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Mechanisms of Tolerance Flashcards

1
Q

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
A
  • 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
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2
Q

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 …
A
  • 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
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3
Q

What is immunological tolerance?

A

Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained

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4
Q

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)

A

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)

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5
Q

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)

A

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)

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6
Q

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)

A

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)

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7
Q

Like immunity, tolerance is … specific

A

Like immunity, tolerance is antigen specific (unlike “immunosuppression”)

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8
Q

The immunological equilibrium: balancing lymphocyte activation and control

A
  • Must have activation but also tolerance enduced and maintained to avoid response to self and harmless antigens that we encounter
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9
Q

Tolerance to self antigens is induced in … … organs (bone marrow and thymus) and then maintained in the …

A

Tolerance to self antigens is induced in central lymphoid organs (bone marrow and thymus) and then maintained in the periphery

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10
Q

Tolerance to self antigens is induced in central lymphoid organs (… and …) and then maintained in the periphery

A

Tolerance to self antigens is induced in central lymphoid organs (bone marrow and thymus) and then maintained in the periphery

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11
Q

B cells develop in the … … whereas T cells develop in the ….

A

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.

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12
Q
  • 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 …
A
  • 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.
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13
Q

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).
A
  • 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).
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14
Q

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. …).
A
  • 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).
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15
Q

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
A
  • 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
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16
Q
A
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17
Q

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
A
  • 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
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18
Q

TCR genes undergo DNA rearrangement in thymus

  • Germline DNA - many … fragments - un-rearranged
  • Different segments can join and rearrange
  • …
A
  • Germline DNA - many alternative fragments - un-rearranged
  • Different segments can join and rearrange
  • Expressed
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19
Q

Generation of adaptive immune receptor by … … events in bone marrow

A

Generation of adaptive immune receptor by somatic recombination events in bone marrow

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20
Q

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
A
  • 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
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21
Q

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
A
  • 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
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22
Q

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
A
  • 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
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23
Q

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
A
  • 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
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24
Q

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
A
  • 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
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25
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
26
Naïve T cells are self ... restricted and self ...
Naïve T cells are self **MHC** restricted and self **tolerant**
27
_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.
28
What is anergy?
absence of the normal immune response to a particular antigen or allergen.
29
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.
30
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.
31
_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
32
_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
33
_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
34
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**
35
What is immunosenescence?
progressive deterioration of immune responses mainly associated with age
36
_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
37
_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)
38
_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)
39
_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)
40
_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)
41
_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
42
_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**
43
_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**
44
T cells from bone marrow negative for CD4,CD8,TCR: ... ...
T cells from bone marrow negative for CD4,CD8,TCR: **double negative**
45
_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)
46
_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)
47
_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)
48
_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)
49
_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
50
_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
51
_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**
52
_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
53
_Binding - Positive v Negative Selection_
54
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
55
* 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
56
... 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)
57
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)
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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
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Tolerance needs to be induced and maintained outside the thymus - what is this called?
Peripheral tolerance
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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
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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
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...-... 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
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_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
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_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**
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_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)
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_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)
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... ... 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
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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
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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:
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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
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_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
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_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
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_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**
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_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
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... 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
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Blocking CTLA-4 promotes tumor ...
Blocking CTLA-4 promotes tumor **rejection**
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...-4 limits immune responses to tumors
**CTLA**-4 limits immune responses to tumors
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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)
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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**)
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_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
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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
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... 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
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_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
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_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
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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*
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depletion of CD25(+)CD4(+) T cells leads to ...
depletion of CD25(+)CD4(+) T cells leads to **autoimmunity**
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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
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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**
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_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
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_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
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_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
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_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
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_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)
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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)
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Layers of Self-tolerance
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* 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
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* 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
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* 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
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_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.
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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**.
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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.
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_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**
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_Dosage of Antigen_ * Very small or large favors ... * Intermediate favors ...
* Very small or large favors **tolerance** * Intermediate favors **immunogenicity**
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_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**).
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_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)
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_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
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.../... 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
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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

Year 2 Medicine (162 decks)

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