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8/13/2019 Ari Reaksi Alergi
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Prof.DR.dr.Harijono KS. SpKK
Tempat/Tgl lahir: Bondowoso, 7 September 1946Alamat : 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
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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
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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
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b.imunoprofilaksis (= imunisasi):
-pasif natural transplasental Ab transferartifisialtx Imunoglob
-aktif natural infeksi
artifisial vaksinasi
II. Imunoterapi :
imuno supresi:-kortikosteroid
-cyclophosphamid-azathioprin, dsb
anti alergi : antihistamin
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Anti Histamin
Obat yang bekerja sbg antagonis terhadapHistamin
Mediator patogenetik major pada berbagai penyalergi
Dikeluarkan oleh sel mast dan atau basofilsetelah stimulus Ag degranulasi
Berasal dari a.a histidin, sekali terlepas darah(2,5-5 mnt)reseptor histamin H1pd jar tbh:sel otot polos bronkus, usus halus dan pemb drh
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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-adrenergikglaukoma (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
ritus dan efek sedasinya yg ringan.
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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 hidroksizindan
Fexofenadin metabolit aktif as karboksilat terfenadin
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KORTIKOSTEROID
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Pemahaman Tentang
Reaksi Alergi
Harijono Kariosentono*PG. Konthen**
*Bag. I.Kes.Kulit & Kelamin FK UNS Surakarta** Bag.I.Peny.Dalam FK Unair Surabaya.
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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
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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.
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Hipersensitifitas
Respon imun yang menyimpang/berlebihan
Antigen :
EksternalAutoantigen (self antigen) penyakit
autoimun
Ada 4 macam tipe : I, II, III, IV
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Four Types of Hypersensitivities
Type 1 = allergy
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The four types of hypersensitivity reactionThe four types of hypersensitivity reaction
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Gell And Combs Classification Of
Immune-mediated Allergic Response
TYPE MECHANISM MANIFESTATIONS
I IgEdependent
Anaphylaxis,
urticaria
IIComplement-mediated
cytotoxicityCytopenias
III Immune complexdeposition
Vasculitis /nephritis
IVDelayed-type
hypersensitivity
Dermatitis or
hepatitis
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Allergy(type I hypersensitivity mediated by IgE on mast cells)
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Epidemiologi
Penyakit alergi menjadi epidemi abad ke-21
Di negara maju :
Prevalensi
Atopi : 3040%
Asma : 510%
Rinitis : 1020 %
Alergi makanan : 13 %
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Clinical course of the disease
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The apperance of atopic eczema on the back of
a knee in a child allergic to rice and eggs
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Urticarial reaction to Penicillin
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*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 ivyand mango sapContact Dermatitis
DTH as a result of a contact-sensitizing agent*
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Changing of target organ in clinical allergy
D R O
AR A D RA D O
A = Asthma R = Rhinitis D = Dermatitis O = other clinical manifestations
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Symptom Severity Versus Age
0 1 2 4 8 16 32 64
Age (years)
Symptom
severity
Eczema Food
allergy
Asthma Rhinitis
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Atopi
Reaksi alergi / inflamasi yang dimediasi oleh Th2
Faktor Lingkungan
Sensitisasi alergen
Saudara kandung sedikitHidup terlalu bersihAntibiotika pada usia < 2 th
Vaksinasi
Pencetus
Infeksi virus
Paparan alergen
MerokokPolutan indoor / out door
Faktor Genetik
Adanya alele HLA spesifik
Polimorfisme FcRI-Polimorfisme gena IL-4Polimorfisme CD14
Polimorfisme lokus lainnya
Defek organ target
Epitel saluran nafas
Kulit
Saluran cerna
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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
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Pollutant
O3, NO2,
SO2
Exogenic factors :
POLLUTANT - ALLERGEN - VIRUS
Allergen
Mite
Pollen
Virus
Rhino
Virus
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Dust Mite
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What are the
characteristics of
allergens?
It is not fully understood how
or why, but these type of
antigens tend to stimulate IL-4production; IL-4 production
tends to lead to more IL-4
production . IL-4 favors class
switching to IgE
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Induction and effector mechanisms in Type I HypersensitivityInduction and effector mechanisms in Type I Hypersensitivity
Allergy and Anaphylaxis
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Allergy and Anaphylaxis
TH1
TH2
B
cAMP
cGMP
++++
+
ALLERGEN
IgE
SYNTHESIS
ATTACHMENT
TO MAST
CELL
CROSS-LINKING
BY ALLERGEN
CALCIUM
INFLUX DEGRANULATION &
MEDIATOR RELEASE
VASCULAR
PERMEABILITY
CHEMOTAXIS
BRONCHIAL
CONSTRICTION
MUCUSSECRETION
OEDEMA
SKIN TEST
NON-IgE TRIGGERS
noradrenalinACH C3aC5a
IFN
IL-4
IgE
Ca2+
adrenalinDSCG
steroids
antihistamines
PG, LT
MEDIATORS
INHIBITORS
10 min.
