You are on page 1of 72

Prof.DR.dr.Harijono KS.

SpKK
Tempat/Tgl lahir : Bondowoso, 7 September 1946
Alamat
: Jl. Gatot Subroto 230 Surakarta
Pendidikan
:
- Lulus dokter th 1972 FK.Unair
- Spesialis Penyakit Kulit & Kelamin th 1977 FK
Unair
Pendidikan tambahan :
- Pendidikan S III : Pasca sarjana Unair th lulus
th.2003

Pekerjaan/ Jabatan :
- Guru besar th 2004
- Ketua seksi alergi imunologi bag. I.Kesehatan
Kulit & Kelamin FK UNS th 1997-sekarang
- Anggota komite medik RSUD Dr.Moewardi th
2003-2008
- Ketua Program Sutudi I.Kesehatan Kulit &
Kelamin FK UNS th 1999-2003/ 2008-sekarang

Karya Ilmiah:
- 13 buah penelitian
- 17 Publikasi Ilmiah
- 3 Buku teks: 2 sbg kontributor dan 1 sbg
penulis utama

APLIKASI OBAT IMUNOSUPRESI &


ANTI ALERGI
Pengobatan penyakit atau kelainan akibat
gangguan respons imun:
I.

Pengobatan kausatif (terhadap agen


penyebab)
a.eliminasi agen: antibiotik, antivirus,
antijamur, anti parasit dsb

b.imunoprofilaksis (= imunisasi):
-pasif natural transplasental Ab transfer
artifisial tx Imunoglob
-aktif
natural infeksi
artifisial vaksinasi

II. Imunoterapi :
imuno supresi:-kortikosteroid
-cyclophosphamid
-azathioprin, dsb
anti alergi : antihistamin

Anti Histamin
Obat yang bekerja sbg antagonis terhadap
Histamin
Mediator patogenetik major pada berbagai peny
alergi
Dikeluarkan oleh sel mast dan atau basofil
setelah stimulus Ag degranulasi
Berasal dari a.a histidin, sekali terlepas darah
(2,5-5 mnt) reseptor histamin H1 pd jar tbh:
sel otot polos bronkus, usus halus dan pemb drh

Anti histamin
Reseptor H2: peran < H1 pada path.is peny alergi,

produksi asam lambung


Reseptor H3 : berhubungan dengan sistem saraf, fungsi : ?
Rangsangan histamin reseptor H1 atau brsm H2 :
-wheal & flare ok permeabilitas vaskular
-pruritus ok aktivasi saraf sensorik
-mucosal oedem ok vasodilatasi > pd mukosal dan
permeabilitas
-rhinorrhea ok sekresi > sel goblet & kel sub mukosa
disertai permeabilitas pd meningkat

ANTIHISTAMIN
AH1 generasi lama (I=pertama)
generasi kedua=baru (non-sedating)
generasi ketiga
AH2
ANTIHISTAMIN 1 Gen I (1940):
- Klorfeneramin (CTM), difenhidramin, hidroxsizin, prometazin,
pirilamin, tripolidin.
- Efek sampng: sedativ ok larut dlm lemak shg sawar drh
otak,
konstipasi, disuria, serotomia, batuk, nausea dan vomitus
ok. memacu hambatan reseptor kolinergik,a-adrenergik
glaukoma (pd usia lanjut) ok efek midriasis
- Tidak digunakan lagi secara rutin utk peny alergik kec
hidroxsizin pada urtikaria kronik dan dermatitis atopik sbg anti
pru

ANTIHISTAMIN 1 Gen. II :

AKRIVASTIN, ASTEMIZOL, AZELASTIN, LORATADIN,


KETOTIFEN, OKSATOMID DAN TERFENADIN

Afinitas dan selektrifitas thd reseptor H1 > tinggi dp gen I


Efek sedasinya minimal mgkn krn selektivitas thd R H1
perifer > daripada sentral
Dosis: eg loratadin = 10 mg 1 X/hari

ANTIHISTAMIN 1 Gen. III :


Setirizin metabolit asam karboksilat dari hidroksizin
dan
Fexofenadin metabolit aktif as karboksilat terfenadin

KORTIKOSTEROID

Pemahaman Tentang
Reaksi Alergi

Harijono Kariosentono*
PG. Konthen**
*Bag. I.Kes.Kulit & Kelamin FK UNS Surakarta
** Bag.I.Peny.Dalam FK Unair Surabaya.

