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 ritus dan efek sedasinya yg ringan.

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

I II III IV

IgE dependent Complement-mediated cytotoxicity Immune complex deposition Delayed-type hypersensitivity

Anaphylaxis, urticaria Cytopenias Vasculitis / nephritis 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 Versus Age

Symptom severity

4 8 Age (years)
Food allergy

16

32

64

Eczema

Asthma

Rhinitis

Faktor Genetik
Adanya alele HLA spesifik Polimorfisme FcRI- Polimorfisme gena IL-4 Polimorfisme CD14 Polimorfisme lokus lainnya

Faktor Lingkungan
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 TLR27 CD148
Treg

Allergen-specific IgG4

?
Prostanoid receptor12 allergen

DC

IL-109, TGF-10 B cell

GATA315 STAT617

? IL4R19,20 18 STAT6 IL4 SOCS22

IL135,6 IL13R121
CD4 Thp
Tbet16

CD4 Th2 IL419,20 IL135,6 Allergen-specific IgE IFN- CD4 Th1

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

ALLERGEN NON-IgE TRIGGERS
ACH noradrenalin C3a C5a

SKIN TEST
10 min.

IgE SYNTHESIS

TH2
B
IL-4

TH1
IFN

OEDEMA
MUCUS SECRETION
BRONCHIAL CONSTRICTION

IgE Fc

+ + + + cGMP cAMP +
PG, LT

ATTACHMENT TO MAST CELL

MEDIATORS

CHEMOTAXIS

CROSS-LINKING BY ALLERGEN CALCIUM INFLUX

DSCG adrenalin steroids Ca2+ antihistamines

INHIBITORS DEGRANULATION & MEDIATOR RELEASE

VASCULAR PERMEABILITY

Sequence of events in immediate hypersensitivity reactions

First exposure to allergen
Allergen

Repeated exposure to allergen

Activation of mast cells : release of mediators

B cell

TH2 cell

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

Mediators

Vasoactive amines, lipid mediators

IgE-secretine B cell IgE

Cytokines

Mast cell

Production of IgE

First exposure to allergen

Immediate hypersensitivity reaction (minutes after repeated exposure to allergen)

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

Mekanisme seluler dan molekuler pada reaksi alergi

IL-4 APC
8
1 2

IL-4

Late Phase Allergic Reaction (hours) IL-4,IL-13 VCAM 9 Eotaxin

T cell
3

Th2
4

IL-4, IL-13 CD40L B cell

Further wheezing Sustained blockage of the nose Persistent inflammation

Antigen

5 6 8

IgE

+
8

Eo-poesis Eo survival Eo activation

Tissue Eosinophils Acute Allergic Reaction (minutes) Wheezing Urticaria Sneezing, rhinorrhea Conjunctivitis

8 Leukotrienes Mast cell

Histamine

Prostaglandins PAF

Vasc. permeability Vasodilatation Smooth muscle contraction Mucus secretion

Mechanism of early and late phase allergic reaction

0
APC

8
Late phase

24
TNF- IL- IL-3 IL-4 IL-5 IL-8 GM-CSF IL-3 IL-4 IL-5 IL-6 IL-13 RANTES IL-4 IL-13 MIP-1
VCAM-1

48 (h)

Early phase

Very late phase

Epithelium
RANTES MCP-4 Eotaxin

Ag
FcRI

MBP, ECP, EDN, CLC etc

Mast cells
Th2 B cells Eos

MBP, ECP, EDN, CLC etc

IL-4
Th0

Histamin, PGD2, LTs etc

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

Th2

RANTES Eotaxin IL-8 GM-CSF Endothelium PAF

ICAM-1 VCAM-1 E-selectin

Baso Histamin, LTC4

RANTES Eotaxin IL-8 GM-CSF PAF

Endothelium
Eos 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

Sel B
IL-4R CD40

CD40L (CD154) CD28

B7-1 (CD80)

TCR CD4

MHC II

Mast cell and its mediators

PLA2

AA + PAF

Preformed mediators
Histamine Heparin Tryptase (Chymase) Kininogenase TNF- TGF- (IL-3, 4, 5) (IL-13)

Mast Cell

CO

5-LO

PGD2

LTC4 LTD4 LTE4

LTB

Mlanges of mast cell mediators

Nerves Itch Recruit reflexes Sneezing Malaise Glands Mucus secretions Vessel Vasodilatation Mucosal Thickening Permeability Watery rhinorrhea

Mast cell degranulation by antigen (allergen) cross-linking of FcR-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,

Compounds Released from Eosinophils

Eosinophils
have Fce receptors

Biologic effects of mediators of immediate hypersensitivity

Vascular leak Biogenic amines (e.g., histamines) 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 Bronchoconstriction

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 High dose antigen e.g. DPT, viral or bacterial infection MHC/ peptide IL-12 Th1 + IFN Th IL-2 IFN B IgG1

Th1

Delayed hypersensitivity

CD4+ve Helper T cell

T Cell Differentiation During Human Immune Responses (Immune Deviation)

IL-4 + MHC/ peptide Th2 IL-4, IL-13 Th2 IL-5

eosinophil

Dendritic cell

eosinophil Low dose antigen e.g. allergens B 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

Th1

IL-2 IFN-gamma TNF-beta

Cell mediated cytotoxicity Macrophage activation B cell help

Th0

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 TH2

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 : (GlucoCorticoid Response Element)

GRE + Transkripsi

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