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THE IMMUNE RESPONSE

IN
TRAUMA PATIENTS

Mamiek Dwi Putro,dr.SpB.KBD.FInaCS,FICS

Kuliah untuk PPDS PRABEDAH


MEKANISME PERTAHANAN TUBUH

Defense Mechanism of The Body:


Nonspecific and Specific
The Immune System is the Third Line of Defense Against Infection
MACAM SEL DALAM SISTEM
IMUNITAS
ASAL LIMPOSIT

16-22
FUNGSI LIMPOSIT

• T cells • B cells
• secrete lymphokines • differentiate into plasma cells
• help activate T cells • produce antibodies
• cause T cell proliferation • humoral immune response
• activate cytotoxic T cells
• stimulate leukocyte production
• stimulate B cells to mature
• activate macrophages
• secrete toxins that kill cells
• secrete growth-inhibiting factors
• secrete interferon
• cellular immune response

16-23
RESPON IMUNITAS
Response of immune system to Antigen.

2 Tipe :

- Immune Respon from “B-Cell” (B Lymphocyte)


 “Humoral Immunity”

* Produce antibody

- Immune Respone from “T-Cell” (T Lymphocyte)


 “Cell Mediated Immunity”

* Helper T-Cell
* Supressor T-Cell & Cytotoxic cell
* Secretion Lymphokine
AKTIFASI “T CEll - B CEll”

16-26
MHC : major histocompatibility complex
Duality of Immune System

Humoral (Antibody-Mediated) Immunity

– Involves production of antibodies against


foreign antigens.
– Antibodies are produced by a subset of
lymphocytes called B cells.
– B cells that are stimulated will actively secrete
antibodies and are called plasma cells.
– Antibodies are found in extracellular fluids
(blood plasma, lymph, mucus, etc.) and the
surface of B cells.
– Defense against bacteria, bacterial toxins, and
viruses that circulate freely in body fluids,
before they enter cells.
– Also cause certain reactions against
transplanted tissue.
INJURIES AGENT

ISCHEMIA

INJURY INSULT
INFECTION

INFLAMMATION
Innitial response to injuries agent : non spesific immunities
Injurious agent of inflammation
Inflammation

Bacteriemia
Other
Infection SIRS
Fungemia
Sepsis Trauma
Parasitemia

Viremia Burn
Other Pancrea
titis
Blood borne infection

Chong D. Sepsis Syndrome. Down load. January, 2004


SYSTEMIC INFLAMATORY RESPONSE
SYNDROME ( SIRS )

Body temp > 38° C or < 36° C


Heart rate > 90 / minutes
Respiratory rate > 20/ minute or Pa CO2 < 32
mmHg
WBC > 12000 or 4000

Presence >2 clinical findings


BODY RESPONSES TO INJURIES

Immune System Response

Hormonal/ Endocrine System Response

Central nervous system Response

Cellular response

Metabolic & changes of nutrional response


Hormones
ENDOCRINE NERVOUS
Neuropeptide
SYSTEM SYSTEM

Cellular
respons
Metabolic/
nutrition
Hormones respons Cytokines

Cytokines Neuropeptides

IMMUNE
SYSTEM

Body respons to Injury


HORMONES & CYTOKINES

SOURCES TARGET ACTIVITIES ACTION

Specificity
HORMONES Secreted by a rather limited Single action Endocrine
specialyzed to one single
cell type of target
cell
(Except insulin)

CYTOKINES Produced by Numerous Wide paracrine


many cell target cells spectrum of autocrine
types activity endocrine

Redundancy
Components of inflammation
Chemical mediators
CYTOKINES MEDIATORS

Pro - Inflamatory cytokines

Anti – Inflamatory cytokines

Endogenous reseptor antagonists/ soluble


cytokines reseptor
PRO-INFLAMATORY MEDIATORS
( Pro-inflammatory cytokines )

Tumor Necrosis Factor alpha


IFN γ
IL-1
IL-8
IL-6
Etc
ANTI-INFLAMATORY MEDIATORS
( Endogenous Production of Anti-
inflammation Cytokines )

IL-4
IL-10
IL-13
TGF ß ( tissue growth factor betha)
etc
Endogenous Receptor antagonis/ soluble
cytokine receptor
sTNF RI
IL – reseptor antagonist ( IL-1 Ra )
TNF – RII ( p75 )

Closely related mediator with central


regulatory role
In trauma patients if HIGH in plasma level
predicted lethal outcome
SITOKIN
Glikoprotein diproduksi oleh banyak sel sbg
respons terhadap rangsangan spesifik / non
spesifik, segera dilepas, tidak disimpan dalam sel

