AUTOIMUNITAS Rita Evalina Rusli
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 >>
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 (-)
Karakteristik : over-reactive immune response immune system menyerang bagian tubuh sendiri Pemeran immune system adalah white blood cells. The most common blood cell involved in autoimmune responses is the lymphocyte Lymphocytes constitute 25% of the body’s white blood cells Tiap T cell dilengkapi dengan receptor yang akan berikatan pada specific antigen. Bila antigen ini adalah antigen asing sel Th akan mensekresikan cytokines, mengatur proteins yg memperantarai immune response, menstimulasi sel lain dari immune system untuk merusak antigen. (See Figure 1). T cell sitotoksik bereaksi untuk membunuh penyerbu
the antigen being presented to a helper T cell, which subsequently secretes cytokines that elicit an immune response
Definisi Autoimmune disease is a disease resulting from autoimmunity. - Proof of autoimmunity - Proof of pathogenicity of the immune reaction
Regulation of TH development by cytokines IFN-γ ‘danger signal’ IFN-γ LT TNF TH1 IL-12 IL18 Tc1 Inflammation Mφ activation cytotocity naive T TCR IL-4 TH2 IL-4 IL-5 IL-13 IgE production Allergy auto-antigen auto-peptide
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 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 dan antigen klamidia, tripanosoma cruzi
Kemiripan pada autoimunitas
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 vasektomi
Faktor yang berperan……….. C. Kegagalan autoregulasi - regulasi imun : pertahankan hemostasis - kegagalan sel Ts dan Tr Th dirangsang autoimunitas D. Aktivasi sel B poliklonal - penyebab : virus (EBV), LPS, parasit malaria E. Obat-obatan F. Faktor keturunan
Pembagian penyakit autoimun Menurut mekanisme 1. melalui autoantibodi 2. melalui antibodi dan sel T 3. melalui kompleks Ag-Ab 4. melalui komplemen B. Menurut sistem organ
Spectrum of autoimmune disease (AID) Organ specific < --- > Systemic
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Systemic lupus erythematosus 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 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)
SLE impaired clearance of apoptotic cells Early apoptotic cell clearance by phagocytes no necrosis no danger signals no immune response Secondary necrotic cell impaired clearance secondary necrotic cells danger signals inflammation exposure of autoantigens autoimmune reaction > ANA In SLE
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 Lupus nephritis due to IgG and C3 deposits Therapy Immunosuppressive (steroids, CY, azathioprine, MMF) Anti-CD20 ? Autologous stem-cell transplantation ?
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Immunotherapy in autoimmune disease 1. Immunosuppression Prednisolone Azathioprine Cyclophosphamide Cyclsporin A Mycophenolate mofetil (MMF) FK506 Anti-CD4 Anti-TNF
Immunotherapy in autoimmune disease 2. Reduction of antibodies 1. Plasma exchange effective - in acute disease - if Ab are direct pathogenic 2. Anti-CD20 (rituximab) - 33-37 KD phosphoprotein - on normal /malignant B cells - function unknown - no ligand defined - promising in RA and SLE 3. Intravenous immunoglobulin (IVIg) - via FcγR ?
Immunotherapy in autoimmune disease Modulating specific immune reactivity 1. expansion /activation of regulatory CD25+CD4+ T cells 2. expansion /activation of regulatory NKT cells 3. oral tolerance induction 4. nasal tolerance induction 5. vaccination with tolerogenic DCs 6. Interference with cytokine production 7. autologous haematopietic-stem-cell transplantation
THERE’S STILL A LOT TO LEARN ……..!!!!!! THANK YOU
Autoimmune hemolytic anemia (AIHA)
Goodpasture’s syndrome pathogenesis and therapy - Antibodies to GBM (glomerular basement membrane) - Epitope: type IV collagen α3-chain present in glomeruli and lung - Disruption of BM - Necrotizing crescentic GN Therapy - Plasmapheresis - Immunosuppression Linear deposits of IgG and C3 In glomeruli
Pemphigus pathogenesis and therapy - Antibodies to cadherin (Dsg3) cause skin blistering Therapy Immunosuppression IVIg?? Pemhigus vulgaris IgG and C3 on keratinocytes
Receptor autoantibodies (Type II) causing blockage or stimulation Pernicious anemia Vit B12 binding site on (vit B12 deficiency) intrinsic factor Myasthenia gravis Acetylcholine receptor (muscle weakness) Graves’ disease TSH-receptor (hyperthyroidism) no signal signal
Myasthenia gravis pathogenesis and therapy (Immuno)therapy - Anti-cholineesterases - Immunosuppression (prednisolone,azathioprine,CY, methotrexate,cyclosporin A) - Thymectomy Crisis: - Plasma exchange - IVIg
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 K.A. von Basedow, German doctor, 1840
Spectrum of thyroid autoimmune disease Hashimoto m T TSH destruction blocking stimulation growth TSH TSH TSH-receptor TSH-receptor Primary hypothyroidism Graves’ disease