lecture 6 imunodefisiensi r gunadi

7/31/2019 Lecture 6 Imunodefisiensi r Gunadi

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Imunodefisiensi

Rachmat Gunadi


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Pendahuluan

Imunodefisiensi : suatu keadaan dimana

sistem imun tidak berfungsi dengan benar

sebagaimana mestinya sebagai sistem

pertahanan tubuh manusia.

Konsep : Kolonel Ogden Brutton 1952.


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Aktifitas Pertahanan Tubuh :

Pertahanan permukaan tubuh (kulit, mukosa)

Fagositosis & Bakterisidal

Peradangan Respon Antibodi

Respon Selular


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Penyebab Kegagalan Imun :

Genetik

Defisiensi metabolisme dan biokimia

Devisiensi vitamin dan mineral Gangguan embriogenesis

Penyakit autoimun

Defisiensi imun didapat


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Klasifikasi Imunodefisiensi :

WHO :

1. Primer

2. Sekunder


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Imunodefisiensi Primer

Dibagi menjadi :

Spesifik (Adaptif) Non spesifik (Innate/Alamiah/Bawaan)


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Rina-Susilowati 20 May 2010 3

Immune ResponsesImmune Responses

Immune system protect the individual from pathogensImmune system protect the individual from pathogens


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Imunodefisiensi Primer Non Spesifik

(Alamiah) Dibagi menjadi :

Defisiensi sel fagositik Defisiensi sistem komplemen


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Imunodefisiensi Primer Spesifik

(Adaptif) Dibagi menjadi :

Defisiensi sel T Defisiensi sel B


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Rina-Susilowati 20 May 2010 7

Adaptive Immune ResponsesAdaptive Immune Responses

Immune system protect the individual from pathogensImmune system protect the individual from pathogens


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Defisiensi Limfosit B (Antibodi)

Kadar antibodi turun

Hipogamaglobulinemia : semua imunoglobulin

Bentuk lain : spesifik tertentu imunoglobulin Ig M, Ig G, Ig A

Gejala : Infeksi berulang, Alergi


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Immunodeficiency: B Cell Development


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Defisiensi Ig A selektif

Paling sering dijumpai

1: 800 dari populasi normal (Ammann 1971)

Perdebatan normal / tidak Berhubungan dengan atopi

Kongenital : genetik (kromosom x) : pria


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Defisiensi Limfosit T

Jarang

Biasanya disertai dengan gangguan limfosit B

Sub populasi : Limfosit T Sitotoksik

Limfosit T Helper

Limfosit T Supresor

(Mudah mengalami infeksi)


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Defisiensi Limfosit T

Sindroma DiGeorge

Aplasia / Hipoplasia kelenjar timus kongenital

Sering disertai gangguan pertumbuhan wajah,tyroid, jantung.

Limfosit T yang diproduksi terdapat gangguan

pembentukan surface antigen.

Terapi : transplantasi kelenjar tymus janin


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Defects in thymus structure or thymocyte homing, blocks

T cell development and induces severe immunodeficiency

Deletion of the gene

TBX1

that encodes the

transcription factor,

T-box 1.


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Defects in antigen presentation induces selective

Immunodeficiency of the corresponding

MHC class-restricted T cells


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Severe Combined

Immunodeficiency Disease (SCID)

Kegagalan stem sel berdiferensiasi : sel T / B

Rentan Infeksi Virus, Bakteri, Parasit, Jamur

Lab : Limfopenia Bila tidak diobati meninggal dalam 1 tahun

Terapi : Transplantasi sumsum tulang

Tidak boleh vaksinasi : organisme hidup yangdilemahkan


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Severe Combined

Immunodeficiency Disease (SCID)

Genetik : autosom resesif, kromosom x

Defisiensi enzim Adenosine Deaminase (ADA)

