L28. Self vs. Non-Self Discrimination Flashcards
What is tolerance?
The mechanism of the body to ensure that the immune system is not self reactive (makes sure it doesn’t attack itself)
What are the two main types of tolerance? Where do they occur?
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Central Tolerance: occurs during the development of these lymphocytes
- Thymus for T cells
- Bone marrow for B cells
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Peripheral Tolerance: occurs to circulating/regional lymphocytes that already exhibit specificity for antigens
- Secondary lymphoid tissue (nodes)
- Peripheral tissues
What are the four main mechanisms used to induce tolerance? Define them
Deletion: induction of apoptosis
Anergy: switching off the cell and its processes and reactions
Ignorance: the cell never interacts with its antigen therefore is never activated
Regulation: the actions of the cell are dampened down such that they don’t have any major effect (Treg)
Which is more efficient, B cell or T cell tolerance?
T cell tolerance is much more efficient
What processes (anergy, regulation, deletion, ignorance) are involved in B cell central tolerance?
What mechanisms are involved in peripheral B cell tolerance?
Central: Anergy and Deletion
Peripheral: Ignorance and Anergy
During B cell development (Central), the developing B cells (IgM expressing) are exposed to different antigens.
Draw and describe the outcomes of the following situations
What 2 signals are required for B cells to successfully respond and survive?
- Interaction of the Ig with its specific antigen
- Co-activation signals from CD4 T helper cells via the CD40L and cytokine signalling
What are the steps that occur after B cell activation?
Draw the two possible outcomes: with and without T cell help
Without T cell help: there is low affinity activation leading to a short lived plasma cell that secretes some antibodies. This dies shortly after.
With T cell help: there is high affinity activation in the germinal centre leading to isotype switching and affinity maturation forming long lived plasma cells and memory B cells
Where does T cell development occur?
In the Thymus
Immature in the cortex eventually maturing as they pass the junction and towards the medulla
What are the stages of T cell development?
DN = double negative
DP = double positive
T cells require some small level of self reactivity. What is meant by this?
What is the implication of this on the antigen affinity?
This is because T cells need to have the ability to recognise MHC molecules for presentation and interaction with them
The affinity of T cells to their specific antigens is quite low compared to the affinity of by B cells
What are the main 2 mechanisms involved in central tolerance of T cells?
Deletion
Regulation (Tregs selection)
In which cell stage (of the development of T cells) undergoes selection?
Describe the two processes
The double positive thermocyte stage
1. Positive Selection
MHC recognition capacity is selected for. Those that do not succesfully recognise MHC molecules undergo death by neglect.
2. Negative Selection
T cells that are found to react to self peptides (presented on the MHC) are removed by apoptosis
What is the goldilocks theory?
This states that immature T cell receptors that make the cut into mature T cells have a finite affinity for their antigen.
The affinity to self is limited by negative selection and is promoted by positive selection
How do developing T cells of the thymus get exposed to all the self peptides of the body for negative selection to occur comprehensively?
A transcription factor called Autoimmune Regulator of Expression is expressed in thymic epithelial cells of the medulla (at the corticomedullary junction)
This leads to the ectopic expression of peripheral proteins (and antigens) in the thymic medulla
What do defects in AIRE gene lead to?
Autoimmune Polyglandular (or Polyendocrine) syndrome, type 1 (APS-1)
This is a comprehensive autoimmune disease due to failure of negative selection
Describe peripheral tolerance in terms of ignorance for T cells (2 main ways it occurs)
- This is basically the fact that antigens are sequestered or “protected” in sites that are not easily accessible to the blood/lymph which contains the self reactive T cell.
- There amount of antigen present at any one time is not enough to trigger a T cell response
What is the 2 signal theory for activating naive T cells?
Signal 1
TCR interaction with the antigen presented on MHC
Signal 2
Co-stimulation with the activated antigen presenting cell through CD28 (tcell): CD80/86 (APC) interactions
What is peripheral anergy in relation to the 2 signal theory?
When a naive self-reactive T cell comes into contact with its peptide, the peptide is not bound to MHC.
Thus the T cell has signal 1 but it lacks signal 2 from any activated APC. Therefore there is a resultant anergy leading failure to activate and proliferate.
What are the peripheral regulation mechanism of T cells? [2]
T regulatory cells are a Th subset that express TGFb, IL-10 and other anti-inflammatory and immunosuppressive signals
- Natural Tregs (nTreg) are immunosuppressive against self reactions
- Induced Tregs (iTreg) are formed when a T cell is activated in the presence of TGFb
- They secrete immunosuppresive cytokines
- Express CTLA4
- Create a suppressive environment
What is CTLA4? How does it act?
It binds to CD80/86 on the antigen presenting cells and blocks their ability to activate T cells (via the CD28 receptor).
It has a much higher avidity for the receptor and thus outcompetes it. It delivers inhibitory signals to activated cells (prevents 2nd signal)
What are the 3 key components to developing autoimmune disease?
- Genetic susceptibility (especially MHC expression)
- Loss of self tolerance
- Envirmonment/ Immune State (eg. immunosuppression)
Why are most autoimmune diseases not constantly active? [2]
- Usually the antigens are not readily available to react to
- There is normally no active signal 2 for costimulation (either activated APC for T cell activation or parallel self-reactive CD4 cell for B cell activation)
What is the difference between an autoimmune response and an autoimmune disease?
Response: occurs regularly in the body and is a transient response to tissue damage.
Disease: a chronic ongoing autoimmune response with ongoing damage leading to clinical sequelae
What are the 2 types of autoimmune diseases? Give examples
- Organ specific
eg. Pancreatic islet cells, Thyroid, Ovarian, Adrenal, Gastric parietal cells, MS (myelin), MG (NicR) - Systemic
eg. Systemic Lupis Erythromatosus. Rheumatoid Arthritis
How are macrophages involved in autoimmune disease?
The inflammatory response is what mediates most of the damage leading to nitric oxide release, proteases and ROS
How would a loss of central tolerance occur?
Multisystem autoimmunity
A defect in AIRE gene leading to decreased central tolerance mechanisms
eg. APC-1
How would a loss in peripheral tolerance occur? Give an example
A mutation in Foxp3 gene which is a transcription factor that determines Treg commitment and function.
Eg. Immunodysregulation polyendocrinopathy and enteropathy X linked syndrome (IPEX syndrome)
Describe the autoimmune nature of Type I Diabetes
- How it is self reactive?
- To what tissue?
- The genetic risk
How
It is a CD4/CD8 T cell mediated attack (Type IV hypersensitivity)
Organ
Autoimmune destruction of the beta cells of the pancreas leading to decreased insulin secretion
Genetic Risk
Increase suseptibility with expression of HLA DR3-DQ2 and HLA DR4-DQ8
Describe the autoimmune nature of multiple sclerosis
- How it is self reactive?
- To what tissue?
- The genetic risk
How
CD8 T cell attack on myelin
It is believed to be a switch between Th1 and Th17 for proinflammation and Th2 for remission
Where
T cell attack myelin antigens leading to inflammation and progressive CNS degneration (episodic paralysis)
Genetic Risk
Increase susceptibility with expression of HLA DR15 and HLA DR6
How do autoimmune diseases begin? (what is the trigger?
Usually the trigger is some form of cytotoxic infection which causes inflammation and damage to tissues enabling self-peptides to be taken up by macrophages and other APCs
It is also believed that the activated DCs in infection may act to help activate the self-reactive T cells in co-stimulation
