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Year 2 Medicine > Mechanisms of Tolerance > Flashcards

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
Q

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

A

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

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26
Q

Naïve T cells are self … restricted and self …

A

Naïve T cells are self MHC restricted and self tolerant

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27
Q

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.
A
  • 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.
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28
Q

What is anergy?

A

absence of the normal immune response to a particular antigen or allergen.

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29
Q

Children without thymus (Di-George syndrome) or mice lacking a thymus (nude mice) do not have … T cells.

A

Children without thymus (Di-George syndrome) or mice lacking a thymus (nude mice) do not have mature T cells.

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30
Q

The … is absolutely required for the differentiation of immature precursor into mature T cells.

A

The thymus is absolutely required for the differentiation of immature precursor into mature T cells.

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31
Q

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
A
  • 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
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32
Q

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
A
  • 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
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33
Q

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
A
  • 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
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34
Q

The human thymus is fully developed before … and increases in size during …

A

The human thymus is fully developed before birth and increases in size during puberty

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35
Q

What is immunosenescence?

A

progressive deterioration of immune responses mainly associated with age

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36
Q

T cell development occurs in defined thymic microenvironment

  • Thymic … (epithelial cells + connective tissue) provides the … for T cell development and selection
A
  • Thymic stroma (epithelial cells + connective tissue) provides the microenviroment for T cell development and selection
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37
Q

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)
A
  • 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)
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38
Q

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)
A
  • 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)
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39
Q

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)
A
  • 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)
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40
Q

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)
A
  • 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)
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41
Q

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
A
  • 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
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42
Q

Positive selection

  • Retention of thymocytes expressing TcR that are … in their recognition of antigen by self MHC
    • i.e. selection of the …
A
  • Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen by self MHC
    • i.e. selection of the USEFUL
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43
Q

Negative selection

  • … of thymocytes expressing TcR that either recognise … antigens presented by self MHC
    • i.e. selection of the …
A
  • Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC
    • i.e. selection of the HARMFUL
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44
Q

T cells from bone marrow negative for CD4,CD8,TCR: … …

A

T cells from bone marrow negative for CD4,CD8,TCR: double negative

45
Q

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)
A
  • 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
Q

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)
A
  • 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
Q

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)
A
  • 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
Q

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)
A
  • 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
Q

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
A
  • 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
Q

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
A
  • 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
Q

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 …
A
  • 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
Q

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
A
  • 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
Q

Binding - Positive v Negative Selection

A
54
Q

The thymus screens for T cells that fall into a narrow window of … for MHC molecules

A

The thymus screens for T cells that fall into a narrow window of affinity for MHC molecules

55
Q
  • How can the thymus express all self antigens ?
  • How do we become self tolerant to antigens expressed by specialised tissues?
A
  • 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
Q

… is necessary for self tolerance - Mutations of … lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)

A

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
Q

AIRE is necessary for … … - Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)

A

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)

58
Q

How is tolerance established to antigens that cannot be expressed in the thymus?

A
  • 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
59
Q

Tolerance needs to be induced and maintained outside the thymus - what is this called?

A

Peripheral tolerance

60
Q

Auto-immunity/allergy - breakdown of … …: the immune system responds to self or environmental ag

A

Auto-immunity/allergy - breakdown of peripheral tolerance: the immune system responds to self or environmental ag

61
Q

Auto-…/… - breakdown of peripheral tolerance: the immune system responds to self or environmental ag

A

Auto-immunity/allergy - breakdown of peripheral tolerance: the immune system responds to self or environmental ag

62
Q

…-… 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

A

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

63
Q

Mechanisms of Peripheral Tolerance

  • 4 mechanisms - what are they?
A
  • 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
64
Q

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 …
A
  • self reactive lymphocytes fail to recognise or respond to some self antigens in the periphery
  • cells neither die nor become anergic
65
Q

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)
A
  • 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)
66
Q

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)
A
  • 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)
67
Q

… … chamber is an immune-privileged site. Normally, self-antigens in this site are not exposed to the immune system

A

Eye anterior chamber is an immune-privileged site. Normally, self-antigens in this site are not exposed to the immune system

68
Q

Eye anterior chamber is an …-… site. Normally, self-antigens in this site are not exposed to the immune system

A

Eye anterior chamber is an immune-privileged site. Normally, self-antigens in this site are not exposed to the immune system

69
Q

What is Sympathetic ophthalmia?

