Mechanisms of Tolerance Flashcards
Immunological Tolerance
- The immune system is tolerant to … (…-tolerance)
- The immune system is tolerant to … antigens such as food or environmental ag
- The immune system is tolerant to … microbiota
- Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained
- The immune system is tolerant to self (self-tolerance)
- The immune system is tolerant to harmless antigens such food or environmental ag
- The immune system is tolerant to commensal microbiota
- Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained
Immunological Tolerance
- The immune system is tolerant to self (self-tolerance)
- The immune system is tolerant to harmless antigens such food or environmental ag
- The immune system is tolerant to commensal microbiota
- Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is … and …
- The immune system is tolerant to self (self-tolerance)
- The immune system is tolerant to harmless antigens such food or environmental ag
- The immune system is tolerant to commensal microbiota
- Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained
What is immunological tolerance?
Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained
T cells express TCR/CD3 (plus CD4 or CD8) - antigen must be presented to be recognised - in the groove of MHC Class … (CD8) or … (CD4)
T cells express TCR/CD3 (plus CD4 or CD8) - antigen must be presented to be recognised - in the groove of MHC Class I (CD8) or II (CD4)
T cells express TCR/CD.. (plus CD4 or CD8) - antigen must be presented to be recognised - in the groove of MHC Class I (CD8) or II (CD4)
T cells express TCR/CD3 (plus CD4 or CD8) - antigen must be presented to be recognised - in the groove of MHC Class I (CD8) or II (CD4)
B cells recognise any form of non-self antigen - activate B cells to produce soluble …, whereas T cells do not recognise native antigens - the antigen has to be … to T cells - APC process the antigen first and present it into … - T cells recognise the antigen on … via their … (T cell receptor)
B cells recognise any form of non-self antigen - activate B cells to produce soluble antibody, whereas T cells do not recognise native antigens - the antigen has to be presented to T cells - APC process the antigen first and present it into MHC - T cells recognise the antigen on MHC via their TCR (T cell receptor)
Like immunity, tolerance is … specific
Like immunity, tolerance is antigen specific (unlike “immunosuppression”)
The immunological equilibrium: balancing lymphocyte activation and control
- Must have activation but also tolerance enduced and maintained to avoid response to self and harmless antigens that we encounter
Tolerance to self antigens is induced in … … organs (bone marrow and thymus) and then maintained in the …
Tolerance to self antigens is induced in central lymphoid organs (bone marrow and thymus) and then maintained in the periphery
Tolerance to self antigens is induced in central lymphoid organs (… and …) and then maintained in the periphery
Tolerance to self antigens is induced in central lymphoid organs (bone marrow and thymus) and then maintained in the periphery
B cells develop in the … … whereas T cells develop in the ….
B cells develop in the bone marrow whereas T cells develop in the thymus - T cells and B cells maturation’s environment support the different stages of their development.
- B cells develop in the bone marrow. T cells develop n the thymus.
- T cells and B cells maturation’s … support the different stages of their …
- B cells develop in the bone marrow. T cells develop n the thymus.
- T cells and B cells maturation’s environment support the different stages of their development.
Self-tolerance- “A Learning Experience”
- How does the immune system learn to discriminate between self and non-self?
- The primary repertoire of lymphocytes is enormous as a result of … …
- This repertoire contains self-reactive TCRs/BCRs but a normal immune system does not exhibit self-reactivity (i.e. autoimmunity).
- How does the immune system learn to discriminate between self and non-self?
- The primary repertoire of lymphocytes is enormous as a result of combinatorial diversity
- This repertoire contains self-reactive TCRs/BCRs but a normal immune system does not exhibit self-reactivity (i.e. autoimmunity).
Self-tolerance- “A Learning Experience”
- How does the immune system learn to discriminate between self and non-self?
- The primary repertoire of lymphocytes is enormous as a result of combinatorial diversity
- This repertoire contains self-reactive TCRs/BCRs but a normal immune system does not exhibit …-reactivity (i.e. …).
- How does the immune system learn to discriminate between self and non-self?
- The primary repertoire of lymphocytes is enormous as a result of combinatorial diversity
- This repertoire contains self-reactive TCRs/BCRs but a normal immune system does not exhibit self-reactivity (i.e. autoimmunity).
Generation of diversity of B and T cells repertoire
- In the germ line there are many … … genes and a smaller number of … … genes.
- The selection of each gene segment out of a range of many available is determined by random somatic … …
- This mechanism is common to B and T cells
- In the germ line there are many variable region genes and a smaller number of constant region genes.
