AUTOIMUNITAS Rita t E va E lina R usli

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AUTOIMUNITAS

Rita Evalina Rusli

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Pendahuluan

Respons imun terhadap self antigen

Self antigen menimbulkan aktivasi,

proliferasi, diferensiasi sel T autoreaktif

menjadi sel efektor kerusakan

Self tolerance sel T/B keduanya gagal

Potensi pada semua individu karena

limposit dapat ekspresikan reseptor

spesifik untuk banyak self antigen

3,5% populasi

Wanita >>

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Pend……….

Autoantigen, autoantibodi

Sel autoreaktif limfosit yang mempunyai

reseptor untuk autoantigen, bila ada

respons imun SLR (sel limposit reaktif)

Normal : SLR terpajan autoantigen

respons imun tidak terjadi (ada sistem

yang mengontrol)

Sebagian orang : autoantibodi (+),

penyakit (-)

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Karakteristik : over

Karakteristik : over--reactive immune response reactive immune response immune system menyerang bagian tubuh sendiri immune system menyerang bagian tubuh sendiri Pemeran immune system adalah white blood

Pemeran immune system adalah white blood cells.

cells. The most common blood cell involved in The most common blood cell involved in autoimmune responses is the

autoimmune responses is the lymphocytelymphocyte

Lymphocytes constitute 25% of the body’s white Lymphocytes constitute 25% of the body’s white blood cells

blood cells

Tiap T cell dilengkapi dengan receptor yang akan Tiap T cell dilengkapi dengan receptor yang akan berikatan pada specific

berikatan pada specific antigenantigen. . berikatan pada specific

berikatan pada specific antigenantigen. .

Bila antigen ini adalah antigen asing sel Th akan Bila antigen ini adalah antigen asing sel Th akan mensekresikan

mensekresikan cytokinescytokines, mengatur proteins yg , mengatur proteins yg memperantarai immune response, menstimulasi memperantarai immune response, menstimulasi sel lain dari immune system untuk merusak

sel lain dari immune system untuk merusak antigen. (See Figure 1).

antigen. (See Figure 1).

T cell sitotoksik bereaksi untuk membunuh T cell sitotoksik bereaksi untuk membunuh penyerbu

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the antigen being presented to a helper T cell, the antigen being presented to a helper T cell,

which subsequently secretes cytokines that elicit which subsequently secretes cytokines that elicit an immune response

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Definisi

--

Autoimmune disease is a disease resulting

from autoimmunity.

-- Proof of autoimmunity

Proof of autoimmunity

-- Proof of autoimmunity

Proof of autoimmunity

-- Proof of pathogenicity of the immune

Proof of pathogenicity of the immune

reaction

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Tc1

Regulation of T

_H

development by cytokines

‘danger signal’ IL-12 IL18 T_H1 IFN-γ LT TNF IFN-γ Inflammation Mφ activation cytotocity naive T TCR IL-4 T_H2 IL-4 IL-5 IL-13 IL-4 cytotocity IgE production Allergy auto-peptide auto-antigen

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Faktor yang berperan

A. Infeksi dan kemiripan molekular

- Virus dan bakteri

- beberapa bakteri memiliki epitop yang sama

dengan Ag sel diri rangsangan terhadap sel T merangsang sel B autoantibodi

T merangsang sel B autoantibodi

- Kerusakan bukan oleh karena mikroba, tapi

akibat respons imun

- Deman rematik paska infeksi streptokok

antibodi thdp streptokok diikat miokard karditis

- Terdapat juga homologi antara protein jantung

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Kemiripan pada autoimunitas

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Faktor yang berperan………..

B. Sequestered antigen

- self antigen karena letak anatominya

tidak terpajan dg sistem imun

- normal, tidak ditemukan untuk dikenal

sistem imun perubahan anatomik

jaringan (inflamasi, iskemia, trauma)

dapat memajankan sequestered antigen

- uveitis paska trauma, orchitis paska

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C. Kegagalan autoregulasi

- regulasi imun : pertahankan hemostasis

- kegagalan sel Ts dan Tr Th

dirangsang autoimunitas

Faktor yang berperan………..

D. Aktivasi sel B poliklonal

- penyebab : virus (EBV), LPS, parasit

malaria

E. Obat-obatan

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Pembagian penyakit autoimun

A. Menurut mekanisme

1. melalui autoantibodi

2. melalui antibodi dan sel T

3. melalui kompleks Ag-Ab

4. melalui komplemen

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Spectrum of autoimmune disease (AID)

Organ specific <

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Figure 13

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Figure 13

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Figure 13

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Figure 13

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Presentation

90% tired, arthritis, arthralgia 80% fever

70% hair loss, anemia, swollen lymph nodes 60% weight loss, malar rash

50% pleuritis, pericarditis, nephritis 40% sun light sensitivity

Systemic lupus erythematosus

SLE : 4 out of 11 ARA criteria (1982 / 1997)

1 Malar rash 2 Discoid lupus 3 Photosensitivity 4 Oral ulcers 5 Arthritis

6 Serositis (pleuritis or pericarditis)

7 Renal disorders (proteinuria or cellular casts) 8 Seizures or psychosis

9 Hemolytic anemia, leukopenia, lymphopenia or thrombocytopenia

10 Anti-DNA antibody, anti-Sm antibody or antiphospholipid antibody positive 11 Positive antinuclear antibody test (positive ANA)

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SLE impaired clearance of apoptotic cells

Early apoptotic cell

Early apoptotic cell Secondary necrotic cellSecondary necrotic cell

In SLE clearance by phagocytes no necrosis no danger signals no immune response impaired clearance

secondary necrotic cells danger signals

inflammation

exposure of autoantigens autoimmune reaction > ANA

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SLE pathogenesis and therapy

Kelebihan antibodies thd epitop nuclear (ANA) Penyebaran Epitope

Antibodies to DNA

Antibodies to cell wall constituents (eg thrombocytes) Immune complex formation

Complement activation Complement activation

Lupus nephritis due to IgG and C3 deposits Therapy

Immunosuppressive (steroids, CY, azathioprine, MMF) Anti-CD20 ?

