Transcript
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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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Gangguan fungsi Fagositik
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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Gangguan fungsi Fagositik
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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