esther m. sternberg, m.d., director, integrative neural immune program national institute of mental...
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Esther M. Sternberg, M.D., Director,Esther M. Sternberg, M.D., Director,
Integrative Neural Immune Program Integrative Neural Immune Program National Institute of Mental Health/NIHNational Institute of Mental Health/NIH
BRAIN - IMMUNEBRAIN - IMMUNE
CONNECTIONSCONNECTIONS
Author: The Balance WithinAuthor: The Balance Within
The Science Connecting Health The Science Connecting Health and Emotionsand Emotions
HEALTH & DISEASEHEALTH & DISEASE
inin
Can Can BelievingBelieving Make You Make You
WellWell
Does Does StressStress Make Make You You SickSick??
What isWhat is StressStress ??
• Initiating eventInitiating event
• PerceptionPerception
• ResponseResponse
• EffectEffect
There are many parts to “There are many parts to “StressStress”:”:
EmotionsEmotions
DiseaseDisease
EmotionsEmotions
DiseaseDisease
Health = BalanceHealth = Balance
The
Four
Humors
PhlegmPhlegm
BloodBloodBlack bileBlack bile
Yellow bileYellow bile
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 WillisLondon, 1679
EmotionsEmotions
DiseaseDisease
Disease = Abnormal AnatomyDisease = Abnormal Anatomy
‘Accept nothing as true which you have not verified yourself.’ Rene´ Descartes, 1644
Anatomical Dissecting Instruments
Andreas Vesalius, De Humani Corporis Fabrica. Venice, 1568
Neuroendocrine Immune InteractionsNeuroendocrine Immune Interactions
EM Sternberg, Nature Reviews Immunology 2006
The immune system signals the The immune system signals the nervous system via many routes.nervous system via many routes.
IL
IL
Antibodies
Nerve cell death andsurvival
Diseases in which Cytokine-Diseases in which Cytokine-Induced Neurodegeneration May Play a Induced Neurodegeneration May Play a
Role:Role:
TraumaticTraumatic•Nerve traumaNerve trauma
InfectiousInfectious•NeuroAidsNeuroAids•ToxoplasmosisToxoplasmosis
DegenerativeDegenerative•Alzheimer’sAlzheimer’s
Inflammatory/autoimmuneInflammatory/autoimmune•Multiple SclerosisMultiple Sclerosis
VascularVascular•StrokeStroke
The immune system signals the The immune system signals the nervous system via many routes.nervous system via many routes.
IL
IL
Antibodies
Nerve cell death andsurvival
Stress responseSickness BehaviorFeverSleep
Memory, cognition, mood
BBBBBB17Kd17Kd
•Leaky areas in BBB:Leaky areas in BBB:OVLT, MEOVLT, ME
•Active TransportActive Transport•Second Messengers:Second Messengers:
NO, PGsNO, PGs
Cytokines can signal the brain:Cytokines can signal the brain:
•Signaling via VagusSignaling via Vagus
What isWhat is StressStress ??
• Initiating eventInitiating event
• PerceptionPerception
• ResponseResponse
• EffectEffect
There are many parts to “There are many parts to “StressStress”:”:
“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)
StressStress = non specific response of non specific response of
the body to any demand.the body to any demand.
The stress response is more The stress response is more specific than Selye predicted.specific than Selye predicted.
D. Goldstein et al.; P. Sawchenko et al.
There Are Many Kinds of There Are Many Kinds of Stress.Stress.
• PsychologicalPsychological – performance, hierarchy, relationship, loss
• PhysicalPhysical – pain, exercise
• PhysiologicalPhysiological – infection, disease, nutritional deprivation, sleep deprivation, hemorrhage, hypoxia, heat/cold
The Brain’s Hormonal Stress The Brain’s Hormonal Stress Response: Hypothalamic Response: Hypothalamic Pituitary Adrenal (HPA) Pituitary Adrenal (HPA)
Axis.Axis.
Adrenals
Nerve Pathways of the Brain’s Nerve Pathways of the Brain’s Stress Response: Sympathetic Stress Response: Sympathetic
Nervous System ResponseNervous System Response
Adrenals
Inverted U-shaped Curve Performance Inverted U-shaped Curve Performance and the Stress Responseand the Stress Response
PeakPeak performanceperformance
Total relaxationTotal relaxation Extreme stressExtreme stress
Brainstem Stress Area (LC) Single Neuron Brainstem Stress Area (LC) Single Neuron RecordingsRecordings
G. Aston-Jones
How Do You Turn Bad Stress How Do You Turn Bad Stress Into Good Stress?Into Good Stress?
By Controlling Stress and By Controlling Stress and Making It Work For You.Making It Work For You.
DEMANDSDEMANDS
CO
NT
RO
LC
ON
TR
OL
PASSIVEPASSIVE
RELAXEDRELAXED HIHISTIMULATIONSTIMULATION
STRESSEDSTRESSED
We Can Learn to Control Some We Can Learn to Control Some Parts of Our Stress Response.Parts of Our Stress Response.