- The selection of each gene segment out of a range of many available is determined by random somatic gene rearrangement
- This mechanism is common to B and T cells
Stages of B cell development in the bone marrow
- Each stage of development is defined by … of Ig heavy/light chain genes, expression of surface Ig, expression of adhesion molecules and cytokine receptors
- Each stage of development is defined by rearrangements of Ig heavy/light chain genes, expression of surface Ig, expression of adhesion molecules and cytokine receptors
TCR genes undergo DNA rearrangement in thymus
- Germline DNA - many … fragments - un-rearranged
- Different segments can join and rearrange
- …
- Germline DNA - many alternative fragments - un-rearranged
- Different segments can join and rearrange
- Expressed
Generation of adaptive immune receptor by … … events in bone marrow
Generation of adaptive immune receptor by somatic recombination events in bone marrow
Mechanisms of B cell self tolerance induction
- Physical removal from the repertoire - …
- Immature B cell recognises abundant, ubiquitous MULTIVALENT
- self Ag (as MHC) on BM stromal cells -> …
- … of function - ANERGY
- Immature B cell recognises soluble self Ag à No Ab cross-linking -> Anergy (absence of the normal immune response to a particular antigen or allergen)
- Alteration of specificity - RECEPTOR EDITING
- Physical removal from the repertoire - DELETION
- Immature B cell recognises abundant, ubiquitous MULTIVALENT
- self Ag (as MHC) on BM stromal cells -> APOPTOSIS
-
Paralysis of function - ANERGY
- Immature B cell recognises soluble self Ag à No Ab cross-linking -> Anergy (absence of the normal immune response to a particular antigen or allergen)
- Alteration of specificity - RECEPTOR EDITING
Mechanisms of B cell self tolerance induction
- Physical removal from the repertoire - DELETION
- Immature B cell recognises abundant, ubiquitous MULTIVALENT
- self Ag (as MHC) on BM stromal cells -> APOPTOSIS
- Paralysis of function - ANERGY
- Immature B cell recognises soluble self Ag à No Ab cross-linking -> … (absence of the normal immune response to a particular antigen or allergen)
- Alteration of … - RECEPTOR EDITING
- Physical removal from the repertoire - DELETION
- Immature B cell recognises abundant, ubiquitous MULTIVALENT
- self Ag (as MHC) on BM stromal cells -> APOPTOSIS
- Paralysis of function - ANERGY
- Immature B cell recognises soluble self Ag à No Ab cross-linking -> Anergy (absence of the normal immune response to a particular antigen or allergen)
- Alteration of specificity - RECEPTOR EDITING
Mechanisms of B cell self tolerance induction
- Physical removal from the repertoire - DELETION
- Immature B cell recognises abundant, ubiquitous MULTIVALENT
- self Ag (as MHC) on BM stromal cells -> APOPTOSIS
- Paralysis of function - ANERGY
- Immature B cell recognises soluble self Ag à No Ab cross-linking -> Anergy (absence of the normal immune response to a particular antigen or allergen)
- Alteration of specificity - … EDITING
- Physical removal from the repertoire - DELETION
- Immature B cell recognises abundant, ubiquitous MULTIVALENT
- self Ag (as MHC) on BM stromal cells -> APOPTOSIS
- Paralysis of function - ANERGY
- Immature B cell recognises soluble self Ag -> No Ab cross-linking -> Anergy (absence of the normal immune response to a particular antigen or allergen)
- Alteration of specificity - RECEPTOR EDITING
T cells central self tolerance induction
- Generation of the TcR repertoire involves many random mechanisms to allow diversity
- The specificity of TcR in the immature repertoire is also random & will include cells with receptors that are:
- Harmful - … select
- Useless - neglect
- Useful - … select
- Generation of the TcR repertoire involves many random mechanisms to allow diversity
- The specificity of TcR in the immature repertoire is also random & will include cells with receptors that are:
- Harmful - negatively select
- Useless - neglect
- Useful - positively select
T cells central self tolerance induction
- Generation of the TcR repertoire involves many random mechanisms to allow diversity
- The specificity of TcR in the immature repertoire is also random & will include cells with receptors that are:
- … - negatively select
- Useless - neglect
- … - positively select
- Generation of the TcR repertoire involves many random mechanisms to allow diversity
- The specificity of TcR in the immature repertoire is also random & will include cells with receptors that are:
- Harmful - negatively select
- Useless - neglect
- Useful - positively select
Only cells that bear antigen receptor with appropriate … for the peptide presented in self MHC complexes complete their … and form the peripheral T cell pool - …% of cells die in the thymus by apoptosis
Only cells that bear antigen receptor with appropriate affinity for the peptide presented in self MHC complexes complete their maturation and form the peripheral T cell pool - 98% of cells die in the thymus by apoptosis
Naïve T cells are self … restricted and self …
Naïve T cells are self MHC restricted and self tolerant
Lymphoid progenitors migrate from the bone marrow to the thymus where they develop into … T cells
- The thymus is absolutely required for the … of immature precursor into … T cells.
