Transcript Corticotropin Releasing Hormone mRNA Regulation in the Brains of

BRAIN - IMMUNE
CONNECTIONS
in
HEALTH & DISEASE
Esther M. Sternberg, M.D., Director,
Integrative Neural Immune Program
National Institute of Mental Health/NIH
Author: The Balance Within
The Science Connecting Health
and Emotions
Can Believing Make
You
Well
Does Stress Make You
Sick?
What is Stress
?
There are many parts to “Stress”:
• Initiating event
• Perception
• Response
• Effect
Emotions
Disease
Emotions
Health = Balance
Disease
Yellow bile
Phlegm
The
Four
Humors
Black bile
Blood
Gregor Reisch, Margarita Philosophica cum Additionibus Novis
Basel 1517
Anatomical Dissecting Theater, Padua:
ca. 1550
Anatomical View of the Brain: ca.1670
Thomas Willis, The Remaining Medical Works of Thomas Willis
London, 1679
Emotions
‘Accept nothing as true which you have not
verified yourself.’ Rene´ Descartes, 1644
Disease = Abnormal Anatomy
Disease
Anatomical Dissecting Instruments
Andreas Vesalius, De Humani Corporis Fabrica. Venice, 1568
Neuroendocrine Immune Interactions
EM Sternberg, Nature Reviews Immunology 2006
The immune system signals the
nervous system via many routes.
Antibodies
Nerve cell death and
survival
Diseases in which CytokineInduced Neurodegeneration May Play a
Role:
Infectious
•NeuroAids
•Toxoplasmosis
Degenerative
•Alzheimer’s
Inflammatory/autoimmune
•Multiple Sclerosis
Vascular
•Stroke
Traumatic
•Nerve trauma
The immune system signals the
nervous system via many routes.
17Kd
BBB
Antibodies
Nerve cell death and
survival
Memory, cognition, mood
Stress response
Sickness Behavior
Fever
Sleep
Cytokines can signal the brain:
•Signaling via Vagus
•Leaky areas in BBB:
OVLT, ME
•Active Transport
•Second Messengers:
NO, PGs
What is Stress
?
There are many parts to “Stress”:
• Initiating event
• Perception
• Response
• Effect
“The chief and primary cause of …the very rapid
increase of nervousness is modern civilization,
which is distinguished from the ancient by these
five characteristics: steampower, the periodical
press, the telegraph, the sciences and the
mental activity of women.”
American Nervousness, Its Causes and
Consequences, George M. Beard, 1881
Hans Selye (ca. 1960)
Stress = non specific response of the
body to any demand.
The stress response is more
specific than Selye predicted.
D. Goldstein et al.; P. Sawchenko et al.
There Are Many Kinds of
Stress.
• Psychological – performance, hierarchy,
relationship, loss
• Physical – pain, exercise
• Physiological – infection, disease,
nutritional deprivation, sleep deprivation,
hemorrhage, hypoxia, heat/cold
The Brain’s Hormonal Stress
Response: Hypothalamic Pituitary
Adrenal (HPA) Axis.
Adrenals
Nerve Pathways of the Brain’s
Stress Response: Sympathetic
Nervous System Response
Adrenals
Inverted U-shaped Curve Performance
and the Stress Response
Peak performance
Total relaxation
Extreme stress
Brainstem Stress Area (LC) Single Neuron
Recordings
G. Aston-Jones
How Do You Turn Bad Stress
Into Good Stress?
By Controlling Stress and
Making It Work For You.
RELAXED
HI
STIMULATION
PASSIVE
STRESSED
CONTROL
DEMANDS
We Can Learn to Control Some
Parts of Our Stress Response.
