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Flashcards in Self non-self discrimination Deck (39):

What is the function of tolerance?

To protect us from self-reactive lymphocytes 


What are the two types of tolerance?

Describe where each type develops?

Central tolerance: thymus (T cells), bone marrow (B cells)

Peripheral tolerance: secondary lymphoid organs in peripheral tissue


What are the broad mechanisms for inducing tolerance?

Delete (eliminate problem)

Anergise (switch off problem)

Ignore (ignore trigger)

Regulate (contain problem)


Which tolerance is more efficient: B or T cell tolerance?

T cell tolerance 

Very common to identify self Ab/auto-Ab in normal, healthy people (tend to be transient and go away)


When and where does B cell tolerance occur?

In bone marrow during development 


Describe the mechanisms of B cell tolerance?

Low affinity non cross-linking self molecule > Mature B cell, clonally ignorant

Soluble celf molecule > Anergic B cell

Multivalent slef molecule > Apoptosis

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Which two signlas are required for the mature B cell to respond and survive?

1) Signlas via the surface Ig-Ag interaction

2) T cell help - CD40L, and some cytokines


What happens to B cells in the absence of T cell help?

Very short lifespan


What does peripheral B cell tolerance rely on?

The fact that T cell tolerance is working, for T cell help


Describe the events that occur following B cell activation?

Low affinitiy > B cell dies

High affinity > memory and plasma B cells formed

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Describe the difference in what T cells and B cells see, in terms of antigens?

B cells see whole proteins

T cells see peptide fragments that are processed and presented at cell surface 

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Where does T cell development occur?

In the thymus


Describe the process of T cell development in the thymus?

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Why are T cells, by definition, self-reactive?

They see self Ag (MHC)


Which stage/type of T cells undergo positive and negative selection?

Double positive thymocytes


Describe positive selection?

Positive selection: thymocytes that express TCRs capable of recognising self-MHC are selected to survive


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Describe negative selection?

Negative selection: removal of immature lymphocytes that have strong reactivity to self peptide

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Desribe the Goldilocks theory of T cell selection?

T cell selection is dependent on receptor affinity for self MHC

No affinity > death by neglect

Low/intermediate affinity > positive slection

High affinity > negative selection


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How do T cells see Ag that aren't expressed in the thymus?

Some tissue specific antigens are expressed in thymic epithelial cells under the control of AIRE (autoimmune regulator of expression) transcription factor 

AIRE results in ectopic expression of peripheral tissue proteins in thymic medulla 


Where is AIRE expressed?

Thymic medullary epithelial cells


What is the function of AIRE?

Distirbutes itself wherever DNA is accessible in the thymic medulla and turn on gene expression non-specifically

Results in gene expression that is not normally expressed in the thymus > T cells exposed to peripheral Ag


What is the outcome of defects in AIRE?

Failure of negative selection for some Ag > autoimmunity


Describe the difference between central and peripheral T cell tolerance?

Central tolerance: involves immature/developing lymphocytes, occurs in primary lymphoid organs

Peripheral tolerance: involves mature lymphocytes, occurs in secondary lymphoid organs and peripheral tissues


Describe the mechanisms by which T cell tolerance is achieved centrally and in the periphery?

Central tolerance: deletion, selection of Tregs

Peripheral tolerance: deletion, anergy, ignorance, regulation


What happens to T cells that do not receive any costimulation?

T cells become anergic 

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Describe the role of immunosuppressive T cells in maintaining self tolerance?

Treg cells have specific anti-inlammatory effector type mechanisms

Their expression is associated with transcription of foxp3 

Treg cells can suppress all manner of CD4 and CD8 responses

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Describe the different classes of Treg cells? 

nTregs: derived from the thymus during T cell development

iTregs: derived following the activation of naive CD4 T cells in the presence of TGFb



What is the role of iTregs?

Secrete immunosuppressive cytokines

Express CTLA4 and inihibit co-stimulation

Release molecules that create a suppressive environment 


How does CTLA4 work?

Binds B7 (CD80 and CD86) more avidly than does CD28 > delivers inhibitory signlas to activated T cells 

So, high levels of CTLA4 > inhibit ability of naive T cells to be activated or sustain their activation 

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What are the three key components of in the pathogenesis of autoimmune disease?

1) Genetic susceptibility

2) Environmental

3) Loss of self-tolerance 


Why are autoreactive lymphocytes not always activated?

1) Ag is not available

2) Absence of Signal 2

3) Autoreactive B cells, don't have autoreactive CD4 T cells 


Describe the difference between an autoimmune response and an autoimmune disease?

Autoimmune response: loss of self-tolerance > tissue repair/regulation

Autoimmune disease: loss of self-tolerance > continued tissue damage

Autoimmunity results from a chronic autoimmune response with ongoing tissue damage

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Describe the 2 classifications of autoimmune disease?

Give examples of each?

1) Organ-specific: confined to particular organs/cell types, and antigens recognised are organ specific

eg. thyroid, MS, MG

2) Systemic: multiple tissues of body are targeted, and antigens recognised are more ubiquitous

eg. rheumatoid arthritis, SLE


Describe how normal effector mechanisms of B cells, T cells and macriphages can be implicated in response to self antigens?

B cells: production of auto-Ab

T cells: DTH responses, CTL killing of stromal cells, provisiob of B cell help

Macrophages: No, proteases, oxidative radicals


What is the consequence of a defect in the Foxp3 gene?

Loss of Tregs and peripheral central tolerance mechanism > multi-system autoimmunity 


Descibe the autoimmunity that occurs in Type 1 IDDM?

Organ specific, T cell mediated

Autoimmune destruction of pancreatic b-cells

Characterised by infiltration of lymphocytes, weak autoAb response, T cell reactivity to islet proteins

Occurs more frequently in HLA DR3-DQ2 and DR4-DQ8


Describe the autoimmunity that occurs in multiple sclerosis?

CD$ T cells specific for myelin antigens promote and inflammatory response and degrade the myelin sheaths

HLA-DR15 and HLA-DQ6 associated with disease 


How do autoimmune diseases begin?

Recognition of self Ag in presence of inflammation 


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What initiates the inflammation that leads to autoimmune activation?

Bystander activation 

eg. viral infection > might infect the same DC with self Ag > triggers CD4 > can help B cell that is self-reactive 


Molecular mimicry: antigens from pathogen are similar to autoantigens, and able to cross-react with autoreactive Tcells/B cells


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