Immunological tolerance Flashcards
Why is the immune system kept in a fine balance?
It must manage to fight infection whilst tolerating self to prevent autoimmunity
What happens if the immune system is unable to tolerate self?
Autoimmune disorders develop
Examples of autoimmune disorders
Psoriasis
Scleroderma
Multiple Sclerosis
What is the disadvantage of having a wide range of antibodies?
There is increased risk of self-reactivity
What is tolerance?
Prevents undesirable immune responses from taking place
Like those towards self antigens
What are the two mechanisms of tolerance?
Peripheral tolerance
Central tolerance
When does central tolerance take place?
During development
Where does central tolerance take place?
B cells = bone marrow
T cells = thymus
Describe the process behind central B cell tolerance
B cells undergo B cell selection
A functional antigen receptor is produced
If an immature B cell binds to a self-antigen in the bone marrow it can either:
- change specificity through receptor editing
- be deleted through negative selection
Describe the structure of the thymus
Bi-lobed organ
Outer cortex
Inner medulla
Describe the marker expression profile of a T cell
Initially, T cells express no receptors
Then they express both CD4 and CD8 receptors
During education, T cells downregulates one of the CD proteins
Which two processes happen in the thymus during thymic education of T cells?
Positive selection
Negative selection
Describe positive selection
All T cells need to recognise body cell MHC
The MHC class the T cell recognises determines the CD class they express
Involves checking that the TCR can recognise MHC on the APCs
Failure of positive selection causdes apoptosis since they cannot detect MHCs and are therefore not usegul
Describe negative selection
This checks to see whether the T cell recognises self proteins
If they recognise the self proteins strongly, they are destroyed to prevent autoimmunity
Where in the lymph node does positive selection take place?
Cortex
Where in the lymph node does negative selection take place?
Medulla
What is AIRE?
Autoimmune regulator
Transcription factor which turns on the expression of proteins belonging to different tissues in the thymus
So the thymus mimics all the proteins expressed throughout the body
This allows different tissue-specific proteins to be expressed in the thymus
What happens if the thymus is AIRE-deficient?
Increase in T cells which recognise self-antigens
Leads to autoimmunity
What is peripheral tolerance?
Deals with any self-reactive lymphocytes that escape central tolerance
Where does peripheral tolerance take place?
Lymph nodes
Spleen
Mucosal and cutaneous lymphoid tissues
What are the two mechanisms of peripheral tolerance?
Cell intrinsic mechanism - cell is controlling itself
Cell extrinsic mechanism - another cell is controlling the cell
Which cell is involved in the cell extrinsic mechanism?
T regulatory cells
What are the 4 types of cell intrinsic mechanisms?
Ignorance
Anergy
Phenotypic skewing
Apoptosis
What is ignorance?
Self-reactive T cells might never encounter the self-protein they recognize and therefore exist in a state of ignorance.
What is anergy?
Plays on the fact that activation of T cells relies on co-stimulation
The antigens that the self-reactive T cells react to come from the body, so there are no danger signals from the innate immune response accompanying them
Due to the lack of danger cytokines, the expression of costimulatory molecules on APCs is small or inexistent
Without the second signal, T cells are not activated and instead become anergic
When is phenotypic skewing activated?
When the main ways of peripheral immune tolerance are not effective
What is phenotypic skewing?
Since the body cannot prevent immune activation, it’s trying to downregulate the already ongoing response
For harm to be caused, they need to differentiate in a particular way
If they activate but differentiate into an unwanted cell, then functional tolerance will be preserved
Where do Tregs develop?
In the periphery or in the thymus
What do Tregs express?
CD25
What transcription factor do Tregs express?
Foxp3
Where do Tregs come from?
Develop from self-reactive T cells which are modified into becoming inhibitory
Describe an experiment showing the importance of Tregs
Injection of all the T cells into a mouse lacking a thymus led to a healthy mouse
Injection of CD25-depleted T cells into a mouse lacking a thymus led to a mouse with autoimmune disease
This shows that our own T cells are dangerous unless kept in check by CD25+ T regs
T cells recognising self peptide in the periphery are rare
TRUE or FALSE
FALSE
The mouse experiment showed this
T cells recognising self peptide are common
Which inhibitory cytokines do T regs secrete?
IL-10
TGFb
Mechanisms of action of Tregs
Secretion of inhibitory cytokines
Modifying CTLA-4 to alter the function of APCs through removing/blocking costimulatory ligands
Bind and consume IL-2 (growth factor for T cells)
Why is it important to control T cells?
T cells control many other cell types
