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Autoimmune diseases

Interaction among macrophage, bacteria and T cell


: Reaksi sistem imun terhadap Ag jaringan
sendiri.Kehilangan toleransi diri (self tolerance)
menyebabkan sel-sel sistem imun mengenal Ag
tubuh sendiri sebagai asing.
Lymph Process of Self tolerance

Central Tolerance
Peripheral Tolerance
Non-self Ags
Self Ags
Positive and
negative selection
of T cells in the
thymus during the
SELF-TOLERANCE
process
AUTOIMMUNE DISEASE

Immune response to self antigens

Can be mediated by humoral ( type II and III


hypersensitivity reactions ) and / or cellular factors
( type IV hypersensitivity reaction )

Characterized by chronicity and usually


nonreversible
ETIOLOGY
Defect of SELF TOLERANCE mechanisms

1.
1. Excessive
Excessive self
self reactive
reactive Th-cell
Th-cell activity
activity
a.
a. Altered
Altered form
form of
of self
self antigen
antigen (virus
(virus // drug)
drug)
b.
b. Molecular
Molecular mimicry
mimicry (virus
(virus // bacteria)
bacteria)
2.
2. A
A bypass
bypass of
of the
the requisite
requisite self-reactive
self-reactive Th-cell
Th-cell
activity
activity
a.
a. Polyclonal
Polyclonal activation
activation of
of B
B cells
cells
(( LPS
LPS ,, Epstein-Barr
Epstein-Barr virus
virus ))
3.
3. Release
Release of
of sequestered
sequestered Antigens
Antigens
(( sperm
sperm ,, eye
eye lens
lens ))
Altered form of self-antigens

Drugs Diseases
α -methyldopa Anemia
Penicillinamine Myasthenia gravis
Quinidine Granulocytopenia

Molecular mimicry

Shigella flexneri HLA B27


Proteus mirabillis HLA DR4
Coxsackie B virus Myocardium
Trypanosoma cruzi Myocardium
HBV Myelin basic p.
Activation of clones to
Polyclonal activation self antigens
Predisposing
Predisposing factors
factors
1.
1. Genetic
Genetic factor
factor :: HLA
HLA genes
genes
Rheumatoid arthritis DR4 RR. 6.0

IDDM DR3/4 RR. 2.0-5.0

Hashimoto’s thyroiditis DR5 RR. 3.0

Myasthenia gravis DR3 RR. 3.0

2.
2. Sex
Sex :: female
female >> male
male
Rheumatoid arthitis F : M 3:1
SLE F : M 4:1
Sjorgen’s syndrome F : M 9:1

3.
3. Age
Age :: frequency
frequency increased
increased with
with age
age
CLINICAL
CLINICAL CATEGORIES
CATEGORIES ::
Organ
Organ // Tissue
Tissue specific
specific
Disease Presumed Tissue involvement
mediation
Guillain-Barre syndrome T Nervous system
Myasthenia gravis H Nervous system
Hashimoto’s thyroiditis H, T Thyroid
Grave’s disease H Thyroid
Diabetes mellitus H, T Pancreas
Goodpasture’s syndrome H Lung and Kidney
Pernicious anemia H Stomach
Autoimmune hemolytic disease H Red blood cells
Pemphigus / Pemphigoid H Skin

Systemic
Systemic
SLE H Kidney,skin,CNS,CV
Rheumatoid arthritis H Joints,vascular bed
Organ specific antigens

Disease
Disease Antigens
Antigens

Diabetes
Diabetes mellitus
mellitus Islet
Islet cell
cell antigens
antigens
Goodpasture’s
Goodpasture’s syndrome
syndrome Basement
Basement membrane
membrane
Grave’s
Grave’s disease
disease TSH
TSH receptor
receptor
Hashimoto’s
Hashimoto’s thyroiditis
thyroiditis Thyroglobulin
Thyroglobulin
Myasthenia
Myasthenia gravis
gravis Acetylecholine
Acetylecholine receptor
receptor
Pernicious
Pernicious anemia
anemia Gastric
Gastric parietal
parietal cell
cell
Rheumatoid
Rheumatoid arthritis
arthritis IgG
IgG
Pemphigus
Pemphigus vulgaris
vulgaris Desmosomes
Desmosomes
Pemphigoid
Pemphigoid Basement
Basement membrane
membrane
AIHA
AIHA Erythrocytes
Erythrocytes
Male
Male infertility
infertility Spermatozoa
Spermatozoa
DIAGNOSIS

Elevated serum gamma-globulin


Presence of diverse autoantibodies
Depressed level of serum complement
Immune complex in serum
Depressed level of suppressor factors
Biopsy
MACAM2 PENY. AUTOIMUN

I. Penyakit autoimun organ.


1. Autoimune hemolytic anemia (AHA)

: ok destruksi oleh AB terhadap Ag pada permukaan erythrosit


(autoantibodi antierytrosit)
2. Tyroiditis Hashimoto.
- Sebagian besar eutiroid, ttp dapat juga hipotiroid / hipertiroid.
- Dijumpai :
• Autoantibodi anti tiroglobulin.

