Download - Immunological tolerance
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IMMUNOLOGICAL TOLERANCEJINTANA CHATAROOPWIJIT9 DECEMBER 2016
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DEFINITION
• Tolerance : Unresponsiveness to antigen that is induced by previous exposure to that antigen
• Inherent property of immune system• Response against foreign antigen (nonself)
without attacking host (self)• Specific lymphocyte + Antigen --> activated
lymphocyte --> immune responses or tolerance ( inactivation/elimination )
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DEFINITION
• Tolerogens/Tolerogenic antigens : antigens that induced tolerance
• Self-tolerance : Tolerance to self antigens• Autoimmunity : Failure of self-tolerance -->
immune reaction against autologous antigens
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PHYSIOPATHOLOGY OF IMMUNE TOLERANCE-RELATED DISEASE
• Complex• Influenced by
• Genetic susceptibility• Route of exposure• Antigen dose• Time of exposure• Structural characteristics of allergen and antigen• Coexposure with stimulators of innate immune response ex.
Infections or commensal bacteria
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TOLERANCE
1. Central Tolerance2. Peripheral Tolerance
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CENTRAL TOLERANCE
• First step of tolerance during maturation in thymus
• Prethymic T cells enter thymus and reach subcapsular region --> proliferate as large lymphoblast
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CENTRAL TOLERANCE
• Maturing cells move deeper into cortex and adhere to cortical epithelial cells ( increased in expression of CD3, CD4, CD8 and TCR )
• T cell receptors (TCRs) on thymocytes are exposed to MHC molecules through these contact
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CENTRAL TOLERANCE
• TCRs + autoantigens (medullary thymic epithelial cells, interdigitating cells and macrophage at corticomedullary junction) --> deleted
• Cells expressing CD4 or CD8 --> periphery
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FACTORS TO INDUCE NEGATIVE SELECTION OF SELF REACTIVE THYMOCYTE (INTRATHYMIC SELECTION)• Not known• Possible factors
• Affinity of antigen recognition• Type of antigen-presenting cells presenting the antigen• Locally availability of cytokine in thymus• Presence of antigen in thymus ( local or delivery by
blood )• Affinity of thymocyte T cell receptors (TCRs) to
recognize antigen
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AIRE ( AUTOIMMUNE RESPONSE ELEMENT)
• Transcription factor controlling expression of some organ-specific "peripheral antigens" in thymus
• Component of multiple protein complex• Function : Transcriptional regulator to
promote expression of selected tissue-restricted antigen in thymus
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AUTOIMMUNE POLYENDOCRINE SYNDROME TYPE 1 (APS1) OR AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY/DYSPLASIA (APECED)
• In mouse model : knockout of AIRE gene• In mice : low level several proteins in
medullary thymic epithelial cells in peripheral organs ex. pancreatic insulin
• Characterized by antibody and lymphocyte-mediated injury to multiple endocrine organs ( parathyroids, adrenals and pancreatic islet )
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PATHWAY OF APOPTOSIS
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NECROSIS VS APOPTOSIS
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TWO SIGNAL MODEL : ANERGY
Signal 1Recognition by
helper lymphocyte
No YesTarget
lymphocyte(Naive CD4 T
cell)Signal 2
APC + costimulator molecules
-->Costimulatory
signal
Signal1 : TcR bind their peptide/class II MHC complex
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REGULATION OF T CELL RESPONSES BY INHIBITORY RECEPTORS
• Balance between engagement of activating and inhibitory receptors --> outcome of antigen recognition by T cells particularly CD4+ cells
• Inhibitory receptors with physiologic self-tolerance : CTLA-4 and PD-1
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CTLA-4
• Negative regulator of adaptive immune responses
• Bind to B7 (CD80 and CD86) costimulatory molecules on APCs
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CTLA-4
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CTLA-4
