203 L14 Flashcards
Autoimmunity
Hypersensitivity type 3
Auto antibodies bind to —– antigen. This immune complex can get lodged in ——— and can activate ———. This results in the destruction of part of the ———- so the immune complex can move into different ——–. They can then activate the immune response which can cause tissue damage
————- can become activated and release things that are damaging to the host tissue
——- cells can become activated and degranulate
———- are recruited by C5a
All these then drive tissue damage
Auto antibodies bind to self antigen. This immune complex can get lodged in vasculature and can activate complement. This results in the destruction of part of the vasculature so the immune complex can move into different tissues. They can then activate the immune response which can cause tissue damage
Macrophages can become activated and release things that are damaging to the host tissue
Mast cells can become activated and degranulate
Neutrophils are recruited by C5a
All these then drive tissue damage
What is immunological tolerance?
A state of unresponsiveness to an antigen
Immunological tolerance
When a lymphocyte encounters an ——- it can either be activated, leading to an ——– response, or when it encounters a —— —— inactivated/eliminated, leading to ———-.
Self-reactive lymphocytes that have the potential to respond to ——- ——- are called ——— lymphocytes
If immunological tolerance mechanisms fail to remove or control ———— lymphocytes, ——— diseases can occur if the resulting autoimmune response leads to tissue damage
Immunological tolerance
When a lymphocyte encounters an antigen it can either be activated, leading to an immune response, or when it encounters a self antigen inactivated/eliminated, leading to tolerance.
Self-reactive lymphocytes that have the potential to respond to self antigens are called autoreactive lymphocytes
If immunological tolerance mechanisms fail to remove or control autoreactive lymphocytes, autoimmune diseases can occur if the resulting autoimmune response leads to tissue damage
How is tolerance to self antigens achieved?
Central tolerance and peripheral tolerance
Central tolerance
Central tolerance is the ——— of strongly self-reactive —- and —- cells during their development
Central tolerance occurs in the ——— for T cells and the ——– ——- for B cells. These are refereed to as the ——– ——— organs.
The organs that the T and B cells migrate to are the ——— lymphoid organs. These are sites where there is a high concentration of ———- enabling the circulating —cells to test their receptors against foreign antigens.
Central tolerance
Central tolerance is the deletion of strongly self-reactive T and B cells during their development
Central tolerance occurs in the thymus for T cells and the bone marrow for B cells. These are refereed to as the primary lymphoid organs.
The organs that the T and B cells migrate to are the secondary lymphoid organs. These are sites where there is a high concentration of antigen enabling the circulating T cells to test their receptors against foreign antigens
Education of T cells - positive and negative selection.
Positive selection
Lymphocytes are positively selected based on their —— of interaction with the —– —— complex expressed on —– —— epithelial cells. A — cell which “does not recognise —– at all” will undergo “death by neglect”.
T cells come into the ——– as immature precursors called ———-.
Positive selection occurs in the ——– when ——— are double ——– for —– and ——. The —— receptors begin to form on the surface of the ——– in the ——-. —— ——- epithelial cells have the — ——. If the ——— with ——– receptors have a ——- affinity to ——– presented on the ——– ——- epithelial cells they are ——— selected.
Negative selection:
Lymphocytes are negatively selected based on their —— of interaction with ——- ——- —– complexes presented by —- cells, —— and ——/——- epithelial cells. A T cell which receives “very ——- signals” will undergo “apoptotic death”. BUT some ——- cells can escape.
Can occur in the —– or ——.
T cells with the ——- receptors that have a strong affinity to self peptide: self MHC (self antigen) are ——– selected.
The self ——— can be presented on the ——- epithelial cells, ———epithelial cells or ——– macrophages and ——- cells.
Education of T cells - positive and negative selection.
Positive selection
Lymphocytes are positively selected based on their affinity of interaction with the self MHC complex expressed on thymic cortical epithelial cells. A T cell which “does not recognise - self at all” will undergo “death by neglect”.
T cells come into the thymus as immature precursors called thymocytes.
Positive selection occurs in the cortex when thymocytes are double positive for CD4 and CD8. The antigen receptors begin to form on the surface of the thymocytes in the cortex. Thymic cortical epithelial cells have the self MHC. If the thymocytes with antigen receptors have a strong affinity to MHC presented on the thymic cortical epithelial cells they are positively selected.
Negative selection:
Lymphocytes are negatively selected based on their affinity of interaction with self antigen MHC complexes presented by dendritic cells, macrophages and cortical/medullary epithelial cells. A T cell which receives “very strong signals” (autoreactive) will undergo “apoptotic death”. BUT some autoreactive cells can escape.
Can occur in the cortex or medulla.
T cells with the antigen receptors that have a strong affinity to self peptide: self MHC (self antigen) are negatively selected.
The self antigen can be presented on the cortical epithelial cells, medillary epithelial cells or medullary macrophages and dendritic cells.
Most thymocytes have antigen receptors that —- to bind to self MHC so are non selected.
