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STRESS AND IMMUNE

SYSTEM
C. SINGGIH WAHONO
Divisi Reumatologi-Imunologi
Lab/SMF IPD RSSA/FK UB
email: singgih_wahono@yahoo.com

Psychoneuroimmunology (PNI)
Interaksi antara proses psikologis
dengan sistem saraf serta sistem
imun.
Terrjadi kerjasama antara berbagai
displin ilmu: psychology,
neuroscience, immunology,
endocrinology, physiology, infectious
disease, rheumatology, etc.

Stress itu apa?


Merupakan mekanisme pertahanan
alamiah
Suatu respons psikologis dan
fisiologis terhadap suatu kebutuhan
dan tekanan baik dari dalam individu
maupun dari luar.

External vs Internal Stressor


External stressors: lingkungan fisik
(misal: nyeri, suhu dingin atau
panas), lingkungan dengan stres
psikologis(misalnya: suasana kerja
yang tidak mendukung, hubungan
antar manusia yang tidak baik).
Internal Stressors: fisik (infeksi,
inflamasi), psikologis.

10

Stressor Time Windows


Immediate acute phase (timbul dalam hitungan menit) the
fight/flight response, merupakan reaksi terhadap ancaman
yang terjadi segera:
Misalnya: kebisingan, isolasi, kelaparan, infeksi serius,
memikirkan adanya ancaman, dll.
Short-term stressors (berlangsung beberapa hari sampai
minggu)
Misalnya: ujian, pindah rumah, pasca kebakaran, dll.
Chronic stressors (berlangsung beberapa bulan sampai
bertahun-tahun): situasi yang berlangsung lama dan naik turun,
misalnya: merawat anggota keluarga yang menderita
penyakit Alzheimers , tekanan tinggi ditempat kerja yang
berlangsung terus, ketidak harmonisa ]n perkawinan,
kemiskinan, dll.

Jalur Stress

Corticotropin
releasing hormone
(CRH)

Adrenocorticotropi
hormone
(ACTH)

STRESS EFFECTS

Immediate
effect (Efek
segera)
Sympathetic
nervous response
Epinephrine and
norepinephrine
released
Time - 2 to 3
seconds
Like a phone call

Intermediate effect

Adrenal response
Epinephrine and
norepinephrine
release from
adrenal medulla
Time- 20 to 30
seconds
Like a telegram

Prolonged effect

ACTH,
vasopressin and
thyroxine affect
various metabolic
processes
Time - minutes,
hours, days or
weeks
Like an overnight

Bagaimana Stress ikut berperan


dalam timbulnya penyakit?

Bagaimana Stress
mempengaruhi sistem Imun?

Innate and adaptive immunity

Antigen phagocytosed
by APC

Macrophage

Th1
T helper

APC

MHC 2

CD4+
Th2
help
Intracellular microbes/
virus

B cell
T cytolytic

Plasma cell

MHC 1

Virus infected cell

CD8+

Effector T cytolytic

BIRDVIEW OF ADAPTIVE IMMUNITY

Th1 and Th2 cytokines

Sel imun:
Mempunyai reseptor untuk hormon dan
neurotransmiter

Jaringan Limfoid (limfonodi, :


innervated by the autonomic nervous
system (ANS)
Noradrenergic nerve tracts in the thymus
and spleen

Stressors causing inflammation


process, activate immune system
to signal the brain or activate
nerves nearby that signal the brain
Activate hypothalamus to initiate
cascade hormones released from
pituitary and adrenal gland causing
increased of glucocorticoid
(cortisol)

Communication systems include:


HPA
Sympathetic nervous system (SNS)
Noradrenergic innervate immune
system
Cytokines induce symptoms of
illness

STRESSOR

NO

MODERATING VARIABLES
Genetic predisposition
Previous life experiences
Coping
Social support

Psychological Stress?

YES

HYPOTHALAMIC
ACTIVATION

CRH
PITUITARY FACTORS
ACTH

SYMPATHETIC ACTIVATION
Norepinephrine

Medulla
GLUCOCORTICOIDS

Cortex
Adrenal Glands

IMMUNE SYSTEM

EPINEPHRINE

HPA Axis

GOODMAN & GILMAN'S,2006

NE and epinephrine can alter


lymphocyte migration:
Immediate exposure (30 min)
lymphocytes,
natural killer cells
Longer exposure (days)
NK cells

NE can alter innate and adaptive


immune function in organs and in
circulation:
Fine tunes immune responses,
allowing for quick adjustments
(within minutes)
Shift from Th1 to Th2

Leukocytes express glucocorticoid receptors:

cortisol acts on glucocorticoid receptors to have the


following effects
inhibit lymphocyte proliferation
inhibit production of pro-inflammatory cytokines
Shift from Th1 to Th2 cell activity by stimulating
synthesis of IL-10, IL-4

11

Innate Immune System Mobilization in


the Immediate Acute Phase of a Stressor
Redistribution of immune cells
(increase in leukocytes in blood)
Increase in innate, non-specific
immunity (increased NK cell activity)
Decrease in specific immunity

Alterations in Specific Immunity following


Exposure to Short-term Stressors:

