autoimunitas

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 : overover-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
antigen..
Bila antigen ini adalah antigen asing sel Th akan
mensekresikan cytokines
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’
IL-12
IL18
IFN-γ
LT
TNF
TH1
Tc1
Inflammation
Mφ activation
cytotocity
TCR
naive T
IL-4
TH2
auto-antigen
auto-peptide
IL-4
IL-4 IgE production
IL-5
Allergy
IL-13
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
A. 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
Figure 1313-1
Figure 1313-4
Figure 1313-6
Figure 1313-31
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
Secondary 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
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 ?
Figure 1313-27 part 1 of 3
Figure 1313-27 part 2 of 2
Figure 1313-27 part 3 of 3
Immunotherapy in autoimmune disease
1. Immunosuppression
1.
2.
3.
4.
5.
6.
7.
8.
Prednisolone
Azathioprine
Cyclophosphamide
Cyclsporin A
Mycophenolate mofetil (MMF)
FK506
AntiAnti-CD4
AntiAnti-TNF
Immunotherapy in autoimmune disease
2. Reduction of antibodies
1. Plasma exchange effective
- in acute disease
- if Ab are direct pathogenic
2. AntiAnti-CD20 (rituximab)
phosphoprotein
- 33
33--37 KD
- on normal /malignant B cells
- function unknown
- no ligand defined
- promising in RA and SLE
3. Intravenous immunoglobulin (IVIg)
- via Fc
Fcγ
γR ?
Immunotherapy in autoimmune disease
4. Modulating specific immune reactivity
1.
1.expansion
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 haematopietichaematopietic-stem
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 deficiency)
Vit B12 binding site on
intrinsic factor
Myasthenia gravis
(muscle weakness)
Acetylcholine receptor
Graves’ disease
(hyperthyroidism)
TSHTSH-receptor
no signal
signal
Myasthenia gravis
pathogenesis and therapy
(Immuno)therapy
- Anti
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
TSH
T
destruction
blocking
TSH
TSH-receptor
Primary hypothyroidism
stimulation
growth
TSH-receptor
TSH
Graves’ disease