Download 6_Autoimmune_2013

Autoimmune diseases
AUTOIMMUNE DISEASES
• Chronic inflammatory conditions
• Repair mechanisms cannot compete with tissue
destruction caused by the immune system
• Variety of symptoms and of target tissues
• Mechanisms of recognition and effector functions are
the same as those acting against pathogens and
environmental antigens
CENTRAL TOLERANCE IS INDUCED AND MAINTAINED IN THE BONE
MARROW AND THYMUS
Clonal deletion of self agressive B and T cell clones (not complete)
B AND T CELLS WITH SELF REACTIVITY ARE PRESENT IN THE
AVAILABLE PERIPHERAL T CELL REPERTOIRE
PERIPHERAL TOLERANCE
Maintenance of self tolerance of T-lymphocytes against tissuespecific self proteins which are not represented in the thymus
Active mechanisms at the level of CD4+ helper T-lymphocytes
AUTOIMMUNE DISEASES
Disturbance of tolerance
Misdirected adaptive immunity to healthy cells and tissues
Deficiency in establishing central T-cell tolerance:
Autoimmune PolyEndocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED),
AIRE deficiency. AIRE: transcription factor inducing expression of many tissue-specific
genes normally not expressed in the thymus.
Rare disease, but more frequently seen in inbred populations Finnish, Iranian Jews and
in the island of Sardine
Symptoms of APECED
Inhibition of autoreactive T-cells in the periphery by regulatory
T-cells. Maintenance of peripheral tolerance
IPEX: Immune dysregulation,
Polyendocrinopathy, enteropathy,
and X-linked syndrome
FoxP3 deficiency
(autoimmune regulator- AIRE)
Sympathetic ophtalmia
Autoimmunity induced by trauma
Immunologically privileged
sites (initiation rather than
access is controlled)
PERIPHERAL TOLERANCE
IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
Normal tissue cells do not express MHC class II
NO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules
and do not produce T cell differentiating cytokines
NO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limited
Antigen presenting cells are not activated in normal tissues
NO SIGNAL 3.
PERIPHERAL TISSUES TOLERIZE THEMSELVES
Autoantibody production is dependent on the
availability of autoreactive T cells
Practically all autoimmune diseases
Involve some T-cell defects
In the absence of T cell help
autoreactive B cells ate trapped
in the T-cell zone and die
Expression of MHC-II on non-immune
cells may contribute to autoimmunity
• in response to IFNγ MHCII expression is
induced on thyroid cells, on the β cells of
the pancreas as well as on microglia.
• Insufficient for the activation of naive Tcells (not normally present in the periphery
anyway), BUT effector T-cells crossreacting
with autoantigens may be activated
Molecular mimicry may lead to severe autoimmune reactions
(T-cell epitopes)
Molecular mimicry may lead to severe autoimmune reactions
(T-cell epitopes)
MECHANISMS OF TYPE II HYPERSENSITIVITY
REACTIONS
NK
Mf
Killing of target
cell by effectormacrophage or
NK-cell
IgG
ADCC
IgG
C'
complement
activation
Killing of target
cell by complementmediated lysis
Receptor-specific
autoantibody
interferes with
signal transduction
Autoimmune hemolytic anemia
Goodpasture's syndrome
Glomerulus stained for IgG deposition by immunofluorescence
Glomerulonephritis uniform,
Only 40% develop lung hemorrhages
Pemphigus vulgaris
Pemphigus is a rare skin disorder characterized by blistering of the skin
and mucous membranes. The most common type is pemphigus vulgaris,
which involves painful sores and blisters on the skin and in mouth.
Autoantibodies attack desmosomes. Antigen: Desmoglein 3
Acute rheumatic fever
Steptococcus pyogenes group A.
Cross reactivity with self antigens
present in hart tissue
(M-protein shows sequence similarity
with myosin. )
Main symptoms:
•Carditis
•polyarthritis (joints become hot, red,
swollen)
•Sydenham’s chorea
Infiltration of T and B (plasma) cells,
macrophages. These look like
granulomas…. They are called Aschoff
bodies.
However only 3% of all patients with
untreated Streptococcal pharingytis
develop rheumatic fever. Likely that
genetic fctors contribute to the
development of the disease !!!
MECHANISMS OF TYPE II HYPERSENSITIVITY
REACTIONS
NK
Mf
Killing of target
cell by effectormacrophage or
NK-cell
IgG
ADCC
IgG
C'
complement
activation
Killing of target
cell by complementmediated lysis
Receptor-specific
autoantibody
interferes with
signal transduction
Graves’ disease
Graves' ophthalmopathy
Temporary symptoms of antibody-mediated autoimmune
diseases can be passed from affected mothers to their
newborn babies.
TSHR, thyroid-stimulating hormone receptor.
Hashimoto’s disease – hypothyreosis
(antibodies and effector T cells)
Infiltration of lymphocytes
Formation of ectopic lymphoid
tissuesLimfocita infiltráció,
extranodális limfoid szövetek.
Mostly Th1 (inflammatory)
response. Cell death,
hypothyreosis
AUTO – ANTIBODIES IN MYASTENIA GRAVIS
NEURO-MUSCULAR JUNCTION
MYASTENIA GRAVIS
Nerve
impulse
Nerve impulse
Acetilcholin receptor
Muscle
Internalization
NO Na+ influx
NO muscle contraction
In systemic lupus erythematosus (SLE) the immune
response is broadened in a antigen-specific manner.
Reumathois Arthritis
A synovial membrane specific cellular immune response
CD4+ és CD8+ T cells, B cells, plasma cells, neutrophils,
macrophages
Rheumatoid factors– anti- IgG-Fc specific antibodies
Treatment of RA with anti TNFα antibody
MECHANISM OF AUTOREACTIVITY IN INSULINDEPENDENT DIABETES
Type IV hypersensitivity
AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN
SECRETING β-CELLS
Insulin
a cell a cell b cell
glucagon
b cell
108 insulin secreting
cells
Pancreatic islet cells
d cell
d cell
Somatostatin
Type I diabetes
FACTORS INVOLVED IN THE PATHOMECHANISM
OF AUTOIMMUNE DISEASES
ASSOCIATIONS OF HLA ALLOTYPE WITH
SUSCEPTIBILITY TO AUTOIMMUNE DISEASE
Disease
HLA allotype
Relatív risk
Sex ratio
Women/male
Ankylosing spondylitis
B27
87.4
0.3
Acute anterior uveitis
B27
10.04
<0.5
Goodpasture’s syndrome
DR2
15.9
~1
Multiple sclerosis
DR2
4.8
10
Graves’s disease
DR3
3.7
4-5
Myasthenia gravis
DR3
2.5
~1
Systemic lupus erythematosus
DR3
5.8
10 - 20
DR3 and
DR4
3.2
~1
Rheumatoid arthritis
DR4
4.2
3
Pemphigus vulgaris
DR4
14.4
~1
Hashimoto thyroiditis
DR5
3.2
4-5
Insulin dependent diabetes
mellitus
Maximum 20% of predisposed people develop the disease
 environmental factors
Frequency of autoimmune diseases is elevated in vomen
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