• Knockout mice lacking CTLA-4 --> uncontrolled lymphocyte activation with massive enlarge lymph node and spleen and fatal multiorgan lymphatic infiltration : autoimmunity
• Failure of peripheral tolerance and severe T cell mediated disease
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CTLA-4
• Animal model : blocking of CTL-4 with antibodies --> autoimmune disease ex. encephalomyelitis
• In human : Polymorphism in CTLA-4 gene : type 1 diabetes and Graves' disease
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ACTION OF CTLA-4
• Low on most T cells until cells are activated by antigen
• Inhibiting activation of naive T cells• Express on regulatory T cells
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THERAPEUTIC APPLICATION
• Blocking CTLA-4 --> increased immune responses to tumor
• Anti-CTLA-4 antibody : approved for advance melanomas
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PD-1
• Programmed cell death 1• Immunoreceptor tyrosine-based inhibitory
motif-containing receptor• Express on T cell activation
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PD-1
• Recognized 2 ligands1. PD-L1 : expressed on APCs and many other
tissue cells2. PD-L2 : expressed mainly on APCs
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PD-1
• Important in terminating peripheral responses of effector T cell esp. CD8+ cell
• May not be required for function of regulatory T cells
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PD-1
• Engagement with ligand --> • Inactivation of T cells• Inhibit IL-2 production• May play role in suppressive function of
Treg cells
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PD-1
• In mice : PD-1 knocked out --> autoimmune diseases ex. Lupus-like kidney disease and arthritis
• Autoimmune disorder in Pd-1 knockout mice less severe than CTLA-4 knockouts
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A. Direct deletion of immune effector : expression of death-inducing ligand
B. Direct tolerization effector T cells : suppressive cytokines released by tissue cells
C. Suppression effector T cells by regulatory T cells
D. Tolerization of host T cells by tolerizing dendritic cells
E. Ignorance : spatial seperation of T cells and tissue cells ex. Basement membranes
F. Immune priviledge
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IMMUNE PRIVILEDGE
• Certain site in body tolerate induction of antigen without eliciting inflammatory immune response
• Maybe for protect vital structures from potentially damaging effects
• Sites : brain, anterior chamber of eyes, placenta, fetus, testes
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IMMUNE PRIVILEDGE : FETUS
• Express MHC derived from both parents • Peripheral tolerance of mother to fetus -->
fetal survival• Cells of villous trophoblast lack expression of
MHC class I
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IMMUNE PRIVILEDGE : FETUS
• Increase expression of non-classical MHC molecule ex. HLA-G : inhibitory receptor
• Immune deviation to Th2• Increase expression of FasL at placenta
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IMMUNE PRIVILEDGE : EYE AND BRIAN
• Limit capacity for regeneration• Immune response in these area could have
devastating effect on individual• Low or no expression of classical MHC class Ia
protein on cell• "Sympathetic ophthalmia"
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IMMUNE PRIVILEDGE : POSSIBLE MECHANISM
• Limit lymphatic drainage• Cytokine : inhibition of inflammation• TNF-beta and MIF(migration inhibitory
factor) : inhibition of NK cell mediated cytolytic activity
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NATURALLY OCCURING CD4+CD25+FOXP3+ REGULATORY T CELLS
• in healthy : <5% of CD3+CD4+ population• Expression of high levels of alpha chain of
CD25, IL-2 receptor• Hypothesis for generation of Treg cells1. From thymus : specific for self-peptides 2. From naive T cells in periphery : required for
environmental antigen/allergen specific T cells
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NATURALLY OCCURING CD4+CD25+FOXP3+ REGULATORY T CELLS
• TNFRSF18/GITR(glucocorticoid-induced tumor necrosis factor receptor family related-gene
• Expressed by activated Treg cells• Be trigger : role in resistance to Treg cell