Pleitropik : bekerja terhadap berbagai jenis sel


dan efeknya melalui berbagai mekanisme

Banyak fungsi yang sama oleh berbagai sitokin 


efect redundant
Bisa bekerja sinergis maupun bersifat antagonis

Efek melalui ikatan dengan reseptor spesifik pada


permukaan sel sasaran dan cenderung sangat
poten
PENGGOLONGAN SITOKIN

A. Berdasarkan homologi :

1. Sitokin Klas I atau Family Reseptor


Hematopoitin
2. Sitokin reseptor klas II atau IFN
Receptor Family
3. Sitokin reseptor klas III atau TNF
Receptor Family
4. Sitokin reseptor klas IV atau IL-1
Reseptor Family
5. Reseptor Superfamily
immunoglobulin
6. Reseptor Chemokin
B. Berdasar fungsi utama terhadap sel
target :

1. Sitokin yang mengatur fungsi


limposit
2. Sitokin yang turut dalam natural
immunity
3. Sitokin mengaktivasi sel
inflamasi
4. Sitokin yng merangsang
hematopoisis
5. Chemokin adalah sitokin yg bersifat
chemotaktif thd berbagai leukosit
SITOKIN & INFLAMASI
Immunitas non spesifik : respon awal dari infeksi
/ injury / ischemic/ inflamasi
Manifestasi immunitas non spesifik :  respon
inflamasi
Respons non spesifik akan diikuti respon imun
spesifik
Benda asing rangsang
Jaringan tubuh rusak timbul
(host tissue damage) respons
Inflamasi
Injuries Agent
(Injury,Infection,Ischemia,Inflam)
Danger signal / jaringan yang terkena trauma

Inflamasi lokal

3 komponen :
Perubahan kaliber vaskuler
Perubahan
- Protein plasma
- Leukosit
Migrasi ke fokus injury
Danger Signal : mengaktifkan inisiator
inflamasi :
Protein koagulasi
Platelet aktif
Mast cell
Aktivasi komplemen & kontak

 Produk C5a, thrombin, brodikinin

Macrophage lokal memproduksi TNF , IL-,


Chemokin, tissue faktor sebagai antigen
Adanya APC (antigen presenting cell)
Antigen baru dikenal oleh :
- CD4
- CD8

Interaksi endotel-leukosit memproduksi molekul


adhesi ( P-selectin ) transmisi gen
terbentuk E- selectin

ICAM-1 ( Intracellular adhesion molecule -1 ) 


mempengaruhi gerak leukosit
PERGERAKAN LEUKOSIT:

Fase I Inflamasi :

1. Interaksi P. selektin endotel dengan L. selektin


permukaan lekosit
2. Aliran leukosit menjadi lambat, invaginasi dan
rolling
3. Adhesi lebih kuat antara :
endotel (ICAM-1) dengan Leukosit
(-2 integrin)
4. Transmigrasi leukosit melalui

Celah antar sel endotel ke jaringan interstitiil


yang
diperantarai :
- PECAM ( Platelet endothelial
cell adhesion molecule)
- Chemokine

5. Menentukan “specifity for leucocyte recruitment”


Extravasation of PMN’s
Fase II Inflamasi :

1. Proses fagositosis oleh sel leukosit (PMN &


makrofag ) yang telah terakativasi oleh :
- mediator yang keluar
- debris
- sel-sel mati

Aktivitas lisosom dalam sel meningkat


2.Aktivasi leukosit  permukaan dapat mengenali
stimuli

3.Dalam leukosit & makrofage :

- Peningkatan Ca plasma dan enzym


proteinase C serta fosfolipase A2
 terbentuk metabolik arakhidonat
- Degranulasi enzym lisosom
- Sekresi sitokin
- Modulasi molekul adhesi

 Fungsi inflamasi :menghancurkan


melarutkan, membatasi jejas dapat dilakukan
oleh sel
Respon Inflamasi – Respon Imunologi

Stage I

- Respon tubuh terhadap trauma / infeksi


terbatas lingkungan lokal
- Sitokin ↑ berada sekitar jaringan yang
mengalami insult
- Sitokin menarik sel-sel pmn dan
mononoklier membunuh organisme patogen
- Membantu proses penyembuhan
Stage II
Sejumlah kecil sitokin masuk sirkulasi

