autoimmune diseases. central tolerance is induced and maintained in the bone marrow and thymus...
TRANSCRIPT
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 TOLERANCEMaintenance of self tolerance of T-lymphocytes against tissue-specific self proteins which are not represented in the thymus
Active mechanisms at the level of CD4+ helper T-lymphocytes
AUTOIMMUNE DISEASESDisturbance of tolerance
Misdirected adaptive immunity to healthy cells and tissues
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
PERIPHERAL TOLERANCE
IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
(autoimmune regulator- AIRE)
• 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
AUTOIMMUNE DISEASES
MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS
Killing of target cell by effector-macrophage orNK-cell
Killing of targetcell by complement-mediated lysis
complement activation
IgG
IgG
Receptor-specific autoantibodyinterferes withsignal transduction
NKMf
C '
ADCC
Autoimmune hemolytic anemia
Goodpasture's syndrome
Glomerulus stained for IgG deposition by immunofluorescence
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.
Pemphigus vulgaris
Acute rheumatic fever
MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS
Killing of target cell by effector-macrophage orNK-cell
Killing of targetcell by complement-mediated lysis
complement activation
IgG
IgG
Receptor-specific autoantibodyinterferes withsignal transduction
NKMf
C '
ADCC
Graves’ disease
Graves' ophthalmopathy
Hashimoto’s disease – hypothyreosis(antibodies and effector T cells)
Nerve impulse
Nerve impulse
InternalizationNO Na+ influx
NO muscle contraction
MYASTENIA GRAVIS
BLOCKING AUTO – ANTIBODIES IN MYASTENIA GRAVIS
NEURO-MUSCULAR JUNCTION
Muscle
Acetilcholin receptor
InsulinInsulin
cell cell cell cell cell cell
PPaancreatic islet cellsncreatic islet cells
MECHANISM OF AUTOREACTIVITY IN INSULIN-DEPENDENT DIABETESType IV hypersensitivity
AUTOREACTIVE CYTOTOXIC T CELLS KILL INSULIN SECRETING β-CELLS
glucagon Somatostatin108 insulin secreting cells
Type I diabetes
FACTORS INVOLVED IN THE PATHOMECHANISM
OF AUTOIMMUNE DISEASES
Disease HLA allotype Relatív risk Sex ratioWomen/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
Insulin dependent diabetes mellitus
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
ASSOCIATIONS OF HLA ALLOTYPE WITH SUSCEPTIBILITY TO AUTOIMMUNE DISEASE
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 diseasesInvolve 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
Professional APCProfessional APC
Signal 2Co-stimulation
Signal 1pMHC - TCR
Signal 3Cytokines
PRIMARY ACTIVATION OF T LYMPHOCYTES IS UNDER TIGHT CONTROL
DENDRITIC CELLS ARE IMPORTANT REGULATORS OF T CELL RESPONSES DENDRITIC CELLS ARE IMPORTANT REGULATORS OF T CELL RESPONSES
REGULATORY T CELLSREGULATORY T CELLS
Homeostatic regulationHomeostatic regulation
THYMUSTHYMUS
Natural– nTregNatural– nTreg
PERIPHERYPERIPHERY
Induced – iTregInduced – iTreg
Induced regulationInduced regulationTregTreg
Autoimmune diseasesAutoimmune diseases Transplantation toleranceTransplantation tolerance
Malignant diseasesMalignant diseases
DCDC
AKTIVATIONAKTIVATION INDUCTIONINDUCTION
COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND DENDRITIC CELLS DENDRITIC CELLS
FUNCTIONS OF REGULATORY T CELLS FUNCTIONS OF REGULATORY T CELLS
• Maintenance of peripheral toleranceMaintenance of peripheral tolerance
• Prevention of autoimmunityPrevention of autoimmunity
• Limitation of inflammatory processes asthma, inflammatory diseasesLimitation of inflammatory processes asthma, inflammatory diseases
• Inhibition of protection against infectious diseasesInhibition of protection against infectious diseases
• Limitation of anti-tumor immunity and protectionsLimitation of anti-tumor immunity and protections
MECHANISMS OF ACTIONMECHANISMS OF ACTION
Internal and external regulationInternal and external regulation
Various inhibitory mechanismsVarious inhibitory mechanisms
Cell contacts – Cytokines Cell contacts – Cytokines
Interaction with the effector T cells as targetsInteraction with the effector T cells as targets
nTregnTreg
THYMUSTHYMUS
PERIPHERYPERIPHERYFoxP3+
FoxP3-
IL-2/TGFβ MaintenanceMaintenance
nTregnTreg
Effector T
IL-10/IL-35/TGFβSupressionSupression
Effector T
DC
FoxP3-Tr1Tr1
IL-10/ TGFβ
IL-10
SuppressionSuppression SuppressionSuppression
FoxP3+Th3Th3
TGFβ
IL-10/ TGFβ
mTEC
CD4+TCD4+TFoxP3-
iTregiTreg
FoxP3+
PERIPHERYPERIPHERY
ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLSORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS
TregTregCD25IL-2Rα
CTLA4B7 ligand
GITR
MARKERS OF THYMUS DERIVED NATURAL Treg CELLS
CD127IL-7Rα ↓
Treg differentiation, maintenance, functionTranscription factor – many target genesFoxP3 by itself is not sufficient to confer suppressive functions
FoxP3
CD4+CD25+FOXP3+
REGULATORY T CELLS
B71/2
TAPC
CD28 activation
CTLA-4
ITIM
NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4
LATE EXPRESSION
HIGHER AFFINITY TO B7 THAN TO CD28
TO
LER
OG
EN
ITÁ
SIM
MU
NO
GE
NIT
ÁS
DIFFERENCIÁCIÓDIFFERENCIÁCIÓ
TOLEROGENIC DC
STIMULATED DC
THE TOLEROGENIC NATURE OF DENDRITIC CELLS THE TOLEROGENIC NATURE OF DENDRITIC CELLS DEPENDS ON THEIR STIMULATORY STATEDEPENDS ON THEIR STIMULATORY STATE
MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONSFUNCTIONS
IL-35
Inhibitory cytokines
TGFβ
IL-10
Cytolysis
Metabolic disturbance Inhibition of dendritic cell differentiation
Reduced cytokine production (IL-2)Reduced cytokine production (IL-2)Peri-cellular adenosinePeri-cellular adenosine
cAMP transfercAMP transfer
Indolamine-2,3 dioxigenaseIndolamine-2,3 dioxigenaseLAG-3 – CD4 homologueLAG-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.
cell-cell contact
TeffTeff
DC
Treg
TeffTeff
soluble factors
DC
Treg
Treg : effector T cell = 1 : 8Treg : DC = 1 : 0,8
HOGYAN HATNAK A REGULÁLÓ T SEJTEK
EFFICIENT WAY OF INHIBITION THROUGH DENDRITIC CELLS
Defective central tolerance: Autoimmune PolyEndocrinopathy Candidiasis-Ectodermal Dystrophy (APECED), AIRE deficiencyFinnish population, Sardinians, Iranian Jews
APECED’ clinical signs
Regulatory T cells inhibit the activation of autoreactiveT-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 smokeGoodpasture 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