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REAKSI HIPERSENSITIVITASREAKSI HIPERSENSITIVITAS

Febtarini, R, dr. Sp.PK

Bagian Patologi KlinikFKU - 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

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• VON PIRQUET (1906)– Aktivitas berubah– Reaktivitas berubah– Energi berubahatau : 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

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• ANTIGENZat 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

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• HAPTEN– Zat Kimia

– Berat Molekul (rendah) kecil

– Bila bergabung dengan protein badan Antigen

H P A

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• 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

IIComplement-mediated cytotoxicity

Cytopenias

IIIImmune complex deposition

Vasculitis / nephritis

IVDelayed-type hypersensitivity

Dermatitis or hepatitis

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• 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.

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• 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

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

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• 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

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• 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

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AntibodyComplement

CytolysisAntibody

Red blood cell

Antigen

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• 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

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Ag-Ab Complex

Platelet

AggregationComplement

activation

MicrothrombiVasoactive

amine releaseAttract

PolymorphsAnaphylatoxin

Release proteolytic enzymes and

polycationic proteins from granules

Histamin release

Figure 6.3 Type III Complex-mediated hypersensitivity

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• CONTOH KHAS R. TYPE III– 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

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• 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

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• 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

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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

A

ASMA

RINITIS

DERMATITIS

SYOK ANAFILAKSIS D.L.L

ASMA

MACAM-MACAMALERGEN

A. INHALANMAKANANOBAT-OBATANDLL

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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 oedemUrtika, syok, dll

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MACAM-MACAM TES:– 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

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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

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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

The four types of hypersensitivity reactionThe four types of hypersensitivity reaction

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CYTOKINE ADHESION MOLECULES

Bagian Patologi KlinikFKU-UWKS

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ANTIGEN

- Bakteri

- Virus- Parasit- Zat-zat asing- Dll

TERPAPAR

(PAPARAN)

(EXOGEN)

FISIK

TERMIS

MEKANIS

RADIASI

PSIKIS

STATUS NUTRISI

R.I.S R.I.H

KELEMAHAN

UMUM

INAKTIVITAS

DLL

ALERGEN

IMUNOGEN

R.I. ABNORMAL

(MENYIMPANG)

PROTEKSI

SUB NORMAL

S.I DEF

RADIASI

OBAT-OBATAN

ZAT-ZAT TOKSIS

DLL

IMUN (KEBAL)

KLINIK

ALERGI

A.I.

GEN

R.I

01

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FUNGSI CYTOKINE

• MENGATUR (REGULATE)– PERTUMBUHAN SEL– MEMACU AKTIFITAS SEL– PROSES INFLAMASI– PROSES IMUNITAS– TISSUE REPAIR– PROSES FIBROSIS– MORFOGENESIS

02

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IL4

IL5

NK cells

T cells

Costimulant of T cells proliferation

Costimulant of B cells

proliferation

Bone marrow precursor cell proliferation

Macrophage activation and differentiation

Mast cell proliferation

Eosinofil proliferation

IL-4

+ Ig E

+ MHC class II

+ FcR epsilon

+ IgA

myelopoiesis

+ MHC class II

Figure 7-4. Cell sources and target cell effects of IL-4 and IL-5

Target cell effects

Cell sources

IL-5

03

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Transforming Growth Factor

(TGF-β)

Figure 7-4. Cell sources and target cell effects of TGF-β

Inhibits T cell proliferation and lymphokine production

Inhibits B cell proliferation and antibody production

Inhibits early hematopoietic stem cell replication

Attract macrophages

Inhibits natural killer activity

Osteoclast activation in bone

Stimulates and mobilizes fibroblasts wound healing + collagen, fibronectin and collagenaseSuppresses proliferation of epithelial cells, fetal hepatocytes, and endothelial cells

T cells

B cells

macrophages

Platelets

Placenta, bone and kidneys

Cell sources

Target cell effects

04

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TNF-α and TNF-β (LT)

Macrophages

prostaglandins and mediates cytocidal activation

IL-1, IL-6,IL-8. GMCSF

Bone Marrow

Inhibits in vitro hematopoiesis but

stimulates CSF in vivo

PMN’s

Neutrophilia

Metabolic activation

chemoattracts

B-Lymphocytes Proliferate

antibody production

lymphokine production

IL-2 receptors

IFN

CSF

IL-4

LDCF

IL-2

T-Lymphocytes

IL-2, IL-4

IFN-γ

05

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IL-1α and β

Macrophages

prostaglandins and cytocidal activation

IL-6, IL-8, GMCSF, TNF, PA, I-CAM 1

Bone Marrow

hematopoiesis but CSF

PMN’s

Neutrophilia

Metabolic activation

B-Lymphocytes Proliferate

antibody production

lymphokine production

IFN

CSF

IL-4, IL-5

LDCF

IL-2

T-Lymphocytes

IL-2, IL-4

IFN-γ

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Table 7-1. Characterictic properties of cytokinesCytokine 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 TH Cells 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 Monocytes and others 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 cellsInduce cell membran antigens (eg, MHC)

IFN β 25,000 Fibroblasts

IFN γ 20,000-25,000 T-Lymphocytes and NK cells

TNF α 17,000 Macrophages and others Inflammatory, immunoenhancing, and tumorcidal

Vascular thromboses and tumor necrosis

LT=TNFβ 18,000 T-Lymphocytes

TGF-β 25,000 Platelets, bone and others Fibroplasia and immunosuppression Wound healing and bone remodelling09

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The main feature of the best-studied cytokines

Cytokine 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-1αIL-1β

33.00017.500

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 15.000 T cells Stem cells, progenitors Pan-specific colony stimulating factor

IL-4 15.000 T cells B cells, Tcells Division and differentiation

IL-5 ? 15.000 (153 aminoacids)

T cells 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)

50.000

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

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4513

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