REAKSI HIPERSENSITIVITAS Febtarini, R, dr. Sp.PK Bagian Patologi Klinik FKU - UWKS Jum’at, 10-Januari-2014
ANATOMY OF THE IMMUNE SYSTEM
CELLS OF THE IMMUNE SYSTEM
Schematic diagram of structure of Ig Glycoprotein Polypeptide : 82-96% Cbh : 2-14%
ANTIBODIES STRUCTURE CLASS
Ag can bind in pockets or grooves or on extended surfaces in the binding sites of Abs
Membuat (sesorang) menjadi reaktif terhadap zat asing VON PIRQUET (1906) Aktivitas berubah Reaktivitas berubah Energi berubah atau : Reaksi abnormal oleh adanya suatu rangsangan COCA DAM COOKE (1923) Atopi : reaksi alergi yang dipengaruhi oleh faktor keturunan (herediter) SENSITISASI: Membuat (sesorang) menjadi reaktif terhadap zat asing HIPERSENSITIVITAS : Reaksi alergi REAKSI IMUNOLOGIS Antigen – Antibody (Zat Anti) Limfosit Sensitif
ANTIGEN SYARAT ANTIGEN Zat asing yang dapat merangsang pembentukan antibody Antigen = Alergen = Imunogen = Atopen SYARAT ANTIGEN Umumnya protein asing Berat molekul besar Bentuk tetap Mampu menginduksi pembentukan AB Dapat dihancurkan oleh sel-sel tubuh Penting jumlah optimal untuk dapat merangsang pembentukan AB cukup tinggi
HAPTEN Zat Kimia Berat Molekul (rendah) kecil Bila bergabung dengan protein badan Antigen A H P
REAKSI HIPERSENSITIFITAS Menurut Gell & Coombs 4 type Type I = Reaksi Cepat = Reaksi Anafilaksis = Reaksi Reagin Dependent = Immediate Hypersensitivity R Type II = Reaksi Sito-toksik Type III = Reaksi Antigen-Antibody kompleks Type IV = “Cell Mediated Immun Reaction”
Gell And Coombs Classification Of Immune-mediated Allergic Response TYPE MECHANISM MANIFESTATIONS I IgE –dependent Anaphylaxis, urticaria II Complement-mediated cytotoxicity Cytopenias III Immune complex deposition Vasculitis / nephritis IV Delayed-type hypersensitivity Dermatitis or hepatitis
REAKSI TYPE I DASARNYA: Ig E melekat pada dinding sel mast Antigen terikat Fab dari Ig E Terjadi degranulasi sel mast Pengeluaran vasoaktif amin Timbul gejala klinik : Vasodilatasi, Permeabilitas, Perdarahan , exudasi, edema, obstruksi bronkus, kontraksi otot polos.
CONTOH REAKSI TYPE I : Asma Bronkial Ekstrinsik Rinitis Alergika “Hay Fever” (Demam Rumput) Beberapa Jenis Urtikaria Angioneurotik Oedema Alergi Obat Alergi Makanan Gigitan Serangga Anafilaksis Sistemik Dermatitis Atopik Eksim
(type I hypersensitivity mediated by IgE on mast cells) Allergy (type I hypersensitivity mediated by IgE on mast cells)
CARA ANTIGEN MASUK BADAN Kontak langsung dengan permukaan kulit Jalan nafas ( A. Inhalan) Traktus Digestivus Parenteral MACAM ALERGEN: Inhalan : Debu Rumah, Tungau, Jamur, Tepung Sari, Rumput, Serpih Kulit Ingestan : Susu, telur, ikan, kacang-kacangan (Makanan) Injectan : obat-obatan Penisilin, Streptomisin (Parenteral) Lain-lain : Virus/produk bakteri Contactan : Obat-obatan, Zat-zat Kimia
REAKSI TYPE II DASAR: Yang berperan: IgG, IgM Antigen pada dinding sel, dapat berupa Hapten Antibody spesifik terikat pada antigen Kadang-kadang mengikat Complement Sel Lisis
Antigen Red blood cell Complement Antibody Cytolysis Antibody
CONTOH REAKSI TYPE II : Alergi Obat/Zat Kimia Lain Anemia Hemolitik Purpura Trombositopenia, Pansitopenia karena Alergi obat/Zat kimia lain Beberapa Penyakit Autoimun Miastenia gravis Thyroiditis Chronis Acut Post Streptococcus G. Nephritis
Reaksi hipersensitifitas tipe 3 Reaksi kompleks imun (Ag-Ab) di jaringan atau pembuluh darah Ig G Kompleks imunmengaktifkan komplemenkemotaktik faktormakrofag ke jaringanmerusak jaringan
Ag-Ab Complex Platelet Aggregation Complement activation Vasoactive amine release Attract Polymorphs Anaphylatoxin Microthrombi Histamin release Release proteolytic enzymes and polycationic proteins from granules Figure 6.3 Type III Complex-mediated hypersensitivity
CONTOH KHAS R. TYPE III CONTOH DALAM KLINIK: Arthus Phenomen Serum Sickness Penyakit Autoimun CONTOH DALAM KLINIK: Rheumatoid Arthritis Serum Sickness Syndrome Alergi Obat Peri Arteritis Nodosa Sub Acut / Chronic G.N Extrinsik Alergik Alveolitis