- Children without thymus (Di-George syndrome) or mice lacking a thymus (nude mice) do not have … T cells.
- The thymus is absolutely required for the differentiation of immature precursor into mature T cells.
- Children without thymus (Di-George syndrome) or mice lacking a thymus (nude mice) do not have mature T cells.
What is anergy?
absence of the normal immune response to a particular antigen or allergen.
Children without thymus (Di-George syndrome) or mice lacking a thymus (nude mice) do not have … T cells.
Children without thymus (Di-George syndrome) or mice lacking a thymus (nude mice) do not have mature T cells.
The … is absolutely required for the differentiation of immature precursor into mature T cells.
The thymus is absolutely required for the differentiation of immature precursor into mature T cells.
Thymic involution
- The human thymus is fully developed before … and increases in size during …
- Thymus is most active in the young and it … with age
- It progressively shrinks (… replaces areas where thymocytes existed)
- Degeneration is complete by the age of …, but residual thymic activity persists until advanced age
- The reduced production of T-cells does not completely impair immunity. Once established the repertoire of the T-cells is long-lived
- The human thymus is fully developed before birth and increases in size during puberty
- Thymus is most active in the young and it atrophies with age
- It progressively shrinks (fat replaces areas where thymocytes existed)
- Degeneration is complete by the age of 30, but residual thymic activity persists until advanced age
- The reduced production of T-cells does not completely impair immunity. Once established the repertoire of the T-cells is long-lived
Thymic involution
- The human thymus is fully developed before birth and increases in size during puberty
- Thymus is most active in the young and it atrophies with age
- It progressively … (fat replaces areas where … existed)
- … is complete by the age of 30, but residual thymic activity persists until advanced age
- The reduced production of T-cells does not completely impair immunity. Once established the repertoire of the T-cells is long-lived
- The human thymus is fully developed before birth and increases in size during puberty
- Thymus is most active in the young and it atrophies with age
- It progressively shrinks (fat replaces areas where thymocytes existed)
- Degeneration is complete by the age of 30, but residual thymic activity persists until advanced age
- The reduced production of T-cells does not completely impair immunity. Once established the repertoire of the T-cells is long-lived
Thymic involution
- The human thymus is fully developed before birth and increases in size during puberty
- Thymus is most active in the young and it atrophies with age
- It progressively shrinks (fat replaces areas where thymocytes existed)
- Degeneration is complete by the age of 30, but residual thymic activity persists until advanced age
- The reduced production of T-cells does … completely impair immunity. Once established the repertoire of the T-cells is …-lived
- The human thymus is fully developed before birth and increases in size during puberty
- Thymus is most active in the young and it atrophies with age
- It progressively shrinks (fat replaces areas where thymocytes existed)
- Degeneration is complete by the age of 30, but residual thymic activity persists until advanced age
- The reduced production of T-cells does not completely impair immunity. Once established the repertoire of the T-cells is long-lived
The human thymus is fully developed before … and increases in size during …
The human thymus is fully developed before birth and increases in size during puberty
What is immunosenescence?
progressive deterioration of immune responses mainly associated with age
T cell development occurs in defined thymic microenvironment
- Thymic … (epithelial cells + connective tissue) provides the … for T cell development and selection
- Thymic stroma (epithelial cells + connective tissue) provides the microenviroment for T cell development and selection
T cell development occurs in defined thymic microenvironment
- Thymic stroma (epithelial cells + connective tissue) provides the microenvironment for T cell development and selection
- … region - Immature double-negative thymocytes (No CD3, no CD4, CD8)
- … - Immature double-positive thymocytes (have CD3, CD4 and CD8) - undergo positive selection here (thymus epithelial nurse cells here)
- … - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - negative selection here (medullary epithelial cells here)
- Thymic stroma (epithelial cells + connective tissue) provides the microenviroment for T cell development and selection
- Subcapsular region - Immature double-negative thymocytes (No CD3, no CD4, CD8)
- Cortex - Immature double-positive thymocytes (have CD3, CD4 and CD8) - undergo positive selection here (thymus epithelial nurse cells here)
- Medulla - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - negative selection here (medullary epithelial cells here)
T cell development occurs in defined thymic microenvironment
- Thymic stroma (epithelial cells + connective tissue) provides the microenvironment for T cell development and selection
- Subcapsular region - Immature …-… thymocytes (No CD3, no CD4, CD8)
- Cortex - Immature …-… thymocytes (have CD3, CD4 and CD8) - undergo positive selection here (thymus epithelial nurse cells here)
- Medulla - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - negative selection here (medullary epithelial cells here)
- Thymic stroma (epithelial cells + connective tissue) provides the microenviroment for T cell development and selection
- Subcapsular region - Immature double-negative thymocytes (No CD3, no CD4, CD8)
- Cortex - Immature double-positive thymocytes (have CD3, CD4 and CD8) - undergo positive selection here (thymus epithelial nurse cells here)
- Medulla - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - negative selection here (medullary epithelial cells here)
T cell development occurs in defined thymic microenvironment
- Thymic stroma (epithelial cells + connective tissue) provides the microenvironment for T cell development and selection
- Subcapsular region - Immature double-negative thymocytes (No CD3, no CD4, CD8)
- Cortex - Immature double-positive thymocytes (have CD3, CD4 and CD8) - undergo … selection here (thymus epithelial nurse cells here)
- Medulla - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - … selection here (medullary epithelial cells here)