Penyakit : Ataxia teleangiektasia

Wiskott Aldrich Syndome

Tanpa pengobatan bertahan 3 tahun

Bare lymphocyte syndrome


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Distinct mutations in the VDJ gene recombination or DNA repair

machinery cause severe combined immunodeficiency syndromes


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Defects in purine degradation leads to major combined

immunodeficiency syndromes due to the accumulation of

nucleotide metabolites that are toxic for developing

T and B cells

Defects in the purine

degrading enzymes

adenosine deaminase(ADA) or purine phos-

phorylase (PNP) totally

block lymphoid cell

development


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Defects in T cell development or activation lead to major

immunodeficiency syndromes that underline the critical

regulatory role of T cells in the immune system


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Gangguan fungsi Fagositik

Netrofil & Makrofag

Penyebab :

Ekstrinsik

Antibodi, komplemen, limfokin

Intrinsik

Metabolisme : def enzim G6PD, myeloperoxidase,alkalifosfatase, enzim lisosom.

Fungsi abnormal mikrotubuli : Chediak HigashiSyndrome


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Chronic Granulomaous Disease (CGD) :

Defisiensi oksidase NADPH

Gangguan pembentukan hidrogen peroksida Fungsi : membunuh mikroorganisme

Kronik, mulai umur 2 tahun, pada Laki-laki

Genetik : kromosom x, autosom resesif Terapi : transplantasi sumsum tulang


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Leukocyte Adhesion Deficiency (LAD) :

Autosom resesif

Kekurangan komponen glikoprotein padapermukaan leukosit : sulit menempel

Granulosit, monosit, limfosit

Terapi : transplantasi sumsung tulang


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Defects in phagocytic cells permit

widespread bacterial infections


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Gangguan Komplemen

Gangguan opsonisasi, kemotaktis, kompleks imun

Infeksi berulang, Autoimun.

Genetik : Autosom resesif

Defisiensi C1, C2, C3, mirip SLE

C1 : Hereditary angioneurotic edema

C3 : glomerulonefritis kronik

PNH (Paroxismal Norcturnal Hemoglobinuria) :

defisiensi decay accelerating factor -> komplemen


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Defects in complement component cause

defective humoral immune function


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Defects in complement component are associated with susceptibility

to bacterial infections and accumulation of immune complexes


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Defect in cytokine production or action

can cause immunodeficiency

A defect in the c receptor

causes X-linked severe

combined immunodeficiencyX-linked SCID


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Imunodefisiensi Sekunder

Gangguan sistem imun akibat penyakit lain

Sel T / B menghilang, gangguan fungsi

Penyebab : obat-obatan kangker, infeksi

bakteri, keganasan sumsum tulang (leukemia),

HIV AIDS


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a disease without borders

Acquired immune deficiency syndrome (AIDS)


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HIV is a RNA retrovirus of the lentivirus family

that infects mainly CD4 T cells

Macrophage-tropic HIV variant bind to CCR5 on macrophages

DC, & CD4 T cells

Lymphocyte-tropic HIV variant bind only to CXCR4 on activated

CD4 T cells


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Imunodefisiensi : Keganasan Sel T/B

Gamopati

Keganasan sel plasma

Proses translokasi sepotong kromosom ke

kromosom lain

Contoh : Burkit lymphoma, keganasan sel B

setelah infeksi virus Eibstein Barr Virus,

keganasan sel T yang dapat mengalami

translokasi kromosom 8 -> 14.


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Diagnosis

Membutuhkan alat yang canggih

Di Indonesia jarang, terutama di kota besar

Ahli yang kompeten

B l i


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Bone marrow transplantation or

gene therapy can be useful to correct genetic defects

of the immune system.

Bone marrow donor and recipient

must share at least some MHC

molecules to restore immune function

Shared MHC of type b (blue).

Unshared donor MHC of type

a (yellow).


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But an immune reaction against the graft must be avoided

or controlled to prevent a graft rejection

Graft-versus-host disease:

Mature T cells from graft

attack cells of the host.

T cell depletion of the donor

bone marrow prevents graft-

versus-host disease.

Host-versus-graft response:

Competent T cells of the host

can attack the donor bone

marrow stem cells


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Autoimunitas

&Autoimmune Disease


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Autoimunitas vs penyakit autoimun

Autoimunitas : autoantibodi / reaktivitas sel T

Autoimunitas tidak selalu penyakit autoimun

Autoimunnitas bisa : Penyebab penyakit autoimun

Akibat penyakit autoimun

Tidak berhubungan tetapi ditemukan berbarengan

dengan penyakit autoimun


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AUTOIMMUNITY VS.