REAKSI TYPE IV SKEMA: Ikatan antara Ag oleh T Limfosit Pelepasan Mediator dgn Aktivitas Biologis yang luas (MAF) Akibatnya memperbesar Imun respons selluler Akumulasi sel Macrophag & Leukocyt ke tempat reaksi Nekrose Jaringan, Ulserasi lokal
DASAR R. TYPE IV Reaksi terjadi antara Ag. Spesifik dengan limfosit sensitif Pelepasan Lymphokins Menimbulkan sitotoksik langsung tanpa melibatkan lg & complement CONTOH: Sensitivitas reaksi thd TBC Reaksi thd Transplantasi Tumor Imunitas Contact Dermatitis
KARAKTERISTIK REAKSI HIPERSENSITIFITAS Sering akut Kronis Rekuren (Kumat-kumatan) Organ sasaran berubah Satu (single) alergen bermacam-macam manifestasi klinik Satu (single) manifestasi klinik : dapat disebarkan oleh banyak alergen ASMA RINITIS A DERMATITIS SYOK ANAFILAKSIS D.L.L A. INHALAN MAKANAN OBAT-OBATAN DLL MACAM-MACAM ALERGEN ASMA
DIAGNOSIS (ATAS DASAR): KARAKTERISTIK LAIN Herediter (menurun) Dapat diditeksi faktor-faktor pencetus Intensitas: alergen dipengaruhi oleh faktor non alergen Menunjukkan sifat hiperreaktif DIAGNOSIS (ATAS DASAR): ANAMNESIS: - Riwayat Penyakit - Faktor Pencetus - Gejala (keluhan) - Faktor Keluarga - Perjalanan Penyakit FISIK: Tergantung organ sasaran “Wheezing” Mukosa Hidung oedem Urtika, syok, dll
MACAM-MACAM TES: LABORATORIUM PENTING PEMERIKSAN LAIN X Foto: Thorax Tes Kulit Tes Provokasi Bronkial Tes Latihan(Exercise) LABORATORIUM PENTING Jumlah Eosinofil Kadar Ig E (Total/spesifik) dalam PEMERIKSAN LAIN X Foto: Thorax Sinus Paranasalis
MEDIATOR2 PENTING DALAM REAKSI HIPERSENSITIFITAS HISTAMIN: - Dalam sel mast - Kontraksi otot polos - Dilatasi pembuluh darah - Permeabilitas ↑↑ - Exudasi - Oedema LEUKOTRINE : - SRS-A (SlowReactinSubtance of Anaphylaxis) - Kontraksi otot polos SEROTONIN: - Dilatasi pemb. Darah - Permeabilitas ↑↑ - Bronkus Obstruksi Diagnosis: ►Anamnesis ►Lab: Ig.E, Eosinofil ►Fisis ►Faal Nafas ►X-Foto ►Tes Kulit ►Tes Provokasi
SHOCK ORGAN (ORGAN SASARAN) Digunakan oleh DOERR (1922) Artinya: Organ atau jaringan tempat timbulnya reaksi alergi Misalnya: Penyakit Organ Sasaran ASMA ………………………… Jl. Nafas URTIKA ……………………… Kulit RINITIS ……………………… Hidung MIGRAIN ……………………. S.S.P DIARE ……………………….. Tract Digest CONJUNCTIVITIS …………. Mucosa Mata NEUROMIALGIA …………… Sistem Neuro Musk
CYTOKINE ADHESION MOLECULES Bagian Patologi Klinik FKU-UWKS
KLINIK ALERGI A.I. ANTIGEN PSIKIS STATUS NUTRISI ALERGEN IMUNOGEN Bakteri Virus Parasit Zat-zat asing Dll R.I. ABNORMAL (MENYIMPANG) GEN TERPAPAR (PAPARAN) (EXOGEN) IMUN (KEBAL) R.I PROTEKSI SUB NORMAL R.I.S R.I.H FISIK TERMIS MEKANIS RADIASI S.I DEF KELEMAHAN UMUM INAKTIVITAS DLL RADIASI OBAT-OBATAN ZAT-ZAT TOKSIS DLL 01
FUNGSI CYTOKINE MENGATUR (REGULATE) PERTUMBUHAN SEL MEMACU AKTIFITAS SEL PROSES INFLAMASI PROSES IMUNITAS TISSUE REPAIR PROSES FIBROSIS MORFOGENESIS 02
IL4 IL5 NK cells Target cell effects Costimulant of T cells proliferation + Ig E IL-4 + MHC class II Cell sources Costimulant of B cells proliferation + FcR epsilon IL-5 + IgA Bone marrow precursor cell proliferation IL4 myelopoiesis T cells Macrophage activation and differentiation IL5 + MHC class II NK cells Mast cell proliferation Eosinofil proliferation 03 Figure 7-4. Cell sources and target cell effects of IL-4 and IL-5
Transforming Growth Factor Placenta, bone and kidneys Target cell effects Cell sources Inhibits T cell proliferation and lymphokine production Inhibits B cell proliferation and antibody production T cells Inhibits early hematopoietic stem cell replication B cells Transforming Growth Factor (TGF-β) Attract macrophages macrophages Inhibits natural killer activity Osteoclast activation in bone Platelets Stimulates and mobilizes fibroblasts wound healing + collagen, fibronectin and collagenase Placenta, bone and kidneys Suppresses proliferation of epithelial cells, fetal hepatocytes, and endothelial cells 04 Figure 7-4. Cell sources and target cell effects of TGF-β
