Prof.DR.dr.Harijono KS. SpKKTempat/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 UnairPendidikan 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-sekarangAnggota komite medik RSUD Dr.Moewardi th 2003-2008Ketua Program Sutudi I.Kesehatan Kulit & Kelamin FK UNS th 1999-2003/ 2008-sekarangKarya Ilmiah:13 buah penelitian17 Publikasi Ilmiah3 Buku teks: 2 sbg kontributor dan 1 sbg penulis utama

APLIKASI OBAT IMUNOSUPRESI & ANTI ALERGI Pengobatan penyakit atau kelainan akibat gangguan respons imun:

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 HistaminObat yang bekerja sbg antagonis terhadap Histamin

Mediator patogenetik major pada berbagai peny alergiDikeluarkan oleh sel mast dan atau basofil setelah stimulus Ag degranulasiBerasal 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 histaminReseptor 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

ANTIHISTAMINAH1 generasi lama (I=pertama) generasi kedua=baru (non-sedating) generasi ketigaAH2ANTIHISTAMIN 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 TERFENADINAfinitas dan selektrifitas thd reseptor H1 > tinggi dp gen IEfek sedasinya minimal mgkn krn selektivitas thd R H1 perifer > daripada sentralDosis: eg loratadin = 10 mg 1 X/hariANTIHISTAMIN 1 Gen. III :

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

KORTIKOSTEROID

Pemahaman TentangReaksi AlergiHarijono Kariosentono*PG. Konthen**

*Bag. I.Kes.Kulit & Kelamin FK UNS Surakarta** Bag.I.Peny.Dalam FK Unair Surabaya.

PendahuluanPenyakit AlergiPeny yang didasari oleh reaksi hipersensitivitas terhadap benda asing dari lingkungan (alergen)Bermanifestasi pada berbagai macam organ sasaranFaktor yang mendasariGenetikPaparan alergenKondisi lingkungan

Salah bentuk dari imunopatologis

AtopiKecenderungan respon peningkatan IgEAdanya IgE spesifik terhadap suatu komponenSecara praktis : tes kulit yang positifDipengaruhi faktor herediterAlergiManifestasi klinis penyakit atopiDiperantarai IgE (Hipersensitifitas tipe I)Contoh : asma, rinitis alergi, dermatitis atopi, alergi makanan dll.

HipersensitifitasRespon imun yang menyimpang/berlebihanAntigen :EksternalAutoantigen (self antigen) penyakit autoimunAda 4 macam tipe : I, II, III, IV

Four Types of HypersensitivitiesType 1 = allergy

The four types of hypersensitivity reaction

Gell And Combs Classification Of Immune-mediated Allergic Response

TYPE MECHANISM MANIFESTATIONSIIgE dependent Anaphylaxis, urticaria IIComplement-mediated cytotoxicity Cytopenias IIIImmune complex deposition Vasculitis / nephritis IVDelayed-type hypersensitivity Dermatitis or hepatitis

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

EpidemiologiPenyakit alergi menjadi epidemi abad ke-21Di 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

*a contact-sensitizing agent is usually a small molecule that penetrates the skin then binds to self-proteins, making them look foreignCan be caused by poison ivy and mango sapContact DermatitisDTH as a result of a contact-sensitizing agent*

Changing of target organ in clinical allergyDROAA = Asthma R = Rhinitis D = Dermatitis O = other clinical manifestations

Symptom Severity Versus Age01248163264Age (years)Symptom severityEczemaFoodallergyAsthmaRhinitis

AtopiReaksi alergi / inflamasi yang dimediasi oleh Th2Faktor Lingkungan

Sensitisasi alergen Saudara kandung sedikitHidup terlalu bersihAntibiotika pada usia < 2 thVaksinasiPencetus

Infeksi virusPaparan alergenMerokokPolutan indoor / out doorFaktor Genetik

Adanya alele HLA spesifikPolimorfisme FcRI-Polimorfisme gena IL-4Polimorfisme CD14Polimorfisme lokus lainnyaDefek organ target

Epitel saluran nafasKulitSaluran cerna

Faktor GenetikInteraksi faktor genetik-alergen-lingkungan penyakit alergiGen-gen penyandi atopi :InterleukinProtein MHCReseptor IgE berafinitas tinggiEfektor ImunologiKromosom 5Q31-33, 11Q13, 13Q12-14