AUTOIMMUNE DISEASE

Autoimmunity

Existence of harm-less self-reactive

lymphocytes andantibodies Potentially reversible Incidence higher in

older age Significance unclear,

possibly physiological

Autoimmune disease

Dependent ongenetic viral and

hormonal factors Features of severe

tissue damage Clinical symptoms

Protracted coursebut usually fatal Familiar clustering


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AUTOIMMUNE DISEASE

KEY CONCEPTS

Recognition of autoantigens by lymphocytes

is critical

Tissue destruction not just autoimmune cells

must be present

AD involve self-reactive T cells

AD induction almost always depends on

triggering of autoreactive CD4+ T cells


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AUTOIMMUNITY

Self

Tolerance

HEALTHY

PERSON

SUCCES

FAIL

AUTOIMMUNE

DISEASE


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Genetic factors

Environmental factors

Immune

dysregulation Hormones

Damage

Infection

Chemical/

Drugs

- HLA-type

- AIRE mutations

- Antigen clearance

- Signaling

- Costimulation

- Cytokines

Auto immune disease

Breaking self-tolerance


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Causes of Autoimmunity

Susceptibilitygenes (usually

multiple)

Triggering factors(probably

environmental)

Loss of tolerance

( break down of tolerance )

Auto reactive T

cells activation

Auto reactive B

cells activation

Inadequate

regulatory

mechanism


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Auto Ab production

Environment Hormones

Stochastic factorsGenetic factors

Initiation of pathogenesis

Critical

threshold

Dendritic cell

Defective priming DefectiveAntigen presentation

IFN? Secretion

T independentAb production

Increased costimulation

Cytokine help

T cellB cellIncreased activity Increased activity

Abnormal complement fixation

Defective phagocyte activation

Circulating immune complex

Increased apoptosis

Defective AICD

Defective cytokine production

Tissue

damage

Pathogenesis ofPathogenesis ofautoimmune diseasesautoimmune diseases

Autoimmunity

(loss of tolerance)

Autoreactive

T and B cells

activation

Disease

Inflammation


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No Penyakit Autoimun Wanita : Pria1234

5

Rematoid artritisHashimoto tiroiditisMultipel sklerosisMiastenia gravis

SLE

5 : 210 : 12 : 12 : 1

9 : 1


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Patofisiologi Penyakit Autoimun

T-Sel Bypass - Sistem kekebalan tubuh yang

normal memerlukan aktivasi sel B oleh sel T

sebelum dapat menghasilkan antibodi dalam

jumlah besar. Kebutuhan sel-T bisa di bypassseperti contoh infeksi oleh organisme yang

memproduksi super antigen yang mampu

memulai aktivasi poliklonal sel B


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T-Sel-B-Cell abnormal

Penyimpangan Sel B yang dimediasi oleh

reseptor Molekular Mimikri

Idiotype Cross-Reaksi

Disregulasi sitokin

Dendritic apoptosis sel

Epitop drift


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Molecular Mimicry

Nat Rev Imm 2009


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Bystander Activation

Nat Rev Imm 2009


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Epitope spreading

Nat Rev Imm 2009


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Function of Treg cells

Treg cells are crucial for the induction and maintenance of peripheraltolerance to self-antigens

TeffTreg

Teff

Treg

Teff

Treg

Autoimmun

e diseases

Infection

Cancer


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Mekanisme Autoimun

Terdapat beberapa mekanisme autoimun

yaitu:

Spontan

Manipulasi imunologis

Manipulasi genetik


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Terapi

Sulit

Membutuhkan kerjasama berbagai bidang

ilmu kedokteran

Obat masih diteliti

Perkembangan ilmu sangat pesat


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Ringkasan

Immunodefisiensi : dapat terjadi pada siapa

saja dan pada tingkat yang berbeda-beda

Penatalaksanaan masih sulit

Perlu penelitian lebih lanjut


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lecture 6 imunodefisiensi r gunadi

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