Pendahuluan
Penyakit Alergi
Peny yang didasari oleh reaksi hipersensitivitas
terhadap benda asing dari lingkungan (alergen)
Bermanifestasi pada berbagai macam organ sasaran
Faktor yang mendasari
Genetik
Paparan alergen
Kondisi lingkungan

Salah bentuk dari imunopatologis

Atopi

Kecenderungan respon peningkatan IgE


Adanya IgE spesifik terhadap suatu komponen
Secara praktis : tes kulit yang positif
Dipengaruhi faktor herediter

Alergi
Manifestasi klinis penyakit atopi
Diperantarai IgE (Hipersensitifitas tipe I)
Contoh : asma, rinitis alergi, dermatitis atopi,
alergi makanan dll.

Hipersensitifitas
Respon imun yang menyimpang/berlebihan
Antigen :
Eksternal
Autoantigen (self antigen) penyakit
autoimun
Ada 4 macam tipe : I, II, III, IV

Four Types of Hypersensitivities

Type 1 = allergy

The four types of hypersensitivity reaction

Gell And Combs Classification Of


Immune-mediated Allergic Response
TYPE

MECHANISM

MANIFESTATIONS

IgE dependent

Anaphylaxis,
urticaria

II

Complement-mediated
cytotoxicity

Cytopenias

III

Immune complex
deposition

Vasculitis /
nephritis

IV

Delayed-type
hypersensitivity

Dermatitis or
hepatitis

Allergy
(type I hypersensitivity mediated by IgE on mast cells)

Epidemiologi
Penyakit alergi menjadi epidemi abad ke-21
Di negara maju :
Prevalensi
Atopi

: 30 40%

Asma : 5 10%
Rinitis : 10 20 %
Alergi makanan : 1 3 %

Clinical course of the disease

The apperance of atopic eczema on the back of


a knee in a child allergic to rice and eggs

Urticarial reaction to Penicillin

DTH as a result of a contact-sensitizing agent*


Contact Dermatitis
*a contact-sensitizing agent is usually
a small molecule that penetrates the
skin then binds to self-proteins,
making them look foreign

Can be caused by poison ivy


and mango sap

Changing of target organ in clinical allergy

R A

A R D O

A = Asthma R = Rhinitis D = Dermatitis O = other clinical manifestations

Symptom severity

Symptom Severity Versus Age

Eczema

4
8
Age (years)
Food
allergy

16

Asthma

32

64

Rhinitis

Faktor Genetik

Faktor Lingkungan

Adanya alele HLA spesifik


Polimorfisme FcRI-
Polimorfisme gena IL-4
Polimorfisme CD14
Polimorfisme lokus lainnya

Sensitisasi alergen
Saudara kandung sedikit
Hidup terlalu bersih
Antibiotika pada usia < 2 th
Vaksinasi

Atopi
Defek organ target
Epitel saluran nafas
Kulit
Saluran cerna

Pencetus
Infeksi virus
Paparan alergen
Merokok
Polutan indoor / out door

Reaksi alergi / inflamasi yang dimediasi oleh Th2

Faktor Genetik

Interaksi faktor genetik-alergen-lingkungan


penyakit alergi

Gen-gen penyandi atopi :


Interleukin
Protein MHC
Reseptor IgE berafinitas tinggi
Efektor Imunologi

Kromosom 5Q31-33, 11Q13, 13Q12-14

Gene-gene interactions and the pathogenesis


of allergic inflammation
Microbial
products
pollen

Allergen-specific IgG4

CD148

TLR2

Treg

DC

?
Prostanoid
receptor12
allergen

IL-109, TGF-10

B cell
IL4R

19,20

GATA3
STAT617

15

CD4 Thp

IL4

SOCS22

STAT6

18

IL135,6
IL13R121

CD4 Th2
Tbet

IL419,20 IL135,6 Allergen-specific IgE

16

CD4 Th1

IFN-
Basophil
Mast cell

FcERI24

Exogenic factors :
POLLUTANT - ALLERGEN - VIRUS

Pollutant
O3, NO2,
SO2

Allergen
Mite
Pollen

Virus
Rhino
Virus

Dust Mite

What are the


characteristics of
allergens?

It is not fully understood how


or why, but these type of
antigens tend to stimulate IL-4
production; IL-4 production
tends to lead to more IL-4
production . IL-4 favors class
switching to IgE

Induction and effector mechanisms in Type I Hypersensitivity

Allergy and Anaphylaxis


SKIN TEST

ALLERGEN

10 min.