Gene-gene interactions and the pathogenesis of allergic inflammationGATA315STAT617STAT6Tbet16TregDCAllergen-specific IgG4B cellSOCS22?MicrobialproductsAllergen-specific IgECD4 ThpTLR27pollen?Prostanoidreceptor12allergenIL-109, TGF-10CD4 Th2IFN-IL418IL135,6IL4R19,20IL13R121IL419,20IL135,6CD148CD4 Th1BasophilMast cellFcERI24

PollutantO3, NO2,SO2Exogenic factors :POLLUTANT - ALLERGEN - VIRUSAllergenMitePollenVirusRhinoVirus

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 AnaphylaxisTH1TH2BcAMPcGMP+++++ALLERGENIgESYNTHESISATTACHMENTTO MASTCELLCROSS-LINKINGBY ALLERGENCALCIUMINFLUXDEGRANULATION &MEDIATOR RELEASEVASCULARPERMEABILITYCHEMOTAXISBRONCHIALCONSTRICTIONMUCUSSECRETIONOEDEMASKIN TESTNON-IgE TRIGGERSnoradrenalinACHC3aC5aIFNIL-4IgECa2+adrenalinDSCGsteroidsantihistaminesPG, LTMEDIATORSINHIBITORS10 min.Fc

Sequence of events in immediate hypersensitivity reactionsAntigen activationof TH2 cells andstimulation ofIgE class switchingin B cellsFirst exposureto allergenProduction of IgEFirst exposureto allergenRepeated exposureto allergenActivation of mast cells : release of mediatorsCytokinesVasoactive amines,lipid mediatorsLate-phasereaction (2-4 hrsafter repeatedexposureto allergen)Immediatehypersensitivityreaction (minutesafter repeatedexposureto allergen)AllergenB cellTH2 cellIgE-secretineB cellIgEMast cellMediators

Mekanisme seluler dan molekuler pada reaksi alergiIL-4IL-4++81236578+88489APCT cellTh2AntigenIgEB cellMast cellIL-4,IL-13 VCAM Eotaxin Eo-poesis Eo survival Eo activationIL-4, IL-13CD40LHistamineLeukotrienesProstaglandinsPAF Vasc. permeabilityVasodilatation Smooth musclecontraction Mucus secretionIL-5IL-4,IL-13IL-4,IL-13,TNF- Tissue EosinophilsLate PhaseAllergic Reaction(hours)

Further wheezingSustained blockageof the nosePersistent inflammationAcuteAllergic Reaction(minutes)

WheezingUrticariaSneezing, rhinorrheaConjunctivitis

Mechanism of early and late phase allergic reaction 01682448 (h)RANTESEotaxinIL-8GM-CSFPAFTNF-IL-4IL-5IL-8GM-CSFMIP-1MCP-3TNF-IL-IL-3IL-4IL-5IL-8GM-CSFIL-3IL-4IL-5IL-6IL-13RANTESIL-4IL-13MIP-1RANTESEotaxinIL-8GM-CSFPAFRANTESMCP-4EotaxinICAM-1VCAM-1E-selectinHistamin, PGD2,LTs etcMBP, ECP,EDN, CLC etcMBP, ECP,EDN, CLC etcEarly phaseLate phaseVery late phaseIL-4EndotheliumEpitheliumEndotheliumVCAM-1Th2B cellsAgMast cellsFcRITh2Th0EosEosBasoBasoEosTh2Histamin, LTC4APC

Immediate and late skin reactions

Interaksi antara sel Th2 dan sel B yang diperlukan untuk sintesis IgE spesifikSel TSel BIL-4IL-4RCD40CD40L(CD154)CD28TCRCD4B7-1(CD80)MHC II

Preformed mediatorsHistamineTNF-HeparinTGF-Tryptase(IL-3, 4, 5)(Chymase)(IL-13)KininogenasePLA2AA + PAFCO5-LOPGD2LTC4LTD4LTE4LTBMlanges of mast cell mediatorsNervesItchRecruit reflexesSneezingMalaiseGlandsMucussecretionsVesselVasodilatationMucosal ThickeningPermeabilityWatery rhinorrheaMast cell and its mediators

Mast cell degranulation by antigen (allergen) cross-linking of FcR-bound IgE Eosinophils and basophils may also participate

Compounds Released from Mast CellsPre-formed and in granulesSynthesized upon mast cell activation

Mast cell activation and physiological effects of mast-cell derived mediators

Mast cell activation has many effectsWhy? Normally IgE responses are associated with worm infestations. These responses help evacuate the places where the worms often live.

