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