- Thymic stroma (epithelial cells + connective tissue) provides the microenviroment for T cell development and selection
- Subcapsular region - Immature double-negative thymocytes (No CD3, no CD4, CD8)
- Cortex - Immature double-positive thymocytes (have CD3, CD4 and CD8) - undergo positive selection here (thymus epithelial nurse cells here)
- Medulla - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - negative selection here (medullary epithelial cells here)
T cell development occurs in defined thymic microenvironment
- Thymic stroma (epithelial cells + connective tissue) provides the microenvironment for T cell development and selection
- Subcapsular region - Immature double-negative thymocytes (No …)
- Cortex - Immature double-positive thymocytes (have …) - undergo positive selection here (thymus epithelial nurse cells here)
- Medulla - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - negative selection here (medullary epithelial cells here)
- Thymic stroma (epithelial cells + connective tissue) provides the microenviroment for T cell development and selection
- Subcapsular region - Immature double-negative thymocytes (No CD3, no CD4, CD8)
- Cortex - Immature double-positive thymocytes (have CD3, CD4 and CD8) - undergo positive selection here (thymus epithelial nurse cells here)
- Medulla - Mature CD4+,CD8- or Mature CD4-,CD48+ thymocytes - negative selection here (medullary epithelial cells here)
Sorting the useful from the harmful and the useless
- … selection:
- Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen byself MHC
- i.e. selection of the USEFUL
- … selection:
- Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC
- i.e. selection of the HARMFUL
-
Positive selection:
- Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen byself MHC
- i.e. selection of the USEFUL
-
Negative selection:
- Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC
- i.e. selection of the HARMFUL
Positive selection
- Retention of thymocytes expressing TcR that are … in their recognition of antigen by self MHC
- i.e. selection of the …
- Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen by self MHC
- i.e. selection of the USEFUL
Negative selection
- … of thymocytes expressing TcR that either recognise … antigens presented by self MHC
- i.e. selection of the …
-
Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC
- i.e. selection of the HARMFUL
T cells from bone marrow negative for CD4,CD8,TCR: … …
T cells from bone marrow negative for CD4,CD8,TCR: double negative
Positive Selection
- T cells from bone marrow … for CD4,CD8,TCR: double …
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both … and … (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
- T cells from bone marrow negative for CD4,CD8,TCR: double negative
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 & CD8 (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
Positive Selection
- T cells from bone marrow negative for CD4,CD8,TCR: double negative
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 and CD8 (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
- T cells from bone marrow negative for CD4,CD8,TCR: double negative
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 and CD8 (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
Positive Selection
- T cells from bone marrow negative for CD4,CD8,TCR: double negative
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 and CD8 (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
- T cells from bone marrow negative for CD4,CD8,TCR: double negative
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 and CD8 (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
Positive Selection
- T cells from bone marrow negative for CD4,CD8,TCR: double negative
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 and CD8 (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
- T cells from bone marrow negative for CD4,CD8,TCR: double negative
- Then - Double + - somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 and CD8 (small non-dividing cortical thymocytes, short life-span)
- Thymocytes express TCR
- Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE (Induction to survival, differentiation, maturation (long-lived cells)
- Those who cannot, DIE (apoptosis)
Negative selection
- … of thymocytes expressing TcR that recognise … antigens presented by … MHC
- … cells & macrophages at the cortico-medullary junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- Modest binding - lives
- Strong binding - possible autoimmunity - apoptosis
- Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
- Dendritic cells & macrophages at the cortico-medullary junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- Modest binding - lives
- Strong binding - possible autoimmunity - apoptosis
Negative selection
- Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
- … cells & … at the cortico-medullary junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- Modest binding - …
- Strong binding - possible autoimmunity - apoptosis
- Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
- Dendritic cells & macrophages at the cortico-medullary junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- Modest binding - lives
- Strong binding - possible autoimmunity - apoptosis
Negative selection
- Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
- Dendritic cells & macrophages at the cortico-medullary junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- Modest binding - …
- Strong binding - possible … - leads to …
- Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
- Dendritic cells & macrophages at the cortico-medullary junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- Modest binding - lives
- Strong binding - possible autoimmunity - apoptosis
Negative selection
- Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
- Dendritic cells & macrophages at the …-… junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- … binding - lives
- … binding - possible autoimmunity - apoptosis
- Removal of thymocytes expressing TcR that recognise self antigens presented by self MHC
- Dendritic cells & macrophages at the cortico-medullary junction are APC expressing MHC I & MHCII molecules and present self-peptides to T cells
- Modest binding - lives
- Strong binding - possible autoimmunity - apoptosis
Binding - Positive v Negative Selection
The thymus screens for T cells that fall into a narrow window of … for MHC molecules
The thymus screens for T cells that fall into a narrow window of affinity for MHC molecules
- How can the thymus express all self antigens ?
