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PDAT4 > 13 - Tolerance and Autoimmunity > Flashcards

13 - Tolerance and Autoimmunity Flashcards

1
Q

Central Vs Peripheral
Tolerance

A

Central Tolerance
T + B Cell development = negative selection
restricted to Thymus + Bone Marrow = Maturation Sites
Majority of mature cells react ONLY w/ FOREIGN Ag

Peripheral Tolerance
Mature T + B-cell event in PERIPHERY
Restricted to
Spleen / Lymph Node / Non-lymphoid Tissue

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2
Q

T-Cell
Central Tolerance Mechanism

A

CLONAL DELETION
Occurs during EARLY development in THYMUS

Positive Selection then –> Negative Selection

Thymic Epithelial Cells
Express AIRE (autoimmune regulator) gene that regulates expression of 100s of tissue secific Self-ag
Ex. Pre-inulin / Thyroglobulin

Thymic Dendritic Cells
BOTH express low level of:
COSTIMULATORY + ADHESION molecules
that ultimately FAIL to fully activate cell

Express HIGH level of FASL
signals cell death in the setting of the Semi-response

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3
Q

What is
AIRE?

A

AIRE = Autoimmune Regulator Gene
Expressed by
Thymic Epithelial Cells

Regulates Expression of 100s of Tissue-Specific self-Ag
ex = Pre-insulin + Thyroglobulin

  • *CENTRAL TOLERANCE MECHANISM**
  • *CLONAL DELETION for T-Cells**
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4
Q

Positive Selection

Central Tolerance Mechanism
Clonal Deletion - T-Cell

A

in the CORTEX of the thymus

T-cell learns to:

  • *recognize SELF-MHC** bound to AG-peptide
  • *THE COMPLEX**
  • not just free Ag*

Weakly interacting cells –> SURVIVE

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5
Q

Negative Selection
Central Tolerance Mechanism
​Clonal Deletion - T-Cell

A

Occurs in the MEDULLA of the thymus

T-Cell must learn to:
NOT recognize peptides derived from SELF-Ag

T-cell that recognizes SELF-ag –> ELIMINATED

STRONG INTERACTON = DIE OFF

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6
Q

B-Cell’s 3
Central Tolerance Mechanisms

A

Clonal Deletion
Imature B-cell that reacts to SELF-AG –> clonal deletion in bone marrow

Anergy
exposure to soluble-self-AG results in:
incomplete activation –> unresponsiveness to self-AG

Receptor Editing
Self-Ag triggers SECONDARY Light Chain Gene Rearrangements
that alter receptor specificity

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7
Q

What occurs during RECEPTOR EDITING?
B-Cell
Central Tolerance Mechanism
​

A

Self-Ag Recognition
VVVV
Triggers a SECONDARY

LIGHT CHAIN GENE REARRANGEMENT
that will alter receptor specificity

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8
Q

B-Cell with HIGH AVIDITY

What happens?

A

DELETION

or

RECEPTOR EDITING

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9
Q

B-Cell with Moderate Avidity

What happens?

A

ANERGY

B-cell just hangs out

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10
Q

B-Cell with low avidity

What happens?

A

CLONAL IGNORANCE

  • No threat*
  • B-cells just hang out*
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11
Q
  • *CLONAL DIVERSION**
  • *Central Tolerance Mechanism**
A
  • *High-Affinity, Self-Ag specific CD4+ Tcell**
  • *DIVERTED** to become a
  • *T-REGULATORY** cell

10% of CD4+ T-cells are TREGS:
Made in Thymus -> Lymph node migration
Control over Self-Ag reactive T-cells in periphery
Attenuate Immune response to NON-Self-Ag

T-regs express the transcription factor:
FOXP3
which is the master regulator of T-cell development & function

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12
Q

What is FOXP3?

and what are its functions?

A

Transcription Factor expressed by T-REGS (Cd4+ Th)

Master Regulator of Th development & Function

UPREGULATES
expression of CD25 & other treg associated cell-surface olecules
like CTLA-s / TNF receptor molecules

SUPPRESSES
expression of IL2 / INF-y / IL-4

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13
Q

What type of TOLERANCE?

Occurs in
Generative Lymphid Organs = THYMUS + BONE MARROW

Apoptosis = Deletion

Receptor Editing

Development of T-Regs from CD4+t-cells

A

CENTRAL TOLERANCE

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14
Q

What type of TOLERANCE?

Occurs in
Spleen / Lymph Node / Non-lymphoid Tissue

Anergy

Apoptosis

Supression

A

PERIPHERAL TOLERANCE

peripheral tissues

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15
Q

Peripheral Tolerance
in Mature T-Cells

A

some Mature cells will:

have TCR that can respond to SELF-AG NOT encountered in the thymus

encounter HIGH Self-Ag that OVERWHELMS TCR
and will result in REACTION (despite low affinity)

encounter strong secondary signals in response to infection
(despite low affinity)

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16
Q

What is the PROTECTIVE EFFECT?

