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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
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
-methyldopa Anemia
Penicillinamine Myasthenia gravis
Quinidine Granulocytopenia
Molecular mimicry
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
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
Imunologik.
- Klinik : kelemahan otot bil. Simetrik (kas : prox > dulu)
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 :
Immunologic findings
1. Antibody to thyroglobulin
2. Antibody to thyroid microsomal antigens
Effector
Inflammatory
Anti inflammatory drugs
Tissue damage
Anti-inflammatory
Steroid : SLE
Anti-prostaglandin : Rheumatoid arthritis
Anti-TNFRheumatoid arthritis
Immunosuppressive drugs
Peptide analog that will bind MHC molecule and block the response to auto-
antigen
To induce TGF production of gut mucosal system to suppress inflammatory
cytokines :
multiple sclerosis patients fed with MBP
Plasmapharesis