Self non-self discrimination

Question 1

What is the function of tolerance?

Answer 1

To protect us from self-reactive lymphocytes

Question 2

What are the two types of tolerance?

Describe where each type develops?

Answer 2

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

Peripheral tolerance: secondary lymphoid organs in peripheral tissue

Question 3

What are the broad mechanisms for inducing tolerance?

Answer 3

Delete (eliminate problem)

Anergise (switch off problem)

Ignore (ignore trigger)

Regulate (contain problem)

Question 4

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

Answer 4

T cell tolerance

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

Question 5

When and where does B cell tolerance occur?

Answer 5

In bone marrow during development

Question 6

Describe the mechanisms of B cell tolerance?

Answer 6

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

Soluble celf molecule > Anergic B cell

Multivalent slef molecule > Apoptosis

Question 7

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

Answer 7

1) Signlas via the surface Ig-Ag interaction
2) T cell help - CD40L, and some cytokines

Question 8

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

Answer 8

Very short lifespan

Question 9

What does peripheral B cell tolerance rely on?

Answer 9

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

Question 10

Describe the events that occur following B cell activation?

Answer 10

Low affinitiy > B cell dies

High affinity > memory and plasma B cells formed

Question 11

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

Answer 11

B cells see whole proteins

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

Question 12

Where does T cell development occur?

Answer 12

In the thymus

Question 13

Describe the process of T cell development in the thymus?

Answer 13

Question 14

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

Answer 14

They see self Ag (MHC)

Question 15

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

Answer 15

Double positive thymocytes

Question 16

Describe positive selection?

Answer 16

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

Question 17

Describe negative selection?

Answer 17

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

Question 18

Desribe the Goldilocks theory of T cell selection?

Answer 18

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

Question 19

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

Answer 19

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

Question 20

Where is AIRE expressed?

Answer 20

Thymic medullary epithelial cells

Question 21

What is the function of AIRE?

Answer 21

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

Question 22

What is the outcome of defects in AIRE?

Answer 22

Failure of negative selection for some Ag > autoimmunity

Question 23

Describe the difference between central and peripheral T cell tolerance?

Answer 23

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

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

Question 24

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

Answer 24

Central tolerance: deletion, selection of Tregs

Peripheral tolerance: deletion, anergy, ignorance, regulation

Question 25

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

Answer 25

T cells become anergic

Question 26

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

Answer 26

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

Question 27

Describe the different classes of Treg cells?

Answer 27

nTregs: derived from the thymus during T cell development iTregs: derived following the activation of naive CD4 T cells in the presence of TGFb

Question 28

What is the role of iTregs?

Answer 28

Secrete immunosuppressive cytokines Express CTLA4 and inihibit co-stimulation Release molecules that create a suppressive environment

Question 29

How does CTLA4 work?

Answer 29

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

Question 30

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

Answer 30

1) Genetic susceptibility 2) Environmental 3) Loss of self-tolerance

Question 31

Why are autoreactive lymphocytes not always activated?

Answer 31

1) Ag is not available 2) Absence of Signal 2 3) Autoreactive B cells, don't have autoreactive CD4 T cells

Question 32

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

Answer 32

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

Question 33

Describe the 2 classifications of autoimmune disease? Give examples of each?

Answer 33

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

Question 34

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

Answer 34

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

Question 35

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

Answer 35

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

Question 36

Descibe the autoimmunity that occurs in Type 1 IDDM?

Answer 36

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

Question 37

Describe the autoimmunity that occurs in multiple sclerosis?

Answer 37

CD$ T cells specific for myelin antigens promote and inflammatory response and degrade the myelin sheaths HLA-DR15 and HLA-DQ6 associated with disease

Question 38

How do autoimmune diseases begin?

Answer 38

Recognition of self Ag in presence of inflammation

Question 39

What initiates the inflammation that leads to autoimmune activation?

Answer 39

Bystander activation eg. viral infection \> might infect the same DC with self Ag \> triggers CD4 \> can help B cell that is self-reactive OR Molecular mimicry: antigens from pathogen are similar to autoantigens, and able to cross-react with autoreactive Tcells/B cells