• BiofeedbackBiofeedback
• Stress reduction programsStress reduction programs
• Meditation/Yoga/PrayerMeditation/Yoga/Prayer
• Training/practiceTraining/practice
• PsychotherapyPsychotherapy
• Social supportSocial support
• ExerciseExercise
• Lifestyle change (Mediterranean)Lifestyle change (Mediterranean)
Stressors Have Different Effects Stressors Have Different Effects Depending on:Depending on:
• DoseDose
• PatternPattern
• DurationDuration
• GenderGender
Total Load of Stress = “Allostatic Load”Total Load of Stress = “Allostatic Load”
Immune disease results when theImmune disease results when the Neuroendocrine Stress ResponseNeuroendocrine Stress Response
is out of balance:is out of balance:
InfectionInfectionToo muchToo much
InflammationToo littleToo little
Effects of Glucocortioids on Innate ImmunityEffects of Glucocortioids on Innate Immunity
E. Sternberg, NIMH 2001
Effects of Glucocortioids on Cell-mediatedEffects of Glucocortioids on Cell-mediatedImmunityImmunity
E. Sternberg, NIMH 2001
Effects ofEffects ofGlucocortioids on Differentiation of TH CellsGlucocortioids on Differentiation of TH Cells
E. Sternberg, NIMH 2001
General structure of nuclear General structure of nuclear hormone receptors:hormone receptors:
Molecular mechanism of Glucocorticoid/GR Effects on Transcription
Normally the immune system activates Normally the immune system activates the brain’s stress response.the brain’s stress response.
Adrenals
IL
IL
Antibodies
And the Brain’s Stress Response And the Brain’s Stress Response Tunes Down the Immune System.Tunes Down the Immune System.
Adrenals
IL
IL
Antibodies
How Stress Makes You Sick:How Stress Makes You Sick:
Adrenals
IL
Antibodies
IL
Conditions Associated with Chronic Stress:
• Prolonged wound healing J. Kiecolt-Glaser, et al.
• Increased severity and incidence of viral infection S. Cohen, et al.; J. Kiecolt-Glaser, et al.
• Decreased antibody production to vaccine J. Sheridan, et al.; J. Kiecolt-Glaser, et al.
Immune disease results when theImmune disease results when the Neuroendocrine Stress Response Neuroendocrine Stress Response
is out of balance:is out of balance:
InfectionInfectionToo muchToo much
InflammationInflammationToo littleToo little
Lewis RatsLewis Rats• Streptococcal cell wall arthritisStreptococcal cell wall arthritis• Lactobacillus cell wall arthritisLactobacillus cell wall arthritis• Collagen arthritisCollagen arthritis• Adjuvant arthritisAdjuvant arthritis• Experimental allergic encephalomyelitisExperimental allergic encephalomyelitis• Autoimmune myasthenia gravisAutoimmune myasthenia gravis• Autoimmune myasthenia gravisAutoimmune myasthenia gravis• Experimental autoallergic sialadenitis Experimental autoallergic sialadenitis • Experimental autoimmune thyroiditisExperimental autoimmune thyroiditis• Experimental autoimmune adrenalitisExperimental autoimmune adrenalitis• Experimental autoimmune uveitisExperimental autoimmune uveitis• Experimental autoimmune orchitisExperimental autoimmune orchitis• Autoimmune myocarditisAutoimmune myocarditis• Autologous immune-complex nephritisAutologous immune-complex nephritis• Mercuric chloride-induced nephritisMercuric chloride-induced nephritis
Fischer RatsFischer Rats• Streptococcal cell wall arthritisStreptococcal cell wall arthritis• Lactobacillus cell wall arthritisLactobacillus cell wall arthritis• Collagen arthritisCollagen arthritis• Adjuvant arthritisAdjuvant arthritis• Experimental allergic encephalomyelitisExperimental allergic encephalomyelitis• Autoimmune myasthenia gravisAutoimmune myasthenia gravis• Autoimmune myasthenia gravisAutoimmune myasthenia gravis• Experimental autoallergic sialadenitis Experimental autoallergic sialadenitis • Experimental autoimmune thyroiditisExperimental autoimmune thyroiditis• Experimental autoimmune adrenalitisExperimental autoimmune adrenalitis• Experimental autoimmune uveitisExperimental autoimmune uveitis• Experimental autoimmune orchitisExperimental autoimmune orchitis• Autoimmune myocarditisAutoimmune myocarditis• Autologous immune-complex nephritisAutologous immune-complex nephritis• Mercuric chloride-induced nephritisMercuric chloride-induced nephritis
EM Sternberg et al PNAS 1989
Illnesses Associated with Blunted Illnesses Associated with Blunted Hormonal Stress ResponseHormonal Stress Response
ThyroiditisScleroderma
SLE
Arthritis, EAE, Septic Shock,Inflam mation
Rheumatoid Arthritis,SLE, Sjogren’s,Dermatitis, AsthmaFibromyalgia, CFS, IBS
Inflam matory/Autoim mune Disease
Low H ormonalStress Response
Cortisol Responses in Human Cortisol Responses in Human Autoimmune DiseaseAutoimmune Disease
Sjogren’s
SLE
Dermatitis
Asthma
TIME (min)
20 40 600-4002
5
7
9
11
TIME (min)-20
4
6
10
8
90 1206030-30 0-600
20
40
60
80
100
TIME (min)
9075604530150-150
5
10
15
20
25
30
TIME (min)
20 4010 30-30 0-400
2
6
10
14
18
-20 -10
4
8
16
12
80
ControlsPatients
DISEASE
oCRH
Hypoglycemia
PublicSpeaking
MentalArithmetic
STIMULUS
A Buske Kirschbaum et al.
