Immunological tolerance

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IMMUNOLOGICAL TOLERANCE JINTANA CHATAROOPWIJIT 9 DECEMBER 2016

Transcript of 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.”