A

Occurs after an interaction between:
Autoimmune T-cell + Self-AG
on a cell that is:
NOT COMPETENT to DELIVER A COSTIMULATORY SIGNAL

Resulting in functional inactivation
of self-reactive lymphocytes through lack of costim signal

ANERGY

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17
Q

4 Peripheral Tolerance Mechanisms

A

Anergy
state of unstable metabolic arrest –> apoptosis
protective effect = l**ack of costim signal

Deletion
Trigger Apoptosis by
Mitochondrial (INTRINSIC) or Death (EXTRINSIC) pathway

Regulatory T-Cell
Dominant control -> able to inactivate lymphocytes specific for SAME AG

Immune Privilege Sites
Certain tissue DEVOID of immune response
brain / eye / ovary / placenta / testes

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18
Q

B7 of the APC
VVV
CTLA-4 of T-cells

Causes what?

A

INHIBITION OF THE ACTIVITY OF T-CELLS

Peripheral Tolerance: ANERGY

19
Q

What is the MITOCHONDRIAL PATHWAY?

A

Peripheral Tolerance Mechanism = DELETION

INTRINSIC
BCL2/BimmediatedApoptosis

Imbalanced expression of pro-apoptotic proteins
VVVV
Destabilizes MITOCHONDRIAL membrane
VVV
apoptosis

20
Q

What is the DEATH RECEPTOR pathway?

A

Peripheral Tolerance Mechanism = DELETION

EXTRINSIC

Uses FAS/FASL from the outside
VVV
Triggers intracellular “DEATH-INDUCING SIgnaling Comlex”
VVVV
CASPASE producing APOPTOSIS

21
Q

What is Dominant Control?

A

Regulatory T-Cell

Treg specific for self-ag is able to INACTIVATE
other lymphocytes specific for SAME SELF-AG

(Peripheral Tolerance Mechanism)

22
Q

Development & Survival
of T-REGS

Regulatory T-Cell
(Peripheral Tolerance Mechanism)

A

Generated after Clonal Diversion after High-Affinity SELF-AG
specific CD4+ Tcell in THYMUS

Require
IL-2** & **FOXp3
to develop & survive

23
Q

T-REG
FUNCTION

A

In PERIPHERAL TISSUE:
T-regs suppress the activation & effector fxns of other self-reactive & potentially pathogenic lymphocytes

T-REG DEFICIENCY
in periphery is sufficient to evoke chronic T-cell Mediated autoimmunity & immunopathology

TREG ENRICHMENT in MICE –> Graft Acceptance

24
Q

T-Reg Mediated Suppression
MECHANISMS

A

Active Tregs OUT-COMPETE Ag-specific Naive Th Cells
for MHC2/APC binding because of high expression of
Adhesion Molecules = LFA-1

Tregs MODULATE DENDRITIC cell-function
downregulate B7-Expression

Tregs -> further differentiatte to KILL / Inactivate responder T-cells
by Secreting Granzyme/perforin or Immunosupressive Cytokines
IL-10