Decrease in Th1 cellular immune


response (e.g., proliferative response
of lymphocytes)
Increase in Th2 humoral immunity
(e.g., Th2 cytokine production)

1
2

13

Alterations in Non-specific and Specific Immunity


following Exposure to Chronic Stressors:

Decrease in both Th1 cellular and Th2


humoral immune response (e.g., lower
antibody titers to hepatitis B vaccines*)
Decrease in innate, non-specific immune
responses (except inflammatory activity)
Persistent inflammatory activity (e.g.,
increased pro-inflammatory cytokine
production)

14

Effects of Stress on the Immune


System Depend not Only on Timing
but Characteristics of the Person
Immune effects are stronger in
those who:
Are older
More depressed
Less supported

20

Hypothalamus
CRH

Anterior Pituitary
ACTH

Adrenal Cortex
Cortisol

Stressors
immediate-acute
phase
Short-term-days/weeks
Chronic-months/years

Hypothalamus
CRH

Anterior Pituitary

Cortisol suppresses
immune functions
such as proinflammatory cytokine
production via the
glucocorticoid
receptor (GCR).

ACTH

Adrenal Cortex
Cortisol

GCR

Immune Cell

21

Hypothalamus
CRH

Anterior Pituitary
ACTH

2
But stress-> INCREASES pro-2
inflammatory cytokine
production
One mechanism: Glucocorticoid
Resistance: stress induced
downregulation of GCR; cortisol
cannot restrain proinflammatory cytokine
production so cytokine
production increases
(animal/human studies)

Adrenal Cortex
Cortisol

GCR

Immune
Cell

Stress related
Diseases

Chronic stress related to


several health problems:

Heart disease
Diabetes
Ulcers
Growth problems
Immune system suppression
Lower survival rates with cancer

Cardiovascular

Hypertension
Angina
Migraine headaches
Raynauds disease

Reproductive
Amenorrehea
Impotence

Gastrointestinal
Peptic ulcers
Ulcerative
colitis
Irritable bowel
Esophageal
reflux
Dermatological
Eczema
Acne
Psoriasis
Alopecia

STRESS

Musculoskeletal
Tension
headaches
Low back pain
Respiratory
Bronchial
asthma
Hyperventilatio
n

Immune system
Suppression/coll
apse
Malignant cell
changes; cancer
Organ/tissue
rejection

Interactions among The Endocrine, central nervous &


immune system
Stressor

d
an
es s
id ide
pt pt
pe pe
ry ro
u
itt
ita ne
m
tu
Pi her
ns
ra
ot

Endocrine
system

ot
un
m
Im
er

Pi
ho tuit
rm ary
on
e
En
ho doc
rm rin
on e
e

CNS

Endocrine
hormones
Steroids, prolactin,
etc

Immune
system

24

Are these stress-induced


immunologic changes
clinically significant?
Do they contribute to disease
onset or accelerate disease
course?

2
6

28

Mediators of Stress-related Changes


in Wound Healing
diminished mononuclear cell
trafficking to the wound site
reduced expression of cytokine,
chemokine, growth factor genes
decreased production of proinflammatory cytokines in wound
environment*

Effect of stress on Cancer


Decrease cellular immune response
(innate & adaptive) against cancer
Decreased DNA repair capacity
Inhibit cancer cells apoptosis
Behavioral therapy can increase
immune response against cancer

Effect of Stress on
Autoimmune disease
Flare of some autoimmune
diseases, e,g. : SLE, RA, SSA, etc.

Effect of Stress on Infection


Prolonged the course of TB
Streptococcal and stapyloccal
infection is increased
Associated with respiratory
infection, recurrent of genital
herpes, common cold.

Interventions to enhance
immunocompetence

AIDS patients who benefited from


exercise and stress reduction
intervention, :
improvement in T CD4+ /TCD8+
ratios,
CD4+ T cell counts,
NK-cell cytotoxicity.

Interventions to enhance
immunocompetence
Relaxation may mute effects of
stress:
higher NK cellactivity after
relaxation intervention
Reduces pro-inflammatory
cytokines
Cellular immunity enhanced

Interventions to enhance
immunocompetence
Better NK cell activity in breast
cancer patients was related to:
High quality emotional support
from a spouse,
Perceived psychosocial support
from the patients physician
Actively seeking social support

29

How Might Information From the Field


of Psychoneuroimmunology Influence
Your Clinical Practice?
Ask about life stressors (short
term and chronic), impact on
functioning
Ask about how a patient is coping,
social supports. Does it help?
Recognize that vaccinations may
be less protective during stressful
times (consider other
precautions)

How Might Information From the


Field of Psychoneuroimmunology
Influence Your Clinical Practice?
Recognize that wound healing may be
influenced by stress
Recognize that immune functions may
be affected by the use of drugs that
influence the ANS or glucocorticoids
(e.g., -blockers).
Ask about therapy and make
recommendations and/or referrals as
needed (know what is available in the
community).
recognize the limitations in knowledge
when patients ask about whether a
given therapy (visualization, etc) can

Conclusions
There is a significant relationship
between Psychology, neurologic
system, immune system and health/
diseases.
Hopefully, it will provide a better
improvement promoting health,
preventing disease, and improving
the results of conventional therapies