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Figure 13

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Figure 13

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Figure 13

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Immunotherapy in autoimmune disease

1. Immunosuppression

1. 1. PrednisolonePrednisolone 2. 2. AzathioprineAzathioprine 3. 3. CyclophosphamideCyclophosphamide 3. 3. CyclophosphamideCyclophosphamide 4. 4. Cyclsporin ACyclsporin A 5.

5. Mycophenolate mofetil (MMF)Mycophenolate mofetil (MMF) 6. 6. FK506FK506 7. 7. AntiAnti--CD4CD4 8. 8. AntiAnti--TNFTNF

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Immunotherapy in autoimmune disease

2. Reduction of antibodies

1.

1. Plasma exchange effective Plasma exchange effective -- in acute diseasein acute disease -- if Ab are direct pathogenicif Ab are direct pathogenic 2.

2. AntiAnti--CD20 (rituximab)CD20 (rituximab) -- 3333--37 KD 37 KD phosphoprotein

phosphoprotein phosphoprotein phosphoprotein

-- on normal /malignant B cellson normal /malignant B cells -- function unknownfunction unknown

-- no ligand definedno ligand defined

-- promising in RA and SLEpromising in RA and SLE

3. Intravenous immunoglobulin (IVIg)

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Immunotherapy in autoimmune disease

4.

4. Modulating specific immune reactivity

Modulating specific immune reactivity

1.

1.expansion /activation of regulatoryexpansion /activation of regulatory CD25+CD4+ T cells

CD25+CD4+ T cells

2. expansion /activation of regulatory NKT cells 2. expansion /activation of regulatory NKT cells 3. oral tolerance induction

3. oral tolerance induction 3. oral tolerance induction 3. oral tolerance induction 4. nasal tolerance induction 4. nasal tolerance induction

5. vaccination with tolerogenic DCs 5. vaccination with tolerogenic DCs

6. Interference with cytokine production 6. Interference with cytokine production 7. autologous haematopietic

7. autologous haematopietic--stemstem--cellcell transplantation

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THERE’S STILL A LOT TO LEARN ……..!!!!!!

THANK YOU

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Autoimmune hemolytic anemia (AIHA)

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Goodpasture’s syndrome pathogenesis and therapy

-- Antibodies to GBMAntibodies to GBM

(glomerular basement membrane) (glomerular basement membrane) -- Epitope: type IV collagen Epitope: type IV collagen αα33--chainchain

present in glomeruli and lung present in glomeruli and lung -- Disruption of BM Disruption of BM

-- Necrotizing crescentic GN Necrotizing crescentic GN -- Necrotizing crescentic GN Necrotizing crescentic GN Therapy

Therapy

-- PlasmapheresisPlasmapheresis

-- ImmunosuppressionImmunosuppression

Linear deposits of IgG and C3 In glomeruli

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Pemphigus pathogenesis

and therapy

-- Antibodies to cadherin Antibodies to cadherin (Dsg3)

(Dsg3)

cause skin blistering cause skin blistering cause skin blistering cause skin blistering

Therapy Therapy

Immunosuppression Immunosuppression IVIg??

IVIg?? _{Pemhigus vulgaris}

IgG and C3

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Receptor autoantibodies (Type II)

causing blockage or stimulation

Pernicious anemia

Pernicious anemia Vit BVit B1212 binding site on binding site on

(vit B12 deficiency)

(vit B12 deficiency) intrinsic factorintrinsic factor

Myasthenia gravis

Myasthenia gravis Acetylcholine receptor Acetylcholine receptor (muscle weakness)

(muscle weakness)

Graves’ disease

Graves’ disease TSHTSH--receptorreceptor (hyperthyroidism)

(hyperthyroidism)

no signal

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Myasthenia gravis

pathogenesis and therapy

(Immuno)therapy (Immuno)therapy

-- AntiAnti--cholineesterasescholineesterases -- ImmunosuppressionImmunosuppression -- ImmunosuppressionImmunosuppression (prednisolone,azathioprine,CY, (prednisolone,azathioprine,CY, methotrexate,cyclosporin A) methotrexate,cyclosporin A) -- ThymectomyThymectomy Crisis: Crisis:

-- Plasma exchangePlasma exchange -- IVIgIVIg

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Graves’ disease

symptoms and therapy

Hyperthyroidism Exophthalmus Diffuse struma

Ig pass the placenta Therapy - radioiodine - surgery -TSH-R antibodies disappear upon treatment - drugs to balance

thyroid function R.J. Graves, Irish doctor, 1825

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Spectrum of thyroid autoimmune disease

destruction T m TSH Hashimoto stimulation blocking TSH-receptor growth TSH destruction Graves’ disease TSH-receptor TSH Primary hypothyroidism