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
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
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
Where does T cell development occur?
In the thymus
Describe the process of T cell development in the thymus?
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
Describe negative selection?
Negative selection: removal of immature lymphocytes that have strong reactivity to self peptide
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
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
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
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
What are the three key components of in the pathogenesis of autoimmune disease?
1) Genetic susceptibility
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
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
What initiates the inflammation that leads to autoimmune 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