• Infiltrasi limfosit, makrofag, sel plasma dalam kelenjar →

membentuk folikel limfoid


3. Penyakit Grave
: Toxic goiter /exopthalmic goiter
- dijumpai Antibodi (Long acting Thyroid stimulator : LATS /

TSAb = Thyroid Stimulating AB) terhadap reseptor (TSH)


pada permukaan tiroid → merangsang kelenjar tiroid. = T3 dan
T4 >>>.
Grave’s disease (thyrotoxicosis, hyperthyroidism)
An increased number of peripheral B cells correlates with severity

The number of T cells decreases particularly the CD8 cells (Ts)

Several autoantibody (IgG or IgM) against thyrotropin receptor


with different effects are produced:
1. One type of antibody blocks the binding of TSH to thyroid epithelial
cells
2. A second antibody causes the proliferation of of thyroid cells
3. A third type called thyroid - stimulating antibody reactys with TSH
receptor and mimics the thyrotropin hormone

The autoantibody could cross the placenta and causes the hyperthy-
roidism in newborn
Increased frequency in HLA-B35 and DR3
4. SINDROM SJOGREN.
- ditandai : keratokonjungtivitis sikka (mata kering ) ,xerostomia

(mulut kering)
- 40 % : bentuk primer

60 % berhubungan : RA, SLE, skleroderma, (darah = RF,


ANA).
- PA : infiltrasi sel B, sel T periductal lacrimal + hiperplasi ep +

obstruksi lumen → atrofi asiner, fibrosis dan perlemakan


5. Polimiositis / dermatomiositis
- Poliomisitis : peradangan otot skelet diperantarai kel. Imunologik.

- Klinik : kelemahan otot bil. Simetrik (kas : prox > dulu)

- Ok kerusakan serabut otot oleh sel T sitotoxic yang memasuki dan

mengitari serabut otot.


II. Penyakit Autoimun Sistemik
1. SLE (Sistemik Lupus Eritematosus)
- Penyakit demam sistemik, kronik, berulang, dengan gejala

berhubungan dengan semua jar (tu sendi, kulit, membran serosa)


- Perjalanan klinis bervariasi

• Kadang gejala minimal → sembuh tanpa pengobatan.

• Sebagian besar : kambuh berulang → remisi : dapat

dipertahankan dengan imunosupresan.


• Ketahanan hidup 10 tahun = + 70 %
- Gambaran klinis bervariasi .
Ciri kas (tu) :
ANA (antinuclear antibodies)
Sel LE (badan LE (nukleus sel yang rusak
bereaksi dengan AB antinukleus →
kehilangan pola kromatin) yang difagosit
neutrofil / makrofag)

2. Rheumatoid arthritis (RA)


Poliarthritis (nyeri pada berbagai sendi)
Uji serologik : reumatoid faktor
(autoantibodi anti Ig G) timbul pada
persendian.
Rheumatoid
Rheumatoid arthritis
arthritis
Immunologic
Immunologic findings
findings ::
1.
1. Rheumatoid
Rheumatoid factor
factor ::
anti-IgG
anti-IgG immunoglobulin
immunoglobulin (IgM
(IgM ,, IgG
IgG or
or IgA)
IgA) produced
produced by
by B
B cells
cells in
in
the
the synovial
synovial membrane.
membrane.
Has
Has the
the specifity
specifity to
to Fc
Fc fragment
fragment of
of IgG
IgG
2.
2. Immune
Immune complexes:
complexes:
Complement
Complement activation
activation which
which leads
leads to
to inflammatory
inflammatory respons
respons
Large
Large complexes
complexes will
will be
be phagocytized
phagocytized byby macrophage
macrophage which
which
release
release cytokines
cytokines and
and also
also neutrophils
neutrophils which
which release
release digestive
digestive
enzymes.
enzymes. Small
Small complexes
complexes may may circulate
circulate causing
causing vasculitis
vasculitis and
and
lung
lung injury
injury
3.
3. Antinuclear
Antinuclear antibody
antibody could
could also
also present
present in
in patients
patients with
with RA
RA
4.
4. Genetic
Genetic background
background :: HLA-DR4
HLA-DR4 :: susceptible
susceptible
HLA-DR1:
HLA-DR1: protective
protective
5.
5. Cytokines
Cytokines :: TNF,
TNF, IFNg
IFNg ,, IL-1
IL-1 and
and IL-8
IL-8 may
may participate
participate in
in tissue
tissue
damage
damage by
by inducing
inducing inflammatory
inflammatory respons
respons and
and destruction.
destruction.
Systemic lupus erythematosus

