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) Intermediate effect
Sympathetic
nervous response
Epinephrine and
Adrenal response Prolonged effect
norepinephrine
Epinephrine and
released
norepinephrine
Time - 2 to 3
release from
seconds ACTH,
adrenal medulla
Like a phone call vasopressin and
Time- 20 to 30
thyroxine affect
seconds
Like a telegram various metabolic
processes
Time - minutes,
hours, days or
weeks
Like an overnight
 1
Bagaimana Stress ikut berperan
dalam timbulnya penyakit?
Bagaimana Stress
mempengaruhi sistem Imun?
Innate and adaptive immunity
Antigen phagocytosed Macrophage
Th1
by APC

T helper
APC MHC 2

CD4+
Th2
help
Intracellular microbes/ B cell
virus
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

 7
MODERATING VARIABLES
STRESSOR Genetic predisposition
Previous life experiences
Coping
Social support

NO Psychological Stress? YES

HYPOTHALAMIC
ACTIVATION

CRH
PITUITARY FACTORS SYMPATHETIC ACTIVATION
ACTH Norepinephrine

Medulla
EPINEPHRINE

GLUCOCORTICOIDS Cortex

Adrenal Glands

IMMUNE SYSTEM
HPA Axis

GOODMAN & GILMAN'S,2006

 5
NE and epinephrine can alter
lymphocyte migration:

Immediate exposure (30 min)

lymphocytes,
natural killer cells

Longer exposure (days)

NK cells
 6
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

 8

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 IL-
10, 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
Stressors
CRH immediate-acute
phase
Short-term-days/weeks
Chronic-months/years
Anterior Pituitary

ACTH

Adrenal Cortex

Cortisol
 21
Cortisol suppresses
Hypothalamus
immune functions
such as pro-
CRH
inflammatory cytokine
production via the
glucocorticoid
receptor (GCR).
Anterior Pituitary
Kortisol menekan
fungsi kekebalan
ACTH
tubuh seperti produksi
sitokin pro-inflamasi
melalui reseptor
glukokortikoid (GCR).
Adrenal Cortex

Cortisol GCR Immune Cell

 2
Hypothalamus But stress-> INCREASES pro-2
inflammatory cytokine
production
CRH
One mechanism: Glucocorticoid
Resistance: stress induced
downregulation of GCR; cortisol
cannot restrain pro-
inflammatory cytokine
Anterior Pituitary production so cytokine
production increases
(animal/human studies)
ACTH Tapi stres> MENINGKATKAN
produksi sitokin pro-inflamasi
Salah satu mekanisme:
glukokortikoid Resistance: stres
diinduksi downregulation dari
GCR; kortisol tidak bisa
Adrenal Cortex menahan produksi sitokin pro-
inflamasi sehingga peningkatan
produksi sitokin (hewan / studi
Cortisol manusia Immune
GCR

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 Gastrointestinal
Hypertension Peptic ulcers
Angina Ulcerative
Migraine headaches colitis
Raynauds disease Irritable bowel
Esophageal
reflux
Reproductive Dermatological
Amenorrehea Eczema

STRESS
Impotence Acne
Psoriasis
Alopecia

Musculoskeletal
Tension
headaches Immune system
Low back pain Suppression/coll
apse
Respiratory Malignant cell
Bronchial changes; cancer
asthma Organ/tissue
Hyperventilatio rejection
n
Interactions among The Endocrine, central nervous &
immune system

Stressor

CNS

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Endocrine
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Endocrine Steroids, prolactin, Immune
system etc 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 pro-

inflammatory 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