Fc
S f t i i di t
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Sequence of events in immediate
hypersensitivity reactions
Antigen activation
of TH2 cells and
stimulation of
IgE class switching
in B cells
First exposureto allergen
Production of IgEFirst exposure
to allergen
Repeated exposure
to allergen
Activation ofmast cells :
release of mediators
CytokinesVasoactive amines,
lipid mediators
Late-phase
reaction (2-4 hrs
after repeated
exposure
to allergen)
Immediate
hypersensitivity
reaction (minutes
after repeated
exposure
to allergen)
Allergen
B cell
TH2 cell
IgE-secretine
B cell
IgE
Mast cell
Mediators
Mekanisme seluler dan molekuler pada reaksi alergi
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Mekanisme seluler dan molekuler pada reaksi alergi
IL-4 IL-4+ +
8
12
3
6
5
7
8
+
8
8
48
9
APC
T cell
Th2
Antigen
IgE
B cell
Mast cell
IL-4,IL-13 VCAMEotaxin
Eo-poesisEo survivalEo activation
IL-4, IL-13
CD40L
Histamine
Leukotrienes
Prostaglandins
PAF
Vasc. permeabilityVasodilatation
Smooth musclecontraction
Mucus secretion
Tissue Eosinophils
Late PhaseAllergic Reaction
(hours)
Further wheezingSustained blockage
of the nosePersistent inflammation
Acute
Allergic Reaction(minutes)
WheezingUrticaria
Sneezing, rhinorrheaConjunctivitis
Mechanism of earl and late phase
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Mechanism of early and late phaseallergic reaction
0 1 6 8 24 48 (h)
RANTESEotaxin
IL-8GM-CSF
PAF
TNF-IL-4IL-5IL-8GM-CSFMIP-1MCP-3
TNF-IL-
IL-3IL-4IL-5
IL-8GM-CSF
IL-3IL-4IL-5IL-6IL-13RANTES
IL-4IL-13MIP-1 RANTESEotaxin
IL-8GM-CSFPAF
RANTESMCP-4Eotaxin
ICAM-1VCAM-1E-selectin
Histamin, PGD2,
LTs etc
MBP, ECP,
EDN, CLC etc
MBP, ECP,
EDN, CLC etc
Early phase Late phase Very late p hase
IL-4
Endothelium
Epithelium
Endothelium
VCAM-1
Th2 B cells
Ag
Mast cells
FcRI
Th2
Th0
Eos EosBaso
Baso
Eos
Th2
Histamin, LTC4
APC
Immediate and late skin reactions
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Immediate and late skin reactions
I t k i t l Th2 d l B
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Interaksi antara sel Th2 dan sel B yang
diperlukan untuk sintesis IgE spesifik
Sel T Sel B
IL-4 IL-4R
CD40CD40L(CD154)
CD28
TCR
CD4
B7-1(CD80)
MHC II
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Mast CellPreformed mediators
Histamine TNF-
Heparin TGF-Tryptase (IL-3, 4, 5)(Chymase) (IL-13)
Kininogenase
PLA2 AA + PAF
CO 5-LO
PGD2 LTC4LTD4LTE4
LTB
Mlanges of mast cell mediators
Nerves
Itch
Recruit reflexes
Sneezing
Malaise
Glands
Mucus
secretions
Vessel
Vasodilatation
Mucosal Thickening
Permeability
Watery rhinorrhea
Mast cell and its mediators
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Compounds Released from EosinophilsLike mast cels,
Eosinophilshave Fce
receptors
Biologic effects of mediators of
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Biologic effects of mediators of
immediate hypersensitivity
Biogenic amines(e.g., histamines)
Lipid mediators
(e.g., PAF, PGD2, LTC4)
Vascular leak
Broncho-constriction
Broncho-constriction
Intestinalhypermotility
Inflammation
Tissuedamage
Enzymes(e.g., tryptase)
Cytokines
(e.g., TNF)
Lipid mediators(e.g., PAF, PGD2, LTC4)
Activatedmast cell(or basophil)
All t d d t f ll t
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Allergy symptoms depend on route of allergen entry
Can be fatal.
Allergy to insect
venom, drugs,
foods and
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macrophage
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T Cell Differentiation
During Human Immune
Responses
(Immune Deviation)
Th2 Th2
Th
Th1
Th1
B
+ IL-2IFN
IgG1
IFN
Delayedhypersensitivity
CD4+veHelperT cell
IL-12
High dose antigene.g. DPT, viral orbacterial infection
MHC/peptide
IL-4+
IL-5MHC/
peptide
Dendritic cell
Low dose antigene.g. allergens
IL-4, IL-13
B
IgE, IgG4
eosinophil
eosinophil
Mast cell*
Differentiation of Naive CD4+ T Cells into
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Differentiation of Naive CD4 T Cells into
Subsets of Effector Cells
Pathogensinfluence
cytokines that
affect TH0
differentiation
into TH1 or T
H2
Amount of antigen presented and TCR binding strength
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g p g g
influence TH0 differentiation into TH1 or TH2
Weak
binding
TH0
TH2
Strong
binding
TH0
TH1
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IL-12
IL-4
Th0
Th1
Th2
IL-2
IFN-gamma
TNF-beta
IL-4
IL-5
IL-6IL-10
IL-13
IFN-gamma
Cell mediated cytotoxicityMacrophage activation
B cell help
Eosinophilia
Mast Cell
IgE / IgG
Transplantation tolerance (?)
IL-2
IL-4
IFN-gamma
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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 TH2
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KORTIKOSTEROID
Hormon, disintesa kortek Adrenal Efek Mineralokortikoid : - Aldosteron
Glukokortikoid : - Hidrokortison (Kortisol)
Anti Inflamasi
Imunosupressi Sintetik
Metabolisme : Glukoneogenesis
Lipolisis Naik
Protein breakdown
Timbunan calsium turun Osteoporosis
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M k i
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Mekanisme
kerja Kortikosteroid
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Efek Imunosupresi Steroid
1. Proses transkripsi Menurunkan
Molekul pro Inflamasi
2. Menekan Replikasi & Pergerakan sel
Monositopenia, eosinopenia,limfositopenia
TERIMA KASIH
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TERIMA KASIH