Compounds Released from EosinophilsLike mast cels, Eosinophils have Fce receptors

Biologic effects of mediators of immediate hypersensitivityBiogenic amines(e.g., histamines)

Lipid mediators(e.g., PAF, PGD2, LTC4)Vascular leakBroncho-constrictionBroncho-constrictionIntestinalhypermotilityInflammationTissuedamageEnzymes(e.g., tryptase)Cytokines(e.g., TNF)

Lipid mediators(e.g., PAF, PGD2, LTC4)Activatedmast cell(or basophil)

Allergy symptoms depend on route of allergen entryCan be fatal. Allergy to insect venom, drugs, foods and

Target organs of allergy :Respiratory tract .AsthmaNose .Allergic rhinitisEye ..Allergic conjunctivitisSkin .UrticariaCentral Nervous System ..MigraineNeuro-musculosceletal NeuromyalgiaDigestive tract DiarrheaCardiovascular ...Anaphylactic shockOrgan Disease

T Cell Differentiation During Human Immune Responses(Immune Deviation)+IL-2IFNIgG1IFNDelayedhypersensitivityCD4+veHelperT cellIL-12High dose antigene.g. DPT, viral orbacterial infectionMHC/peptideIL-4+IL-5MHC/peptidemacrophageDendritic cellLow dose antigene.g. allergensIL-4, IL-13IgE, IgG4eosinophileosinophilMast cell*

Differentiation of Naive CD4+ T Cells into Subsets of Effector CellsPathogens influence cytokines that affect TH0 differentiation into TH1 or TH2

Amount of antigen presented and TCR binding strength influence TH0 differentiation into TH1 or TH2Weak binding TH0TH2Strong binding TH0TH1

IL-12IL-4Th0Th1Th2IL-2IFN-gammaTNF-betaIL-4IL-5IL-6IL-10IL-13IFN-gammaCell mediated cytotoxicityMacrophage activationB cell helpEosinophiliaMast CellIgE / IgGTransplantation tolerance (?)IL-2IL-4IFN-gamma

Interaction of TH1 and TH2Thus, usually, either TH1 or TH2 dominates and the other is very low

RingkasanOrgan sasaran penyakit alergi bermacam-macamEtiologi : genetik, alergen, lingkunganMekanisme : hipersensitifitas tipe IPeranan penting : IgE, sel mast, basofil, eosinofilHipotesis higiene : alergi merupakan respon TH2

KORTIKOSTEROIDHormon, disintesa kortek AdrenalEfek Mineralokortikoid : - Aldosteron Glukokortikoid : - Hidrokortison (Kortisol) Anti Inflamasi Imunosupressi Sintetik Metabolisme : Glukoneogenesis Lipolisis Naik Protein breakdown Timbunan calsium turun Osteoporosis

Kortikosteroid(KS))Sintesa Protein :Transkripsi DNATranslasi m RNAKomplek Reseptor Kortikosleroid (KRK)KS+ Reseptor =Inti sel : + DNAGRE :(GlucoCorticoid Response Element)GRE +GRE (-) Transkripsi Transkripsi

Mekanismekerja Kortikosteroid

Menurunkan/ Mencegah respon jaringan terhadap proses inflamasiMenghambat Akumulasi sel-sel InflamasiMengurangi dilatasi dan permeabilitas kapilerPeningkatan Sintesa Lipokortin 1 Menghambat enzim fosfolipase A2 Mediator Lipid terbentuk

Efek Imunosupresi SteroidProses transkripsi Menurunkan Molekul pro InflamasiMenekan Replikasi & Pergerakan sel Monositopenia, eosinopenia, limfositopenia

TERIMA KASIH

***********************************************************