• Training/practice
• Biofeedback
• Stress reduction programs
• Meditation/Yoga/Prayer
• Psychotherapy
• Exercise
• Social support
• Lifestyle change (Mediterranean)
Stressors Have Different Effects
Depending on:
• Dose
• Pattern
• Duration
• Gender
Total Load of Stress = “Allostatic Load”
Immune disease results when the
Neuroendocrine Stress Response
is out of balance:
Too much
Infection
Too little
Inflammation
Effects of Glucocortioids on Innate
Immunity
E. Sternberg, NIMH 2001
Effects of Glucocortioids on Cell-mediated
Immunity
E. Sternberg, NIMH 2001
Effects of
Glucocortioids on Differentiation of TH Cells
E. Sternberg, NIMH 2001
General structure of nuclear
hormone receptors:
Molecular mechanism of Glucocorticoid/GR
Effects on Transcription
Normally the immune system activates
the brain’s stress response.
Antibodies
Adrenals
And the Brain’s Stress Response
Tunes Down the Immune System.
Antibodies
Adrenals
How Stress Makes You Sick:
Antibodies
Adrenals
Conditions Associated with
Chronic Stress:
• Prolonged wound healing
J. Kiecolt-Glaser, et al.
• Increased severity and incidence of viral
S. Cohen, et al.; J. Kiecolt-Glaser, et al.
infection
• Decreased antibody production to
J. Sheridan, et al.; J. Kiecolt-Glaser, et al.
vaccine
Immune disease results when the
Neuroendocrine Stress Response
is out of balance:
Too much
Infection
Too little
Inflammation
Lewis Rats
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•
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Streptococcal cell wall arthritis
Lactobacillus cell wall arthritis
Collagen arthritis
Adjuvant arthritis
Experimental allergic encephalomyelitis
Autoimmune myasthenia gravis
Autoimmune myasthenia gravis
Experimental autoallergic sialadenitis
Experimental autoimmune thyroiditis
Experimental autoimmune adrenalitis
Experimental autoimmune uveitis
Experimental autoimmune orchitis
Autoimmune myocarditis
Autologous immune-complex nephritis
Mercuric chloride-induced nephritis
Fischer Rats
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Streptococcal cell wall arthritis
Lactobacillus cell wall arthritis
Collagen arthritis
Adjuvant arthritis
Experimental allergic encephalomyelitis
Autoimmune myasthenia gravis
Autoimmune myasthenia gravis
Experimental autoallergic sialadenitis
Experimental autoimmune thyroiditis
Experimental autoimmune adrenalitis
Experimental autoimmune uveitis
Experimental autoimmune orchitis
Autoimmune myocarditis
Autologous immune-complex nephritis
Mercuric chloride-induced nephritis
EM Sternberg et al PNAS 1989
Illnesses Associated with Blunted
Hormonal Stress Response
Inflammatory/
Autoimmune Disease
Thyroiditis
Scleroderma
Low H ormonal
Stress Response
SLE
Arthritis, EAE, Septic Shock,
Inflammation
Rheumatoid Arthritis,
SLE, Sjogren’s,
Dermatitis, Asthma
Fibromyalgia, CFS, IBS
Cortisol Responses in Human
Autoimmune Disease
STIMULUS
DISEASE
100
80
oCRH
Sjogren’s
60
EO Johnson et al.
40
20
0
-60
-30
0
30 60 90
TIME (min)
120
30
25
Hypoglycemia
20
SLE
15
MA Gutierrez et al.
10
5
0
-15
0
15 30 45 60 75 90
TIME (min)
18
16
14
12
10
Dermatitis
A Buske Kirschbaum et al.
Asthma
A Buske Kirschbaum et al.