mediated-suppresion
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NATURALLY OCCURING CD4+CD25+FOXP3+ REGULATORY T CELLS
• CD103 (alphaEbeta7)• CD122 (beta chain of IL-2 receptor)• Both highly expressed on Treg cells• Correlated with their suppressive activity
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NATURALLY OCCURING CD4+CD25+FOXP3+ REGULATORY T CELLS
• Other proposed markers• Certain chemokine receptors• TLRS• Membrane-bound TGF-beta• Neuropilin 1 ( NRP1 )• Lymphocyte activation gene ( LAG3 )• Granzyme
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NATURALLY OCCURING CD4+CD25+FOXP3+ REGULATORY T CELLS
• Additional marker from gene arrays• GPR83 : G protein-coupled receptor 83• ECM1 : extracellular maxtrix 1• IKZF2 : IKAROS family zinc finger 2-
helios
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REGULATORY T CELL GENERATION
• Augmented by• FOXP3+ T reg cells• Low doses of pathogen-derived molecules :
filamentous, hemagglutinin • Exogenous signals : histamine, adenosine,
vitamin D3 metabolites• Retinoic acid
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REGULATORY T CELL GENERATION : RETINOIC ACID
• Balance of inflammatory Th17 cells and suppressive Treg cells by Th17 cells
• Enhancing expression of FOXP3 through STAT3/STAT5 independent signaling pathway
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REGULATORY T LYMPHOCYTE
• Mostly express high levels of IL-2 receptor alpha chain (CD25)
• Transcription factor for development and function : FOXP3
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FORKHEAD WINGED TRANSCRIPTION FACTOR : FOXP3
• In mice : expressed by naturally occuring Treg cells
• In humans : upregulation in all activated T cells
• Required for development and function of naturally occuring Treg cells
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FORKHEAD WINGED TRANSCRIPTION FACTOR : FOXP3• Directly interact with RUNX1( runt-related
transcription factor 1)• RUNX1( runt-related transcription factor 1)
• Impair expression of IL-2 and IFN-gamma• Exert suppressive activity• In murine : maintain high level of FOXP3
expression
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FORKHEAD WINGED TRANSCRIPTION FACTOR : FOXP3
• Induction of RUNX1 and RUNX3 by TGF-beta : generation and suppresive function of induced Treg cells
• RUNX1 and RUNX3 bind to FOXP3 promotor : expressing functional Treg cells
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FORKHEAD WINGED TRANSCRIPTION FACTOR : FOXP3
• Leucine-rich repeat-containing 32 receptor (LRRC32 or GARP) : key receptor to control FOXP3 levels in naturally occurring Treg cells through positive-feedback loop
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FORKHEAD WINGED TRANSCRIPTION FACTOR : FOXP3
• Cytokines : IL-2, IL-10, TGF-beta• Surface markers : CD25, CTLA4, CD103, GITR,
NRP1, latency-associated peptide (LAP)
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FORKHEAD WINGED TRANSCRIPTION FACTOR : FOXP3
• ICOS+FOXP3+ Treg cells use IL-10 and TGF-beta to suppress dendritric cells and T cells function
• ICOS-FOXP3+ Treg cells express TGF-beta• Marker to differentiate between human
regulatory and activated effector T cell : alpha chain of IL-7R (CD127)
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MUTATION : DIMINISH FUNCTION
• X-linked autoimmune and allergic dysregulation syndrome (XLAAD)
• Immune dysregulation, polyendocrinapathy, enteropathy, X-linked syndrome (IPEX)
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IMMUNE DYSREGULATION, POLYENDOCRINAPATHY, ENTEROPATHY, X-LINKED SYNDROME : IPEX
• Rare autoimmune disease• Mutation of FOXP3 gene• Associated with deficiency of regulatory T
cells• Significant skewing of T lymphocyte toward
Th2 phenotype
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IMMUNE DYSREGULATION, POLYENDOCRINAPATHY, ENTEROPATHY, X-LINKED SYNDROME : IPEX
• Autoimmunity• Severe atopy : eczema, food allergy• Eosinophillic inflammation
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REGULATORY T CELL GENERATION
• Immune response of memory T cells : essential for inflammation and immune regulation processes in diseases ex. allergic rhinitis, asthma, atopic dermatitis
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GENERATION AND MAINTAINANCE OF REGULATORY T CELLS