- How do we become self tolerant to antigens expressed by specialised tissues?
- Autoimmune regulator - (AIRE)
- Transcription factor expressed at high levels by thymic medullary epithelial cells
- Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)
- Mouse knockout: failure to express many self antigens in the thymus and expression of autoantibodies
… is necessary for self tolerance - Mutations of … lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)
AIRE is necessary for self tolerance - Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)
AIRE is necessary for … … - Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)
AIRE is necessary for self tolerance - Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)
How is tolerance established to antigens that cannot be expressed in the thymus?
- T cells bearing TcR reactive with proteins expressed in the thymus are deleted.
- Some self proteins are not expressed in the thymus
- We need to be tolerant also to non-self- non-dangerous antigens
- Tolerance needs to be induced and maintained outside the thymus
-
PERIPHERAL TOLERANCE
- Auto-immunity/allergy - breakdown of peripheral tolerance: the immune system responds to self or environmental ag
Tolerance needs to be induced and maintained outside the thymus - what is this called?
Peripheral tolerance
Auto-immunity/allergy - breakdown of … …: the immune system responds to self or environmental ag
Auto-immunity/allergy - breakdown of peripheral tolerance: the immune system responds to self or environmental ag
Auto-…/… - breakdown of peripheral tolerance: the immune system responds to self or environmental ag
Auto-immunity/allergy - breakdown of peripheral tolerance: the immune system responds to self or environmental ag
…-… B cells can be present without being able to be activated if there is no help available - … tolerance - if help is provided (eg injecting an auto-ag coupled to an immunogenic foreign carrier), B cells will mount an immune response
Auto-reactive B cells can be present without being able to be activated if there is no help available - Split tolerance - if help is provided (eg injecting an auto-ag coupled to an immunogenic foreign carrier), B cells will mount an immune response
Mechanisms of Peripheral Tolerance
- 4 mechanisms - what are they?
-
IGNORANCE:
- lymphocytes fail to recognise or respond
-
CLONAL ANERGY:
- binding of ag makes lymphocyte unresponsive
-
SUPPRESSION:
- interaction with suppressor cells/cytokines to inhibit lymphocytes responsiveness
-
CLONAL EXAUSTION:
- continued stimulation by persistent antigen may ‘wear out’ responsive cells
Clonal Ignorance - Mechanism of Peripheral Tolerance
- self reactive lymphocytes fail to recognise or respond to some self antigens in the periphery
- cells neither … nor become …
- self reactive lymphocytes fail to recognise or respond to some self antigens in the periphery
- cells neither die nor become anergic
Clonal Ignorance
- Self-reactive T cells sometimes ignore antigen
- antigens anatomically … from the immune system: T cells cannot reach cells bearing the antigen
- Tissue grafts placed in these sites are not rejected
- Immunologically … sites (eye, testis, uterus/placenta)
- Immune-… sites allow foreign graft survival
- If sequestred ag is released autoimmunity can result (e.g. anti-sperm Abs in vasectomised males have)
- Self -reactive T cells sometimes ignore antigen
- antigens anatomically sequestered from the immune system: T cells cannot reach cells bearing the antigen
- Tissue grafts placed in these sites are not rejected
- Immunologically privileged sites (eye, testis, uterus/placenta)
- Immune-priviledged sites allow foreign graft survival
- If sequestred ag is released autoimmunity can result (e.g. anti-sperm Abs in vasectomised males have)
Clonal Ignorance
- Self-reactive T cells sometimes ignore antigen
- antigens … sequestered from the immune system: T cells cannot reach cells bearing the antigen
- Tissue grafts placed in these sites are not rejected
- Immunologically privileged sites (eye, testis, uterus/placenta)
- Immune-priviledged sites allow … … survival
- If sequestred ag is released autoimmunity can result (e.g. anti-sperm Abs in vasectomised males have)
- Self -reactive T cells sometimes ignore antigen
- antigens anatomically sequestered from the immune system: T cells cannot reach cells bearing the antigen
- Tissue grafts placed in these sites are not rejected
- Immunologically privileged sites (eye, testis, uterus/placenta)
- Immune-priviledged sites allow foreign graft survival
- If sequestred ag is released autoimmunity can result (e.g. anti-sperm Abs in vasectomised males have)
… … chamber is an immune-privileged site. Normally, self-antigens in this site are not exposed to the immune system
Eye anterior chamber is an immune-privileged site. Normally, self-antigens in this site are not exposed to the immune system
Eye anterior chamber is an …-… site. Normally, self-antigens in this site are not exposed to the immune system
Eye anterior chamber is an immune-privileged site. Normally, self-antigens in this site are not exposed to the immune system
What is Sympathetic ophthalmia?
