a link
between beliefs, behaviors,
optimism, mood… exists
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In Conclusion
“The association between stressful life experiences
and changes in immune function do not establish a
causal link between stress, immune function, and
disease. This chain of events has not yet been
definitively established. However, major links
between these "systems" have been
described and a new understanding
of interactive biological signaling has
begun. Psychoneuroimmunology is
developing the means to explore these
relations and their clinical and
therapeutic implications.”
Ader, Robert; Cohen, Nicholas; & Felten, David , Psychoneuroimmunology: interactions between
the nervous system and the immune system. Lancet 1995; 345 (8942). P.103
Doug MacDonald www.naturalways.com/ yoga-immune-deficiency.htm
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Doug MacDonald
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