• Regulatory T cell1. Thymic / natural regulatory T cells2. Peripheral / adaptive / inducible
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SUBSETS OF REGULATORY T CELLS
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MECHANISM OF ACTION OF REGULATORY T CELLS
• Directly suppress B cell activation• Inhibit proliferation and differentiation of NK
cells• Production of immunosuppresive cytokine ( IL-
10 and TGF-beta )• Reduced ability of APCs to stimulate T cells• Consumption of IL-2
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TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA)
• Tumor product• Promote survival of tumor cells in vitro• Type : 1-3• Mostly : TGF-beta1
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TRANSFORMING GROWTH FACTOR-BETA1 (TGF-BETA1)
• Produced by CD4+ regulatory T cells, activated macrophages and other cells
• Synthesized as inactive precursor • Proteolytically cleaved in Golgi complex and
form homodimer• Mature form is secreted in latent form in
associated with other polypeptides
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TRANSFORMING GROWTH FACTOR-BETA 1 (TGF-BETA1)
• In mice : Suppress airway disease • Target cell : T cells• Association with airway inflammatiom
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• Maintain tolerance esp. Oral tolerance• Inhibit proliferation , differentiation and
survival of B and T lymphocyte• Inhibit immunoglobulin isotype switching and
promote differentiation of IgA secreting plasma
ROLE OF TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA)
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• Promote differentiation of Langerhan cells and DCs with immature phenotype
• In mast cell : promote chemotaxis but inhibit expression of high-affinity receptor for Fc fragment of IgE
• Inhibit human Th2 response in vitro
ROLE OF TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA)
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ROLE OF TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA)
• Regulate differentiation of functionally distinct subsets of T cells
• Promote tissue repair after local immune and inflammatory reaction subside
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INTERLEUKIN-10
• Control of allergy and asthma• Synthesized by B cells, monocyte, DCs NK
cells and T cells• Inhibit proinflammatory cytokine production
TH1 and Th2 cell activation
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INTERLEUKIN-10
• In T cells : IL-10 receptor-associated tyrosine kinase 2 (TYK2) - constitutive reservoir for protein tyrosine phosphatase nonreceptor 6 (PTPN6/SHP1)
• PRPN6 rapidly binds to CD28 and ICOS costimulatory receptors and dephosphorylates them within minutes
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INTERLEUKIN-10
• Member of family of heterodimeric cytokines : IL-22, IL-27 and others
• Consist of two chains• IL-10 receptor belongs to type II cytokine
receptor family
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INTERLEUKIN-10
• Associate with JAK1 and TYK2 Janus family kinase and activate STAT3
• Produced by activated macrophage and dendritic cells, regulatory T cell, TH1 and TH2 cells and some B lymphocyte
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ROLE OF INTERLEUKIN-10
• Inhibit expression of costimulators and class II molecule on dendritic cells and macrophage --> inactivation
• Control of innate immune reactions and cell-mediated immunity
• Inhibit production of IL-12 by activated dendritic cells and macrophage
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MUTATION INTERLEUKIN-10 RECEPTOR
• Rare inherited autoimmune disease• Severe colitis
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FACTORS FOR DETERMINE IMMUNOGENICITY AND TOLEROGENICITY OF PROTEIN ANTIGEN
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B LYMPHOCYTE TOLERANCE
• Maintain unresponsiveness to thymus independent self antigens (polysaccharide and lipid)
• Prevent antibody responses to protein antigens
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CENTRAL TOLERANCE IN B CELLS
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PERIPHERAL TOLERANCE IN B CELLS
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“Thank you.”