Physical trauma in one eye can initiate autoimmune response to both eyes. This can cause blindness in the both damaged and undamaged eyes:
Physical trauma in one eye can initiate autoimmune response to both eyes. This can cause blindness in the both damaged and undamaged eyes: - this is called …
Sympathetic ophthalmia
Induction of Anergy
- Binding of antigen makes lymphocyte unresponsive
- presentation without …
- …-4 signaling
- binding of ag makes lymphocyte unresponsive
- presentation without costimulation
- CTLA-4 signaling
Induction of Anergy
- Binding of antigen makes … unresponsive
- presentation without costimulation
- CTLA-4 signaling
- binding of ag makes lymphocyte unresponsive
- presentation without costimulation
- CTLA-4 signaling
The opposing functions of CD28 and CTLA-4
- Normal response - CD… and B7 - antigen recognition with … - T cell proliferation and differentiation
- Absence of this - Antigen recognition with CTLA-4-4:B7 interaction - restimulation with APC expressing constimulators - leads to T cell a…
- Normal response - CD28 and B7 - antigen recognition with costimulation - T cell proliferation and differentiation
- Absence of this - Antigen recognition with CTLA-4:B7 interaction - restimulation with APC expressing constimulators - leads to T cell anergy
Checkpoint blockade: Removing the brakes on the immune response
- CTLA-4 is an inhibitor of responses
- … CTLA-4 promotes tumour rejection, CTLA-4 … immune responses to tumours
- CTLA-4 is an inhibitor of responses
- Blocking CTLA-4 promotes tumour rejection, CTLA-4 limits immune responses to tumours
… transmits an inhibitory signal to T cells, whereas … transmits a stimulatory signal
CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal
Blocking CTLA-4 promotes tumor …
Blocking CTLA-4 promotes tumor rejection
…-4 limits immune responses to tumors
CTLA-4 limits immune responses to tumors
Anti-…-… antibody is approved for tumor immunotherapy (enhancing immune responses against tumors)
Anti-CTLA-4 antibody is approved for tumor immunotherapy (enhancing immune responses against tumors)
Anti-CTLA-4 antibody is approved for … … (enhancing immune responses against …)
Anti-CTLA-4 antibody is approved for tumor immunotherapy (enhancing immune responses against tumors)
Suppression - Mechanism of Peripheral Tolerance
- Interaction with suppressor cells/cytokines to inhibit lymphocytes responsiveness
- … (r…) cells are critical components in the maintenance of peripheral tolerance through “suppressive” mechanisms
- … suppress the activation of effector responses and are critical for regulating homeostasis and tolerance to self antigens
- Interaction with suppressor cells/cytokines to inhibit lymphocytes responsiveness
- Treg (regulatory) cells are critical components in the maintenance of peripheral tolerance through “suppressive” mechanisms
- Tregs suppress the activation of effector responses and are critical for regulating homeostasis and tolerance to self antigens
Tregs suppress the activation of effector responses and are critical for regulating … and … to self antigens
Tregs suppress the activation of effector responses and are critical for regulating homeostasis and tolerance to self antigens
… cells are critical components in the maintenance of … tolerance through “suppressive” mechanisms
Treg cells are critical components in the maintenance of peripheral tolerance through “suppressive” mechanisms
In both humans and mice, absence of T regulatory cells is associated with aggressive autoimmunity
- … (IL-2Ra) constitutively expressed by Treg cells
- Consumes IL2 to limit expansion of Teff.