Growth Factor menarik Makrofag, Trombosit

Terjadi Reaksi Akut

Terkendali
Tak Terkendali
Pro Inflamatory Mediator
Endogenous antagonist menuju
(Misalnya IL-1 resptor
antagonis )
Antibody meningkat Stage III

– Luka sembuh
– Infeksi teratasi
– Homeostasis pulih
Stage III

Homeostasis tidak berhasil dipulihkan

Sitokin Destruktif
(semula protektif)

Sirkulasi penuh dengan mediator inflamasi


Sitokin meningkat berlipat ganda

Integritas dinding kapiler rusak

Sitokin masuk organ/ jaringan

MOD

Kematian
Hubungan SIRS-CARS-MARS
Initial
Insult
Local Inflammatory Local Anti
response Inflammatory
response

Systemic Reaction
C SIRS( pro inflammatory )
CARS ( anti inflammatory S
Cardiovascular MARS ( mixed )
Compromise Suppression
( shock ) immune system
O
SIRS H
CARS
A
dominan Organ dominan
Homeostasis
Apoptosis Dysfunction
SIRS – CARS
SIRS SIRS
balance
dominan dominan
MACAM – MACAM SITOKIN

Cytokine : TNF-a

Dominant source : Macrophages

Stimulus : Sepsis, ischemia, TNF-a

Primary actions :

- Proinflammatory via feedback induction


of TNF-a, IL-1ß and chemokine production
- Cardiodepressant
- Cause cachexia
- Promotes apoptosis
Cytokine : Fast-Ligand

Dominant source : T-limphocytes,


natural killer cells

Stimulus : Constitutively expressed

Primary actions :
- Induces apoptosis via caspase activation
- Involved in tumor surveillance antiviral
responses
- May control hyper-inflammation
Cytokine : IL-1ß

Dominant source : Macrophages endothelial


cells

Stimulus : Sepsis, ischemia

Primary actions :

- Proinflammatory via induction of TNF-a,


IL-1ß, COX-2 and iNOS
- Synergizes with TNF-a
- Endogenus pyrogen
- Induces adhesion molecule (ICAM 1)
expression
Cytokine : IL-2

Dominant source : T-lymphocytes

Stimulus : Sepsis, ischemia

Primary actions :

- Growth factor for T-lymphocytes and


natural killer cells
- Induces proliferation and activation of
lymphokine activated killer (LAK)cells
Cytokine : IL-6

Dominant source : Macrophages,


T-lymphocytes

Stimulus : Sepsis, TNF-a, and


IL-1ß

Primary actions :

- Can be both pro and anti inflommatory


- Endogenous pyrogen
- Mediates hepatic acute phase response
- Used as an index of magnitude of
systemic inflammation
Cytokine : IL-8

Dominant source : Macrophages

Stimulus : TNF-a, and IL-1ß

Primary actions :

- A chimokine which recruits and activates


neutrophils
- Also used as an index magnitude of
systemic inflammation
Cytokine : IL-10

Dominant source : T-lymphocytes

Stimulus : Sepsis, TNF-a

Primary actions :

- Anti infllamatory via inhibition of TNF-a /


IL-1ß production and NF-?B translocation
- Hematopoietic growth factor
- Induces hepatic acute phase response
Cytokine : IL-11

Dominant source : Fibroblast, epithelial


cells, endothelial cells

Stimulus : Sepsis, TNF-a, IL-1ß,


TGFß

Primary actions :

- Anti inflammatory via inhibition of TNF/


IL-1ß production
- Hematopoietic growth factor
- Induces hepatic acute phase response
Cytokine : IL-12

Dominant source : Macrophages, dendritic


cells, neutrophils

Stimulus : Sepsis

Primary actions :

- Proinflammatory via induction of TNF-a


and interferon gamma
- Synergistic with IL-18
- Induces indefferentiation of TH1 cells
- Activates neutrophils
Cytokine : IL-18

Dominant source : Macrophages,

Stimulus : Sepsis, ischemia, TNF-a

Primary actions :

- Proinflammatory
- Synergizes with IL-12 to induce interferon
gamma
- Synergizes with IL-1ß to cause
myocardial depression
CLINICAL IMPLICATION
The immune response to trauma can
be quantified by measurrement of
soluble inflamatory mediator or
cellular marker
RATIONALE FOR THERAPEUTIC
INTERVENTION

IMMUNONUTRIENT
INTENSIVE INSULIN THERAPHY
ACTIVATED PROTEIN C
IFN gamma
rH G-SFF ( human recombinant
granulocyte stimulating factor )
CYCLOOXYGENASE INHIBITOR