Download Autoimmune - Treg 2012

Autoimmune diseases
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
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
(autoimmune regulator- AIRE)
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
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
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.
Acute rheumatic fever
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
Hashimoto’s disease – hypothyreosis
(antibodies and effector T cells)
BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS
NEURO-MUSCULAR JUNCTION
MYASTENIA GRAVIS
Nerve
impulse
Nerve impulse
Acetilcholin receptor
Muscle
Internalization
NO Na+ influx
NO muscle contraction
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
Tolerance : Role of genetic and environmental factors
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
NEGATIVE REGULATION OF IMMUNE
RESPONSES BY REGULATORY T CELLS
PRIMARY ACTIVATION OF T LYMPHOCYTES IS UNDER
TIGHT CONTROL
Signal 3
Cytokines
Signal 1
Signal 2
pMHC - TCR
Co-stimulation
Professional APC
DENDRITIC CELLS ARE IMPORTANT REGULATORS OF T CELL RESPONSES
COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND
DENDRITIC CELLS
THYMUS
PERIPHERY
Natural– nTreg
Induced – iTreg
REGULATORY T CELLS
Homeostatic regulation
Treg
Induced regulation
INDUCTION
AKTIVATION
DC
Autoimmune diseases
Transplantation tolerance
Malignant diseases
FUNCTIONS OF REGULATORY T CELLS
• Maintenance of peripheral tolerance
• Prevention of autoimmunity
• Limitation of inflammatory processes asthma, inflammatory diseases
• Inhibition of protection against infectious diseases
• Limitation of anti-tumor immunity and protections
MECHANISMS OF ACTION
Internal and external regulation
Various inhibitory mechanisms
Cell contacts – Cytokines
Interaction with the effector T cells as targets
ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS
FoxP3+
PERIPHERY
nTreg
IL-2/TGFβ
Maintenance
mTEC
nTreg
IL-10/IL-35/TGFβ
Supression
Effector T
PERIPHERY
iTreg
FoxP3-
FoxP3-
FoxP3+
CD4+T
THYMUS
DC
IL-10
TGFβ
FoxP3+
FoxP3-
Th3
Tr1
IL-10/ TGFβ
Suppression
IL-10/ TGFβ
Effector T
Suppression
REGULATORY T CELLS
MARKERS OF THYMUS DERIVED NATURAL Treg CELLS
CD4+CD25+FOXP3+
GITR
CTLA4
B7 ligand
Treg
FoxP3
CD25
IL-2Rα
CD127
IL-7Rα ↓
Treg differentiation, maintenance, function
Transcription factor – many target genes
FoxP3 by itself is not sufficient to confer suppressive functions
NEGATIVE REGULATION OF T CELL ACTIVATION BY
CTLA-4
T
APC
CD28
B71/2
activation
ITIM
CTLA-4
LATE EXPRESSION
HIGHER AFFINITY TO B7 THAN TO CD28
THE TOLEROGENIC NATURE OF DENDRITIC CELLS
DEPENDS ON THEIR STIMULATORY STATE
IMMUNOGENITÁS
STIMULATED DC
TOLEROGENITÁS
DIFFERENCIÁCIÓ
TOLEROGENIC DC
MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONS
Inhibitory cytokines
Cytolysis
TGFβ
IL-10
IL-35
Metabolic disturbance
Reduced cytokine production (IL-2)
Peri-cellular adenosine
cAMP transfer
Inhibition of dendritic cell differentiation
Indolamine-2,3 dioxigenase
LAG-3 – CD4 homologue
Inhibition of dendritic cell functions by Treg cells
Sakaguchi,
Nat Immunol, 2010
In the absence of Treg cells the effector T-cells act as adjuvants as they
promote DC activation through increasing the expression of MHC and
co-stimulatory molecules and the production of inflammatory cytokines.
HOGYAN HATNAK A REGULÁLÓ T SEJTEK
Treg : effector T cell = 1 : 8
Treg : DC = 1 : 0,8
DC
Treg
Treg
Teff
Teff
DC
cell-cell contact
soluble factors
EFFICIENT WAY OF INHIBITION THROUGH DENDRITIC
CELLS
Defective central tolerance:
Autoimmune PolyEndocrinopathy Candidiasis-Ectodermal Dystrophy (APECED),
AIRE deficiency
Finnish population, Sardinians, Iranian Jews
APECED’ clinical signs
Regulatory T cells inhibit the activation of autoreactive
T-cells
IPEX: Immune dysregulation,
Polyendocrinopathy, enteropathy,
and X-linked syndrome
FoxP3 deficiency
Antibodies against streptococcal cell-wall antigens cross-react
with antigens on heart tissue
Self peptides that mimic pathogen-derived peptides
can stimulate T-cell responses
Sympathetic ophtalmia
Environmental factors – cigarette smoke
Goodpasture syndrome
Glomerulus stained for IgG deposition by immunofluorescence
Induction of MHC-II expression
on tissue cells facilitates autoimmunity
In SLE the immune response is broadened
in an antigen-specific manner
Age
CD28
KAR