- depletion of …(+)CD4(+) T cells leads to autoimmunity
- FOXP3 Forkhead/winged-helix transcription factor
- critical for TReg activity and development
- Mutations in FOXP3 gene cause IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome] a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
-
CD25 (IL-2Ra) constitutively expressed by Treg cells
- Consumes IL2 to limit expansion of Teff.
- depletion of CD25(+)CD4(+) T cells leads to autoimmunity
- FOXP3 Forkhead/winged-helix transcription factor
- critical for TReg activity and development
- Mutations in FOXP3 gene cause IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome] a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
In both humans and mice, absence of T regulatory cells is associated with aggressive autoimmunity
- CD25 (IL-2Ra) constitutively expressed by Treg cells
- Consumes IL2 to limit expansion of Teff.
- depletion of CD25(+)CD4(+) T cells leads to autoimmunity
- … Forkhead/winged-helix transcription factor
- critical for TReg activity and development
- Mutations in … gene cause IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome] a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
- CD25 (IL-2Ra) constitutively expressed by Treg cells
- Consumes IL2 to limit expansion of Teff.
- depletion of CD25(+)CD4(+) T cells leads to autoimmunity
-
FOXP3 Forkhead/winged-helix transcription factor
- critical for TReg activity and development
- Mutations in FOXP3 gene cause IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome] a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
Mutations in FOXP3 gene cause …
- Mutations in FOXP3 (Forkhead/winged-helix transcription factor) gene cause IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome] a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life)
- FOXP3 is critical for TReg activity and development
depletion of CD25(+)CD4(+) T cells leads to …
depletion of CD25(+)CD4(+) T cells leads to autoimmunity
In both humans and mice, absence of T … cells is associated with aggressive autoimmunity
In both humans and mice, absence of T regulatory cells is associated with aggressive autoimmunity
In both humans and mice, absence of T regulatory cells is associated with aggressive …
In both humans and mice, absence of T regulatory cells is associated with aggressive autoimmunity
Critical role of Treg in promoting tolerance may be exploited to:
- Strengthen or re-establish …-… in autoimmune disease
- Induce tolerance to …-…-antigens in organ transplantation, GVHD and allergy
- Induce tumour immunity in cancer patients
- Strengthen or re-establish self-tolerance in autoimmune disease
- Induce tolerance to non-self-antigens in organ transplantation, GVHD and allergy
- Induce tumour immunity in cancer patients
Critical role of Treg in promoting tolerance may be exploited to:
- Strengthen or re-establish self-tolerance in autoimmune disease
- Induce tolerance to non-self-antigens in … …, GVHD and allergy
- Induce tumour immunity in … patients
- Strengthen or re-establish self-tolerance in autoimmune disease
- Induce tolerance to non-self-antigens in organ transplantation, GVHD and allergy
- Induce tumour immunity in cancer patients
Critical role of Treg in promoting tolerance may be exploited to:
- Strengthen or re-establish self-tolerance in … disease
- Induce tolerance to non-self-antigens in organ transplantation, GVHD and …
- Induce tumour immunity in cancer patients
- Strengthen or re-establish self-tolerance in autoimmune disease
- Induce tolerance to non-self-antigens in organ transplantation, GVHD and allergy
- Induce tumour immunity in cancer patients
Critical role of Treg in promoting tolerance may be exploited to:
- … or re-establish self-tolerance in autoimmune disease
- Induce tolerance to non-self-antigens in organ transplantation, GVHD and allergy
- Induce … immunity in cancer patients
- Strengthen or re-establish self-tolerance in autoimmune disease
- Induce tolerance to non-self-antigens in organ transplantation, GVHD and allergy
- Induce tumour immunity in cancer patients
Activation-Induced Cell Death (AICD)
- … stimulation of T lymphocytes by persistent antigens results in death by … of the activated cell
- Elimination of T cells specific for abundant peripheral antigens: Clonal … (expression of inhibitory receptors on exhausted T cells, e.g. CTLA-4, PD-1)
- Repeated stimulation of T lymphocytes by persistent antigens results in death by apoptosis of the activated cell
- Elimination of T cells specific for abundant peripheral antigens: Clonal exhaustion (expression of inhibitory receptors on exhausted T cells, e.g. CTLA-4, PD-1)
Elimination of T cells specific for abundant peripheral antigens: … exhaustion (expression of inhibitory receptors on exhausted T cells, e.g. CTLA-4, PD-1)
Elimination of T cells specific for abundant peripheral antigens: Clonal exhaustion (expression of inhibitory receptors on exhausted T cells, e.g. CTLA-4, PD-1)
Layers of Self-tolerance
- The same antigen can be … or …, depending on how/when/where it is encountered
- How the antigen is presented to lymphocytes:
- concentration
- timing
- persistence
- tissue distribution
- nature of the cell presenting the antigen
- How the responses of specific lymphocytes to that antigen are regulated
- The same antigen can be tolerogenic or immunogenic, depending on how/when/where it is encountered
- How the antigen is presented to lymphocytes:
- concentration
- timing
- persistence
- tissue distribution
- nature of the cell presenting the antigen
- How the responses of specific lymphocytes to that antigen are regulated
- The same antigen can be tolerogenic or immunogenic, depending on how/when/where it is encountered
- How the antigen is presented to lymphocytes:
- c…
- t…
- persistence
- tissue distribution
- nature of the cell presenting the antigen
- How the responses of specific lymphocytes to that antigen are regulated
- The same antigen can be tolerogenic or immunogenic, depending on how/when/where it is encountered
- How the antigen is presented to lymphocytes:
- concentration
- timing
- persistence
- tissue distribution
- nature of the cell presenting the antigen
- How the responses of specific lymphocytes to that antigen are regulated
- The same antigen can be tolerogenic or immunogenic, depending on how/when/where it is encountered
- How the antigen is presented to lymphocytes:
- concentration
- timing
- p..