H1

IgE
SYNTHESIS

TH2
B

NON-IgE TRIGGERS
ACH noradrenalin

IFN

IL-4

IgE
Fc

ATTACHMENT
TO MAST
CELL

OEDEMA

+ + +
+ cGMP

MUCUS
SECRETION

cAMP
+

MEDIATORS

CROSS-LINKING
BY ALLERGEN
CALCIUM
INFLUX

C3a
C5a

DSCG
adrenalin steroids
Ca2+

PG, LT

BRONCHIAL
CONSTRICTION

CHEMOTAXIS

antihistamines

INHIBITORS
DEGRANULATION &
MEDIATOR RELEASE

VASCULAR
PERMEABILITY

Sequence of events in immediate


hypersensitivity reactions
First exposure
to allergen

Repeated exposure
to allergen

Activation of
mast cells :
release of mediators

Allergen

B cell

TH2 cell

IgE-secretine
B cell

Antigen activation
of TH2 cells and
stimulation of
IgE class switching
in B cells

Mediators

Cytokines

Immediate
hypersensitivity
reaction (minutes
after repeated
exposure
to allergen)

Late-phase
reaction (2-4 hrs
after repeated
exposure
to allergen)

IgE

Mast cell

Production of IgE

Vasoactive amines,
lipid mediators

First exposure
to allergen

Mekanisme seluler dan molekuler pada reaksi alergi


+

IL-4

Late Phase
Allergic Reaction
(hours)

IL-4

APC
T cell

IL-4,IL-13 VCAM 9
Eotaxin

3
1

Th2
4

Antigen

IL-4, IL-13
CD40L

B cell

Eo-poesis
Eo survival
Eo activation

6
8

IgE

-1 3
L
I
,
IL-4

3,
1
, IL
4
L
I
IL-5

Histamine

TN
F-

8 Leukotrienes
Mast cell

Prostaglandins
PAF

Further wheezing
Sustained blockage
of the nose
Persistent inflammation

Tissue Eosinophils

Acute
Allergic Reaction
(minutes)

Vasc. permeability
Vasodilatation
Smooth muscle
contraction
Mucus secretion

Wheezing
Urticaria
Sneezing, rhinorrhea
Conjunctivitis

Mechanism of early and late phase


allergic reaction
0

Early phase

APC

MBP, ECP,
EDN, CLC etc

FcRI

Th2 B cells
Eos
Histamin, PGD2,
LTs etc

Th0

TNF-
IL-4
IL-5
IL-8
GM-CSF
MIP-1
MCP-3

ICAM-1
VCAM-1
E-selectin Eos

Epithelium

RANTES
MCP-4
Eotaxin

MBP, ECP,
EDN, CLC etc

IL-3
IL-4
IL-5
IL-6
IL-13
RANTES

Th2

RANTES
Eotaxin
IL-8
GM-CSF
Endothelium
PAF

TNF-
IL-
IL-3
IL-4
IL-5
IL-8
GM-CSF

Mast cells

48 (h)

Very late phase

Late phase

Ag

IL-4

24

Baso
Histamin, LTC4

IL-4
IL-13
MIP-1
VCAM-1

RANTES
Eotaxin
IL-8
GM-CSF
PAF

Endothelium
Th2

Baso

Eos

Immediate and late skin reactions

Interaksi antara sel Th2 dan sel B yang


diperlukan untuk sintesis IgE spesifik
Sel T
IL-4

CD40L
(CD154)
CD28
TCR
CD4

Sel B
IL-4R
CD40

B7-1
(CD80)
MHC II

Mast cell and its mediators


AA + PAF

PLA2

Preformed mediators
Histamine
Heparin
Tryptase
(Chymase)
Kininogenase

CO

Mast Cell

TNF-
TGF-
(IL-3, 4, 5)
(IL-13)

PGD2

5-LO

LTC4
LTD4
LTE4

Mlanges of mast cell mediators


Nerves

Glands

Vessel

Itch
Recruit reflexes
Sneezing
Malaise

Mucus
secretions

Vasodilatation
Mucosal Thickening
Permeability
Watery rhinorrhea

LTB

Mast cell degranulation by antigen (allergen) cross-linking


of Fc R-bound IgE

Eosinophils and basophils


may also participate

Compounds Released from Mast Cells

Pre-formed
and in
granules

Synthesized
upon mast
cell activation

Mast cell activation and physiological effects of


mast-cell derived mediators

Mast cell activation has many effects

Why? Normally IgE responses are associated


with worm infestations. These responses help
evacuate the places where the worms often live.