25
How are **INDUCIBLE T-Regs Cells** **GENERATED?**
from **Th0 cell** in the presense of **_immunomodulatory cytokines:_** **TGF-B** / **IFN-y** / **IL-10** or **_Repetitive stimulation of NON-PRO APCs_**
26
**Inducible T-reg FUNCTIONS**
*Unlike regular Tregs (source = thymus & require DIRECT cell-contact)* Inducible T-reg Supression is **_*NOT* contact dependent_** / ***NOT* Ag-Specific** Functions: **Help _TURN OFF_** the **immune response** once over Produce **Inhibitory Cytokines** = _**TGF-B** / **IL-10**_ Have **high concentration of _CTLA4_** on surface
27
**IMMUNE PRIVILEGE** Peripheral Tolerance Mechanism
Certain tissues ***_devoid of immune response_***: **Brain / Eye lens / Ovary / Placenta / Testes** _**FASL** is **constitutively expressed @ PRIVELEGED SITES**_ binding of active lymphocytes to FasL when entering priv area --\> **CELL DEATH** These cells **secrete TGF-B** that: ***_SUPPRESS_*** **_infiltrating T-cells_** Ex. Cells in EYE always express FASL --\> kills any rogue T-cell that might gain entry
28
When is **TOLERANCE INDUCTION** **Desirable** / **Undesireble**
Desirable when tolerance to: * *Self-Ag** // **Environmental Ag** * *Transpantation // FETUS** *_UNDESIRABLE WHEN:_* **Tolerance to TUMORS** we want or body to **not have tolerance to tumors --\> Fight them off**
29
State of **INDUCED TOLERANCE**: **Duration & Extent**
**Does NOT last indefinitely**, wanes with time --\> dissapears Depends on: * *Molecular Characteristic** of Ag * *Dose & Route** of Ag Competence of immune system: **_Young fetus_** --\> makes **IgM** but ***NOT IgG*** until late takes **months & exposure to develop IMMUNE Maturity** Term babies are **immunocompetent but immature** * *_Old_** = **IMMUNE SENESCENE** * *good MEMORY response** but ***POOR primary response***
30
**Peripheral Tolerance in B-CELLS**
B-cell encounters **self-Ag** in **peripheral tissues**: **_Anergy_** Functional Inactivation **_Deletion_** die by apoptosis **_Regulation by INHIBITATORY RECEPTORS_** prevent B-cell activation
31
**Mechanisms of AutoImmunity**
**_Genetic Susceptibility_** genetic failure of self-tolerance -\> self-reactive lymphocytes **_Reaction to ENVIRONMENTAL stimuli_** Tissue injury / inflammation -\> activates self-reactive lymphocytes **ALSO SOME OVERLAP!** **Multifactoral: Genes + Immune Regulation + environment**
32
**Autoimmunity: GENE DEFECTS**
Clear association between **Genetics & Autoimmune Disease**: **MONOzygotic Twins \> DIzygotic Twins \> Family Member**s \> gen pop Typically a result of: **MULTIPLE GENE DEFECTS** Single gene defect EXCEPTIONS: **Fas/FasL // AIRE // FOXp3 expression** sufficient for disease
33
**What are SINGLE GENE DEFECT exceptions to the rule?**
Defects in these SINGLE GENES are sufficient for a disease: **_FAS/FASL_** APS-1 **_AIRE_** IPEX **_FOXp3 expression_** ALPS
34
**APS-1** Caused by what Single Gene Defect?
**_AIRE_** auto immune regulator Decreased expression of **self-ag** in the **thymus** VVV **defect in NEGATIVE SELECTION**
35
**_IPEX_** Caused by what Single Gene Defect?
**_FOXp3_** Decreased generation of **T-Regs**
36
**_ALPS_** Caused by what Single Gene Defect?
**_FAS / FASL_** Failure of **APOPTOTIC DEATH** of **Self-Reactive T/B-cells**
37
**SEQUESTERED AG** Autoimmunity: Reaction to ENVIRONMENT
Inducing the release of **sequestered self-Ag** *normally HIDDEN from immunity:* **Sites of Privilege** & **Sudden EXPOSURE to HIGH self-ag** due to **Trauma / Infxn** may lead to an **Autoimmune Response**
38
**INFECTION / TISSUE Injury** Autoimmunity: Reaction to ENVIRONMENT
Inducing the **_release of SEQUESTERED self-Ag_** *normally hiddden from immunity (sites of privelge)* Induction of **_Co-stimulatory molecules on APC_** due to infection **_MOLECULAR MIMICRY_** structurally simular microbial Ag --\> **self-ag can CROSS-REACT**
39
**Molecular Mimicry** Autoimmunity: Reaction to ENVIRONMENT
**Sharing of epitopes** between **microbe & host** VVVV **AB's** detected against **infectious agent** begins to **react with NORMAL Self-Ag** VVV **AUTOIMMUNITY** Ex. **RHEUMATIC FEVER** **Multiple Sclerosis** / **Myasthenia Gravis Guillain Barre**/**T1DM**
40
* *ORGAN SPECIFIC** * *Autoimmune Diseases**
* *T1 DM** * *MS / Myasthenia Gravis** * *Graves / Hashimotos** Goodpasture's Syndrome Autoiimmune Hemolytic Anemia
41
Ways for **Antibodies to produce DISEASE** ## Footnote **B-CELL AUTIMMUNE DISEASE**
**Complement fixing IgM** **Opsonization** hemolytic Anemias Formation of **Immune Complexes** **Blockade of Cell-Surface Receptors** MG / Pernicious Anemia **Stimulation of Cell-Surface Receptors** Graves **Maternal Transfer**
42
What **Classification of AUTOIMMUNE DISEASE?** ## Footnote **Myasthenia Gravis** **GRAVES** **SLE** **Goodpasture Syndrome**
**Effector Mechanism** **_B-CELLS = autoANTIBODY_**
43
What **Classification of AUTOIMMUNE DISEASE?** ## Footnote **RA** **Hashimotos** **T1DM** **MS**
**Effector Mechanism** ALL ARE **_CD4+ Tcells_** RA / Hashimotos / T1DM = autoantibody also RA / T1DM = CTLs - B-cells also
44
**Selectives IMMUNOTHERAPIES** for **Autoimmne Disease** GOAL IS TO: **_Reduce SYMPTOMS_** & **_Preserve Organ Function_**
**_Monoclonal AB**_ or _**Blocking Antagonists_** Against: Cytokines / Cytokine Receptors / Chemokine Receptors T-cell Synapse **_CTLA4_** downregulates active T-cells **_Regulatory Cytokines_** **_Restoration of Tolerance_**

PDAT4 (34 decks)

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