- … distribution
- … of the cell presenting the antigen
- How the responses of specific lymphocytes to that antigen are regulated
- The same antigen can be tolerogenic or immunogenic, depending on how/when/where it is encountered
- How the antigen is presented to lymphocytes:
- concentration
- timing
- persistence
- tissue distribution
- nature of the cell presenting the antigen
- How the responses of specific lymphocytes to that antigen are regulated
Antigen Properties
- Molecular …
- Smaller, soluble, not-aggregated molecules favors tolerance
- large, aggregated, complex molecules favors immunogenicity
- D…
- very small or large favors tolerance
- intermediate favors immunogenicity
- … of …
- Oral, intratracheal, orbital exposure can activate T cells to secrete TGFb (Tregs).
- Interaction of food proteins with gut-associated lymphoid tissue (GALT) in the intestinal transit is the essential prerequisite for oral tolerance.
- Different cells of the immune system participate in oral tolerance induction, with Regulatory T cells being the most important.
-
Molecular weight
- Smaller, soluble, not-aggregated molecules favors tolerance
- large, aggregated, complex molecules favors immunogenicity
-
Dosage
- very small or large favors tolerance
- intermediate favors immunogenicity
-
Routes of administration
- Oral, intratracheal, orbital exposure can activate T cells to secrete TGFb (Tregs).
- Interaction of food proteins with gut-associated lymphoid tissue (GALT) in the intestinal transit is the essential prerequisite for oral tolerance.
- Different cells of the immune system participate in oral tolerance induction, with Regulatory T cells being the most important.
Interaction of food proteins with gut-associated lymphoid tissue (GALT) in the intestinal transit is the essential prerequisite for oral ….
Interaction of food proteins with gut-associated lymphoid tissue (GALT) in the intestinal transit is the essential prerequisite for oral tolerance.
Different cells of the immune system participate in oral tolerance induction, with … T cells being the most important.
Different cells of the immune system participate in oral tolerance induction, with Regulatory T cells being the most important.
Molecular weight of Antigen
- Smaller, soluble, not-aggregated molecules favors …
- large, aggregated, complex molecules favors immunogenicity
- Smaller, soluble, not-aggregated molecules favors tolerance
- large, aggregated, complex molecules favors immunogenicity
Dosage of Antigen
- Very small or large favors …
- Intermediate favors …
- Very small or large favors tolerance
- Intermediate favors immunogenicity
Routes of administration - Antigen
- Oral, intratracheal, orbital exposure to antigen can activate T cells to secrete TGFb (T…).
- Oral, intratracheal, orbital exposure to antigen can activate T cells to secrete TGFb (Tregs).
Can oral tolerance be used therapeutically?
- There are Clinical trials testing this :
- Multiple Sclerosis (MS) Antigen - Myelin Basic Protein (MPB) 2007 (good/not good results)
- Rheumatoid Arthritis (RA) Antigen - Type II collagen 2009 (good results)
- Type I Diabetes Antigen - Insulin 2017, 2021 (bad results)
Hyposensitisation Immunotherapy
- Using … amount of … (food, pollen) to induce … specific …
- Continuous administration of the allergen, rather than its elimination, to promote the development and maintenance of …
- Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy
- Using small amount of allergens (food, pollen) to induce antigen specific tolerance
- Continuous administration of the allergen, rather than its elimination, to promote the development and maintenance of tolerance
- Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy
…/… desensitisation immunotherapy for peanut allergy holds promise for the control of allergy
Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy
Oral/sublingual desensitisation immunotherapy for … allergy holds promise for the control of allergy
Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy
