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
dipersarafi oleh sistem saraf otonom (ANS)
Saluran saraf noradrenergik di timus dan limpa

 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)
Stres menyebabkan proses inflamasi, mengaktifkan
sistem kekebalan tubuh untuk sinyal otak atau
mengaktifkan saraf di dekatnya yang sinyal otak
Aktifkan hipotalamus untuk memulai hormon cascade
dilepaskan dari hipofisis dan kelenjar adrenal
menyebabkan peningkatan glukokortikoid (kortisol)

 Communication systems include:

HPA
Sympathetic nervous system (SNS)
Noradrenergic innervate immune system
Cytokines induce symptoms of illness
Sistem komunikasi meliputi:
HPA
Sistem saraf simpatik (SNS)
Innervate noradrenergik sistem kekebalan tubuh
Sitokin menginduksi gejala penyakit

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:
NE dapat mengubah bawaan dan adaptif fungsi
kekebalan tubuh dalam organ dan beredar:
Fine tunes immune responses, allowing
for quick adjustments (within minutes)
Shift from Th1 to Th2
"Baik lagu" respon imun, yang
memungkinkan untuk penyesuaian cepat
(dalam beberapa menit)
Bergeser dari Th1 ke 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
kortisol bekerja pada reseptor glukokortikoid memiliki efek berikut
menghambat proliferasi limfosit
menghambat produksi sitokin pro-inflamasi
Bergeser dari Th1 ke aktivitas sel Th2 dengan merangsang sintesis IL10, IL-4

11

Innate Immune System Mobilization in the Immediate Acute

Phase of a Stressor
Sistem kekebalan bawaan Mobilisasi di Fase akut Segera Stressor
sebuah

Redistribution of immune cells (increase in

leukocytes in blood)
Increase in innate, non-specific immunity
(increased NK cell activity)
Decrease in specific immunity
Redistribusi sel kekebalan (peningkatan leukosit dalam darah)
Peningkatan bawaan, kekebalan non-spesifik (peningkatan aktivitas
sel NK)
Penurunan imunitas spesifik

1
Alterations in Specific Immunity following Exposure to Short- 2

term Stressors:
Perubahan dalam Imunitas spesifik berikut Paparan Stresor jangka
pendek:

Decrease in Th1 cellular immune response (e.g.,

proliferative response of lymphocytes)
Increase in Th2 humoral immunity (e.g., Th2
cytokine production)
Penurunan respon imun seluler Th1 (misalnya,
respon proliferatif limfosit)
Peningkatan kekebalan humoral Th2 (misalnya,
Th2 produksi sitokin)

13

Alterations in Non-specific and Specific Immunity following Exposure to

Chronic Stressors:
Perubahan dalam Imunitas Non-spesifik dan khusus berikut Paparan Tekanan kronis

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)
Penurunan kedua respon imun humoral Th1 seluler dan Th2 (misalnya,
titer antibodi yang lebih rendah untuk vaksin hepatitis B *)

Penurunan bawaan, respon imun non-spesifik (kecuali aktivitas

inflamasi)
(Produksi sitokin misalnya, meningkat pro-inflamasi) aktivitas inflamasi
persisten

System Depend not Only on Timing

14
but Characteristics of the Person
Pengaruh Stres tentang Sistem
kekebalan Tergantung tidak hanya
pada Timing tapi Karakteristik
Orang
yang

Immune effects are stronger in those who:

Are older
More depressed
Less supported
Efek kekebalan tubuh lebih kuat pada mereka yang:
lebih tua
lebih depresi
Kurang didukung

20

Hypothalamus
CRH

Anterior Pituitary
ACTH

Adrenal Cortex
Cortisol

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

Hypothalamus
CRH

Anterior Pituitary
ACTH

Cortisol suppresses
immune functions
such as proinflammatory cytokine
production via the
glucocorticoid
receptor (GCR).
Kortisol menekan
fungsi kekebalan
tubuh seperti produksi
sitokin pro-inflamasi
melalui reseptor
glukokortikoid (GCR).

Adrenal Cortex
Cortisol

GCR

Immune Cell

21

Hypothalamus
CRH

Anterior Pituitary
ACTH

Adrenal Cortex
Cortisol

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)
Tapi stres> MENINGKATKAN
produksi sitokin pro-inflamasi
Salah satu mekanisme:
glukokortikoid Resistance: stres
diinduksi downregulation dari
GCR; kortisol tidak bisa
menahan produksi sitokin proinflamasi sehingga peningkatan
produksi
sitokin (hewan / studi
GCR
manusia 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?
Perubahan imunologi stres akibat ini secara klinis
signifikan?
Apakah mereka berkontribusi untuk timbulnya
penyakit atau mempercepat perjalanan
penyakit?

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
Menurunkan respon imun seluler (bawaan & adaptif)
terhadap kanker
Penurunan kapasitas perbaikan DNA
Menghambat sel kanker apoptosis
Terapi perilaku dapat meningkatkan respon
kekebalan terhadap kanker

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.
Memperpanjang program TB
Infeksi streptokokus dan stapyloccal
meningkat
Terkait dengan infeksi pernapasan, berulang
herpes genital, flu biasa.

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.
Pasien AIDS yang mendapatkan manfaat dari
latihan dan intervensi pengurangan stres,:
peningkatan T CD4 + / rasio TCD8 +,
Jumlah CD4 + T,
Sitotoksisitas sel NK.

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
Aktivitas sel NK yang lebih baik pada pasien kanker
payudara terkait dengan:
Kualitas tinggi dukungan emosional dari pasangan,
Dirasakan dukungan psikososial dari dokter pasien
Aktif mencari dukungan sosial

of Psychoneuroimmunology Influence29
Your Clinical Practice?
Bagaimana Mungkin Informasi Dari
Bidang Psychoneuroimmunology
Pengaruh?
Clinical Practice Anda?
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)
Bertanya tentang stres kehidupan (jangka pendek dan
kronis), berdampak pada fungsi
Bertanya tentang bagaimana seorang pasien
mengatasi, dukungan sosial. "Apakah itu membantu?"
Mengakui bahwa vaksinasi mungkin kurang pelindung
selama masa stres (mempertimbangkan tindakan
pencegahan lainnya)

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
Ada hubungan yang signifikan antara Psikologi, sistem
neurologis, sistem kekebalan tubuh dan penyakit
kesehatan /.
Mudah-mudahan, itu akan memberikan peningkatan
yang lebih baik meningkatkan kesehatan, mencegah
penyakit, dan meningkatkan hasil terapi konvensional