8
6
Public
Speaking
Mental
Arithmetic
4
2
0
-40 -30 -20 -10 0 10 20 30 40
TIME (min)
11
10
9
8
7
6
Cont rols
Patients
5
4
2
0
-40
-20
0
20
40
TIME (min)
60
80
Interruption of the HPA axis and
susceptibility to inflammatory disease
genetic
X
surgical
X
pharmacological
X
Mortality in Animal Models where HPA Axis
is Interrupted
SCW Arthritis
• RU486
• cort
EAE
Sternberg et al. PNAS 89
100% mortality
13% mortality
MacPhee et al. J Exp Med 89
• ADX
• cort
Salmonella
• hypophysect
• cort
MCMV
• ADX
• cort
Shiga toxin
• ADX
• cort
80% mortality
22% mortality
Edwards et al. PNAS 91
100% mortality
5% mortality
Ruzek et al. J. Immunol. 99
100% mortality
20% mortality
Gomez et al. Clin. Exp. Immunol. 03
60% mortality
10% mortality
Neuroendocrine Interactions in
Autoimmune/Inflammatory Disease
JI Webster & EM Sternberg, J. Endocrinol. 2004
“Interruption” of the HPA axis can also occur at
the tissue level through impaired sensitivity to
the effects of GC :
= Glucocorticoid Resistance
GR Resistance could be related to:
• Mutations or polymorphisms in GR or
associated proteins
• Elevated GRß
• Decreased GR number
• Bacterial toxins
Glucocorticoid Resistance &
Autoimmune/Inflammatory Disease
Disease
GR mutation/
polymorphism
Rheumatoid
Arthritis
GRβ
polymorphism
Systemic Lupus
Erythromatosus
(SLE)
GR mutation
SLE Nephritis
GR mutation
Crohn’s Disease
GR
number
Associated
protein
Glucocorticoid
sensitivity
Reference
Derijk et al, 2001. J
Rheumatol, 28
 MDR
Diaz-Borjon et al,
2000. Joint Bone
Spine, 67
Lee, 2004. J Exp
Med, 203
 GR
 GRβ
Jiang et al, 2001.
Clin Chem ACTA,
313
 CBG
Mingrone et al,
1999. J Invest Med,
47
Asthma
Decreased
Leung et al, 1997.
Clin Chest Med, 18
Barnes, 1995. N
Engl J Med, 332
Multiple Sclerosis
Decreased
Derijk et al, 2004. J
Neuroimmunol, 151
Van Winsen et al,
2005. J Clin
Endocrinol Metab,
90
EM Sternberg, Nature Reviews Immunology 2006
Chromosomal Locations of QTLs
Regulating Rat Inflammation
1
2
3
4
5
7
8
9
10
12
18
19
20
X
Y
Modified from Ronald Wilder, Elaine Remmers,
Marie Griffiths, Grant Cannon, et al.
Genetic versus Environmental
Contribution to Inflammatory
Trait Variance
65%
Environmental
35%
Genetic
Maternal Behavior
in LEW/N & F344/N Rats
100
LEW/N
% RETRIVAL
75
50
F344/N
25
0
-25
MINUTES
Video: Maternal Behavior
LEW/N
QuickTime™ and a
H.263 decompressor
are needed to see this picture.
F344/N
QuickTime™ and a
H.263 decompressor
are needed to see this picture.
Separation of rat pups for 5-15
minutes/day for first two weeks
of life leads to permanent
increase in HPA axis
responsiveness into adult life.
Seymour Levine et al. 1975; Michael Meaney et al. 1995
Strain, gender and maternal
environment interactions
determine adult stress
responsiveness in this model.
GENETIC
(MULTI/POLYGENIC)
DEVELOPMENTAL
ENVIRONMENTAL EXPOSURE
SET-POINT OF HOST RESPONSE
NEURAL
NEUROENDO.
SEX HORMONES
(AUTONOMIC)
(HPA, HPT)
(HPG)
IMMUNE RESPONSE
RECOVERY VS PERSISTENCE SX
Acknowledgements
SNIB/NIMH/NIH
Esther Sternberg
A. Sasha Tait
Cherie Butts
Elena Belyavskaya
Heather Gorby
Andrea Marques-Deak
Zhigang Kang
Marni Silverman
Taylor Dennison
Jeanette Webster*
Leonardo Tonelli*
Farideh Eskandari*
Shetha Shukair*
Kristina Duncan*
Monique Dalton*
Cash Horn*
Eve Bowers*
NIAID/NIH
Steven Leppla
Mahtab Moayeri
CDC
Lawrence McDonald
Sherif Zaki
NIAAA/NIH
George Kunos
Pal Pacher
GSK, UK
Stuart Farrow
NIDDK/NIH
Institut Pasteur FR
S. Stoney Simons Michel Popoff
Giovanni Cizza
Kenner Rice
Max Planck, Dusseldorf
Gunther Schutz
OD/NIH
Terry Phillips
FDA
Felice D’Agnillo