Immunologic findings :

1. LE cell phenomena
Neutrophils with ingested nuclear material of lymphocytes
2. Antinuclear antibody : IgG or IgM to DNA
Anti ssDNA
Anti dsDNA : a complement fixing antibody
closely related to active SLE and glomerulonephritis
Anti both ss and dsDNA
3. Other antibodies :
antibodies against RNA, mitochondria, rbc, ribosome etc.
4. Genetic aspects :
HLA DR2 : more likely to produce dsDNA
5. Altered complement levels, hypergammaglobulin and low number of T
cells
IDDM
IDDM

Immunologic
Immunologic findings
findings ::
Destruction
Destruction process
process mediated
mediated by:
by:
CTL
CTL or
or delayed
delayed type
type hypersensitivity
hypersensitivity (CD4+Th1)
(CD4+Th1)
Antibodies
Antibodies against
against islet
islet cells
cells (IgG2
(IgG2 &
& IgG4)
IgG4) and
and also
also anti-
anti- insulin
insulin
antibodies
antibodies

Genetic
Genetic background
background ::
Risk
Risk is
is increased
increased in
in people
people with
with HLA-DR3
HLA-DR3 and
and DR4
DR4 haplotypes
haplotypes
HLA
HLA DQ
DQ variations
variations in
in beta-chain
beta-chain alleles
alleles may
may confer
confer either
either protection
protection or
or
susceptibility.
susceptibility.

The
The onset
onset of
of IDDM
IDDM is
is often
often preceded
preceded byby viral
viral infection
infection :: mumps,
mumps, CMV,
CMV,
influenza,
influenza, rubella,
rubella, coxsackievirus
coxsackievirus .. Molecular
Molecular mimicry
mimicry and
and cross-
cross-
reactive
reactive antigens
antigens may
may trigger
trigger the
the production
production ofof the
the auto-antibodies
auto-antibodies
Myasthenia gravis

Immunologic findings :

Antibody (IgG3) against acetylcholine receptor at the myoneural junction


causing endocytosis of the receptor

Complement could be activated causing further problems

60-80 % have enlarged thymus


Hashimoto’ thyroiditis ( Chronic thyroiditis )

Immunologic findings

Various antibody to Thyroid specific antigens can be detected :

1. Antibody to thyroglobulin
2. Antibody to thyroid microsomal antigens

T cell mediayed immunity ( delayed type hypersensitivity ) could also be


demonstrated

Histologic examination shows lymphocytes and plasma cell infiltration,


disappearance of colloid and fibrosis
TREATMENTS

1. Metabolic control : might be useful in certain organ


specific disease :
antithyroid drugs , vit B12
2. Antiinflammatory ( steroidal / nonsteroidal )
Immunosuppressive cytotoxic drug
3. Anticholinesterase drugs / thymectomy:
Myasthenia gravis
4. Plasmapharesis:
SLE, GBSyndrome, Goodpature’s syndrome
5. Splenectomy:
ITP , AIHA
Gene therapy Bone marrow graft
Stem cell
Differentiation
Thymus graft Antigen induced
Thymus factor tolerance

B/T Anti Class II


Anti CD4
Activation
Proliferation Anti mitotic drugs

Total ll.nn irradiation


T Blast Anti-IL2R
Antigen induced
suppression
Maturation

Effector

Immuno-suppress Cell-med Hypers. Antibody Plasmapharesis

Inflammatory
Anti inflammatory drugs
Tissue damage

Metabolic control Metabolic defect Structural defect Tissue graft


Metabolic control

Insulin : Juvenile diabetes


B12 : Pernicious anemia
Anti thyroid : Grave’ disease
Anti-cholinesterase : Myasthenia gravis
Thymectomi : myasthenia gravis

Anti-inflammatory

Steroid : SLE
Anti-prostaglandin : Rheumatoid arthritis
Anti-TNFα : Rheumatoid arthritis
Immunosuppressive drugs

Cyclosporine A ( blocks IL-2, anti-mitotic) : uveitis , IDDM , psoriasis , ITP , Crohn’s


disease ,
Myasthenia gravis
Azathioprine , cyclophosphamide , methotrexate in combination with steroid : SLE , RA ,
CAH

Immunological control strategies

Cellular manipulation : anti-Class MHC Class II, anti-IL2R : SLE


Idiotype control : IV injection of Ig pool from many donors : reccurent abortion associated
with ACA
auto antibody to FVII
Antigen manipulation

Peptide analog that will bind MHC molecule and block the response to auto-
antigen
To induce TGFβ production of gut mucosal system to suppress inflammatory
cytokines :
multiple sclerosis patients fed with MBP

Plasmapharesis

SLE (not successful)


Goodpasteur’s syndrome (successful)