A Buske Kirschbaum et al.
MA Gutierrez et al.
EO Johnson et al.
Interruption of the HPA axis and susceptibility to inflammatory disease
pharmacologicalpharmacological XX
geneticgenetic
surgicalsurgical XX
XX
SCW ArthritisSCW Arthritis Sternberg et al. PNAS 89
• RU486• cort
100% mortality 13% mortality
EAEEAE MacPhee et al. J Exp Med 89
• ADX• cort
80% mortality22% mortality
SalmonellaSalmonella Edwards et al. PNAS 91
• hypophysect• cort
100% mortality 5% mortality
MCMVMCMV Ruzek et al. J. Immunol. 99
• ADX• cort
100% mortality 20% mortality
Shiga toxinShiga toxin Gomez et al. Clin. Exp. Immunol. 03
• ADX• cort
60% mortality 10% mortality
Mortality in Animal Models where HPA Axis is Interrupted
Neuroendocrine Interactions in Neuroendocrine Interactions in Autoimmune/Inflammatory DiseaseAutoimmune/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
GR number
Associated protein
Glucocorticoid sensitivity
Reference
Rheumatoid Arthritis
GRβ polymorphism
Derijk et al, 2001. J Rheumatol, 28
Systemic Lupus Erythromatosus
(SLE)
GR mutation MDR Diaz-Borjon et al, 2000. Joint Bone Spine, 67
Lee, 2004. J Exp Med, 203
SLE Nephritis GR mutation GR Jiang et al, 2001. Clin Chem ACTA, 313
Crohn’s Disease GRβ 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 QTLsChromosomal Locations of QTLsRegulating Rat InflammationRegulating Rat Inflammation
Modified from Ronald Wilder, Elaine Remmers, Marie Griffiths, Grant Cannon, et al.
1 2 3 4 5 7 8 9 10 12 18 19 20 X Y
Genetic versus Environmental Genetic versus Environmental Contribution to InflammatoryContribution to Inflammatory
Trait VarianceTrait Variance
35%35%GeneticGenetic65%65%
EnvironmentalEnvironmental
Maternal Behavior Maternal Behavior in LEW/N & F344/N Ratsin LEW/N & F344/N Rats
-25
0
25
50
75
100
MINUTES
% RETRIVAL
LEW/N
F344/N
% R
ET
RIE
VA
L
Video: Maternal BehaviorVideo: Maternal Behavior
LEW/NLEW/N F344/NF344/N
QuickTime™ and aH.263 decompressor
are needed to see this picture.
QuickTime™ and aH.263 decompressor
are needed to see this picture.
Separation of rat pups for 5-15 Separation of rat pups for 5-15 minutes/day for first two weeks minutes/day for first two weeks of life leads to permanent of life leads to permanent increase in HPA axis increase in HPA axis responsiveness into adult life.responsiveness into adult life.Seymour Levine et al. 1975; Michael Meaney et al. 1995
Strain, gender and maternal Strain, gender and maternal environment interactions environment interactions determine adultdetermine adult stress stress
responsiveness in this model.responsiveness in this model.
GENETIC(MULTI/POLYGENIC)
ENVIRONMENTAL EXPOSURE
DEVELOPMENTAL
SET-POINT OF HOST RESPONSE
NEURAL(AUTONOMIC)
NEUROENDO.(HPA, HPT)
SEX HORMONES(HPG)
IMMUNE RESPONSE
RECOVERY VS PERSISTENCE SX
Acknowledgements
SNIB/NIMH/NIH
Esther SternbergA. Sasha TaitCherie ButtsElena BelyavskayaHeather GorbyAndrea Marques-DeakZhigang KangMarni SilvermanTaylor Dennison
Jeanette Webster*Leonardo Tonelli*Farideh Eskandari*Shetha Shukair*Kristina Duncan*Monique Dalton*Cash Horn*Eve Bowers*
NIAID/NIHSteven LepplaMahtab Moayeri
NIDDK/NIHS. Stoney SimonsGiovanni CizzaKenner Rice
CDCLawrence McDonaldSherif Zaki
NIAAA/NIHGeorge KunosPal Pacher
GSK, UKStuart Farrow
OD/NIHTerry Phillips
FDAFelice D’Agnillo
Institut Pasteur FRMichel Popoff
Max Planck, DusseldorfGunther Schutz