Inhibits in vitro hematopoiesis but stimulates CSF in vivo T-Lymphocytes IL-2, IL-4 IFN-γ IFN CSF IL-4 LDCF IL-2 lymphokine production IL-2 receptors B-Lymphocytes Proliferate antibody production TNF-α and TNF-β (LT) Macrophages prostaglandins and mediates cytocidal activation IL-1, IL-6,IL-8. GMCSF PMN’s Neutrophilia Metabolic activation chemoattracts Bone Marrow Inhibits in vitro hematopoiesis but stimulates CSF in vivo 05
IL-1 α and β T-Lymphocytes IL-2, IL-4 IFN-γ IFN CSF IL-4, IL-5 LDCF lymphokine production B-Lymphocytes Proliferate antibody production IL-1 α and β Macrophages prostaglandins and cytocidal activation IL-6, IL-8, GMCSF, TNF, PA, I-CAM 1 PMN’s Neutrophilia Metabolic activation Bone Marrow hematopoiesis but CSF 06
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Table 7-1. Characterictic properties of cytokines MW Principal Cell Sources Primary Type of Activity Preeminent Effects IL-1 17,500 Macrophahes and others (see Table 7-2) Immunoaugmentation Inflammatory and hematopoietic IL-2 15,500 T Lymphocytes and LGL T and B Cell growth factor Activates T and NK cells IL-3 14,000-28,000 T Lymphocytes Hematopoetic growth factor Promotes growth of early myeloid progenitor cells IL-4 20,000 TH Cells T and B cell growth factor; promotes IgE reactions Promotes Ig E switch and mast cell growth IL-5 18,000 Stimulates B cells and eosinophils Promotes IgA switch and eosinophilia IL-6 22,000-30,000 Fibroblast and others Hybridoma growth factor; augments inflammation Growth factor for B cell and polyclonal immunoglobulin production IL-7 25,000 Stromat cells Lymphopoietin Generates pre-B and Pre-T cells and is lymphocyte growth factor IL-8 8,800 Macrophages and others Chemoattracts neutrophils and T Lymphocytes Regulates lymphocyte homing and neutrophil infiltration G-CSF 18,000-22,000 Monocytes and others Myeloid Growth factor Generates neutrophil M-CSF 18,000-26,000 Macrophages growth factor Generates macrophage GM-CSF 14,000-38,000 T cells and others Monomyelotic growth factor Myelopoiesis IFN α 18,000-20,000 Leukocytes Antiviral, antiproliferativee, and immunomodulating Stimulates macrophages and NK cells Induce cell membran antigens (eg, MHC) IFN β Fibroblasts IFN γ 20,000-25,000 T-Lymphocytes and NK cells TNF α 17,000 Inflammatory, immunoenhancing, and tumorcidal Vascular thromboses and tumor necrosis LT=TNFβ T-Lymphocytes TGF-β Platelets, bone and others Fibroplasia and immunosuppression Wound healing and bone remodelling 09
The main feature of the best-studied cytokines Mol.wt Cell source(s) Main cell target(s) Main actions IFN γ 40-50.000 (dimer) T cells, NK cells Lymphocytes, monocytes, tissue cells Immunoregulation, B cell differentation, some antiviral action IL-1α IL-1β 33.000 17.500 Monocytes, dendritic cells, some B cells, fibroblasts, epithelial cells, endothelium, asctrocytes, macrophages Thymocytes, neutrophils, T and B cells, tissue cells Immunoregulation, inflammatory, fever IL-2 15.000 T cells T cells, B cells, monocytes Proliferation, activation IL-3 Stem cells, progenitors Pan-specific colony stimulating factor IL-4 B cells, Tcells Division and differentiation IL-5 ? 15.000 (153 aminoacids) B cells, eosinophils Differentiation IL-6 20.000 Macrophages, T cell, fibroblasts, some B cells T cells, B cells, thymocyets, hepatocytes Differentiation, acute phase protein synthesis IL-8 (Family) 8.000 Macrophages, skin cells Granulocyte, T cells Chemotaxis TNFα 50.000 Macrophages. lymphocytes Fibroblasts, endothelium Inflammation, catabolism (cachexia), fibrosis, production of other cytokines (IL-1, IL-6, GM-CSF) and adhesion molecules TNFβ (Lymphotoxin) Fig. 7.14 Summary of the main features of the best studied from study of cDNA sequences. Only the most important cytokines. In some cases the molecular weight is derived targets and action are shown 10
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