Like mast cels,

Eosinophils
have Fce
receptors

Compounds Released from Eosinophils

Biologic effects of mediators of


immediate hypersensitivity
Vascular leak
Biogenic amines
(e.g., histamines)

Bronchoconstriction

Lipid mediators
(e.g., PAF, PGD2, LTC4)
Intestinal
hypermotility
Activated
mast cell
(or basophil)

Cytokines
(e.g., TNF)
Lipid mediators
(e.g., PAF, PGD2, LTC4)
Enzymes
(e.g., tryptase)

Inflammation

Tissue
damage

Allergy symptoms depend on route of allergen entry

Can be fatal.
Allergy to insect
venom, drugs,
foods and

Target organs of allergy :


Organ

Disease

Respiratory tract . Asthma


Nose . Allergic rhinitis
Eye .. Allergic conjunctivitis
Skin . Urticaria
Central Nervous System ..

Migraine

Neuro-musculosceletal Neuromyalgia
Digestive tract Diarrhea
Cardiovascular ... Anaphylactic shock

macrophage
-

IL-12

CD4+ve
Helper
T cell

High dose antigen


e.g. DPT, viral or
bacterial infection
MHC/
peptide

Th1

Delayed
hypersensitivity

Th1
IL-2
IFN

+
IFN

IgG1

Th

IL-4
+

eosinophil

Th2

Th2

IL-5

- --

IL-4, IL-13

Low dose antigen


e.g. allergens

eosinophil
B

- --

Dendritic cell

MHC/
peptide

T Cell Differentiation
During Human Immune
Responses
(Immune Deviation)

IgE, IgG4
Mast cell*

Differentiation of Naive CD4+ T Cells into


Subsets of Effector Cells
Pathogens
influence
cytokines that
affect TH0
differentiation
into TH1 or TH2

Amount of antigen presented and TCR binding strength


influence TH0 differentiation into TH1 or TH2

Weak
binding
TH0

Strong
binding
TH0

TH2

TH1

IL-12

Th0

Th1

IL-2
IFN-gamma
TNF-beta

Cell mediated cytotoxicity


Macrophage activation
B cell help

IL-2
IL-4
IFN-gamma

IL-4

Th2

IL-4
IL-5
IL-6
IL-10
IL-13
IFN-gamma

Eosinophilia
Mast Cell
IgE / IgG

Transplantation tolerance (?)

Interaction of TH1 and TH2

Thus,
usually,
either TH1
or TH2
dominates
and the
other is
very low

Ringkasan
Organ sasaran penyakit alergi bermacam-macam
Etiologi : genetik, alergen, lingkungan
Mekanisme : hipersensitifitas tipe I
Peranan penting : IgE, sel mast, basofil, eosinofil
Hipotesis higiene : alergi merupakan respon TH 2

KORTIKOSTEROID
Hormon, disintesa kortek Adrenal
Efek
Mineralokortikoid : - Aldosteron
Glukokortikoid : - Hidrokortison (Kortisol)
Anti Inflamasi
Imunosupressi
Metabolisme : Glukoneogenesis
Lipolisis
Naik
Protein breakdown
Timbunan calsium turun

Sintetik

Osteoporosis

Kortikosteroid
(KS))

Sintesa Protein :

Transkripsi DNA

Translasi m RNA

KS + Reseptor = Komplek Reseptor Kortikosleroid (KRK)

Inti sel : + DNA

GRE +
Transkripsi

GRE :
(GlucoCorticoid
Response Element)

GRE (-)
Transkripsi

Mekanisme
kerja Kortikosteroid

Menurunkan/ Mencegah respon jaringan


terhadap proses inflamasi
Menghambat Akumulasi sel-sel Inflamasi
Mengurangi dilatasi dan permeabilitas kapiler
Peningkatan Sintesa Lipokortin 1
Menghambat enzim fosfolipase A2 Mediator
Lipid terbentuk

Efek Imunosupresi Steroid

1. Proses transkripsi Menurunkan


Molekul pro Inflamasi
2. Menekan Replikasi & Pergerakan sel
Monositopenia, eosinopenia,
limfositopenia

TERIMA KASIH