A

Physical trauma in one eye can initiate autoimmune response to both eyes. This can cause blindness in the both damaged and undamaged eyes:

70
Q

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 …

A

Sympathetic ophthalmia

71
Q

Induction of Anergy

  • Binding of antigen makes lymphocyte unresponsive
  • presentation without …
  • …-4 signaling
A
  • binding of ag makes lymphocyte unresponsive
  • presentation without costimulation
  • CTLA-4 signaling
72
Q

Induction of Anergy

  • Binding of antigen makes … unresponsive
  • presentation without costimulation
  • CTLA-4 signaling
A
  • binding of ag makes lymphocyte unresponsive
  • presentation without costimulation
  • CTLA-4 signaling
73
Q

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…
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
74
Q

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
A
  • CTLA-4 is an inhibitor of responses
  • Blocking CTLA-4 promotes tumour rejection, CTLA-4 limits immune responses to tumours
75
Q

… transmits an inhibitory signal to T cells, whereas … transmits a stimulatory signal

A

CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal

76
Q

Blocking CTLA-4 promotes tumor …

A

Blocking CTLA-4 promotes tumor rejection

77
Q

…-4 limits immune responses to tumors

A

CTLA-4 limits immune responses to tumors

78
Q

Anti-…-… antibody is approved for tumor immunotherapy (enhancing immune responses against tumors)

A

Anti-CTLA-4 antibody is approved for tumor immunotherapy (enhancing immune responses against tumors)

79
Q

Anti-CTLA-4 antibody is approved for … … (enhancing immune responses against …)

A

Anti-CTLA-4 antibody is approved for tumor immunotherapy (enhancing immune responses against tumors)

80
Q

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
A
  • 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
81
Q

Tregs suppress the activation of effector responses and are critical for regulating … and … to self antigens

A

Tregs suppress the activation of effector responses and are critical for regulating homeostasis and tolerance to self antigens

82
Q

… cells are critical components in the maintenance of … tolerance through “suppressive” mechanisms

A

Treg cells are critical components in the maintenance of peripheral tolerance through “suppressive” mechanisms

83
Q

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
A
  • 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
84
Q

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
A
  • 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
85
Q

Mutations in FOXP3 gene cause …

A
  • 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
86
Q

depletion of CD25(+)CD4(+) T cells leads to …

A

depletion of CD25(+)CD4(+) T cells leads to autoimmunity

87
Q

In both humans and mice, absence of T … cells is associated with aggressive autoimmunity

A

In both humans and mice, absence of T regulatory cells is associated with aggressive autoimmunity

88
Q

In both humans and mice, absence of T regulatory cells is associated with aggressive …

A

In both humans and mice, absence of T regulatory cells is associated with aggressive autoimmunity

89
Q

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
A
  • 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
90
Q

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
A
  • 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
91
Q

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
A
  • 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
92
Q

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
A
  • 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
93
Q

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)
A
  • 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)
94
Q

Elimination of T cells specific for abundant peripheral antigens: … exhaustion (expression of inhibitory receptors on exhausted T cells, e.g. CTLA-4, PD-1)

A

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)

95
Q

Layers of Self-tolerance

A
96
Q
  • 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
A
  • 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
97
Q
  • 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
A
  • 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
98
Q
  • 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
A
  • 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
99
Q

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.
A
  • 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.
100
Q

Interaction of food proteins with gut-associated lymphoid tissue (GALT) in the intestinal transit is the essential prerequisite for oral ….

A

Interaction of food proteins with gut-associated lymphoid tissue (GALT) in the intestinal transit is the essential prerequisite for oral tolerance.

101
Q

Different cells of the immune system participate in oral tolerance induction, with … T cells being the most important.

A

Different cells of the immune system participate in oral tolerance induction, with Regulatory T cells being the most important.

102
Q

Molecular weight of Antigen

  • Smaller, soluble, not-aggregated molecules favors …
  • large, aggregated, complex molecules favors immunogenicity
A
  • Smaller, soluble, not-aggregated molecules favors tolerance
  • large, aggregated, complex molecules favors immunogenicity
103
Q

Dosage of Antigen

  • Very small or large favors …
  • Intermediate favors …
A
  • Very small or large favors tolerance
  • Intermediate favors immunogenicity
104
Q

Routes of administration - Antigen

  • Oral, intratracheal, orbital exposure to antigen can activate T cells to secrete TGFb (T…).
A
  • Oral, intratracheal, orbital exposure to antigen can activate T cells to secrete TGFb (Tregs).
105
Q

Can oral tolerance be used therapeutically?

A
  • 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)
106
Q

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
A
  • 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
107
Q

…/… desensitisation immunotherapy for peanut allergy holds promise for the control of allergy

A

Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy

108
Q

Oral/sublingual desensitisation immunotherapy for … allergy holds promise for the control of allergy

A

Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy

Year 2 Medicine (162 decks)

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