20% of thymocytes with antigen receptors that bind strongly to self peptide:MHC (self antigens) are ——– selected
Only 1-2% ——— selected - have antigen receptors that recognise foreign peptide on self MHC.
Most thymocytes have antigen receptors that fail to bind to self MHC so are non selected.
20% of thymocytes with antigen receptors that bind strongly to self peptide:MHC (self antigens) are negatively selected
Only 1-2% positively selected - have antigen receptors that recognise foreign peptide on self MHC.
— cells are educated not to recognise self antigens during their development.
So developing —- cells with antigen receptors that have a strong affinity to self antigen are ——- selected.
B cells are educated not to recognise self antigens during their development.
So developing B cells with antigen receptors that have a strong affinity to self antigen are negatively selected.
What are the mechanisms of tolerance?
Central tolerance
Anergy
Suprpression
Ignorance
Signals needed to activate naïve T cells;
—- main signals are necessary for T cell activation
- —– —— receptor recognises
- —— ——- ——– ——–combination
Second signal from ——– —- molecules
Third signal from ——-
——– ——— cell needs to be sufficiently activated to provide ——— signals
3 main signals are necessary for T cell activation
T cell receptor recognises
self MHC foreign peptide combination
Second signal from costimulatory B7 molecules
Third signal from cytokines
Antigen presenting cell needs to be sufficiently activated to provide costimulatory signals
What happens when an APC presents self peptide to T cells?
—— cells also present —— antigens from —- cells in the absence of pathogen attack.
In the absence of pathogen attack the —- cell is not ——, so it doesn’t supply ———- signals.
If a —— cell presenting a —— —– encounters a naive ———– T cell, the receptors recognise it (1st signal) but the ——— cell is incapable of providing the other ———— signals because its not an ———- environment. As a result the naive ——— T cell doesn’t become ———- and is said to have been ——-. So the T cells do not ————.
When exposed a second time even if the ——— cell presenting ——– ——- is capable of providing ————– the naive ———– T cell will still not become ——– because of the first exposure reaction which had ——– the T cell.
Dendritic cells also present self antigens from host cells in the absence of pathogen attack.
In the absence of pathogen attack the dendritic cell is not activated, so it doesn’t supply co-stimulatory signals.
If a dendritic cell presenting a self peptide encounters a naive autoreactive T cell, the receptors recognise it (1st signal) but the dendritic cell is incapable of providing the other costimulatory signals because its not an inflammatory environment. As a result the naive autoreactive T cell doesn’t become activated and is said to have been anergized. So the T cells do not proliferate.
When exposed a second time even if the dendritic cell presenting self peptide is capable of providing costimulation the naive autoreactive T cell will still not become activated because of the first exposure reaction which had anergized the T cell.
B cell activation by antigen
When the APC is recognised and binds to the ——- cell receptor on the B cell the ——- signal is delivered.
The —— bound to the —- cell receptor complex is ———– and processed to generate ——– —– class 2 complex that binds to the —— cell receptors.
CD40L on — cells bind to CD40 on —- cell resulting in ———- signal —— to induce ——– receptor expression on the —- cell.
——– expressed by —– cells bind receptor on —- cells leading to signal —- and — cell activation.
When the APC is recognised and binds to the B cell receptor on the B cell the first signal is delivered.
The antigen bound to the B cell receptor complex is internalised and processed to generate peptide MHC class 2 complex that binds to the T cell receptors.
CD40L on Th cells bind to CD40 on B cell resulting in costimulatory signal 2 to induce cytokine receptor expression on the B cell.
cytokines expressed by Th cells bind to receptors on B cells leading to signal 3 and B cell activation.
What happens when an APC presents self peptide to B cells?
The naive ———- B cell recognises the ——- —– and expresses it on the —— class – receptor. If it doesn’t encounter an autoreactive —- cell it will not get ——— so is —— and undergoes ———-.
If it does encounter an autoreactive — cell, as long as the autoreactive —- cell is ——-, the naive autoreactive — cell will not get ———-.
The naive autoreactive B cell recognises the self antigen and expresses it on the MHC class 2 receptor. If it doesn’t encounter an autoreactive T cell it will not get activated so is anergized and undergoes apoptosis.
If it does encounter an autoreactive T cell, as long as the autoreactive T cell is anergized, the naive autoreactive B cell will not get activated.
Suppression (peripheral tolerance)
———– T cell are specialised ———- T cells that are not —– selected in the thymus.
If ———— T cells encounter self antigen on APC they can ——– surrounding ——– T cells by producing inhibitory ——- like —– and ——.
Regulatory T cell (Treg) are specialised autoreactive T cells that are not negatively selected in the thymus.
If regulatory T cells encounter self antigen on APC they can inhibit surrounding autoreactive T cells by producing inhibitory cytokines like IL-10 and TGF-B.
Ignorance - sequestered antigen release
This is when you have —– —- that have the potential to drive an ———- response that never engage with the ——– immune system because they are ———- to immunologically ———— sites in the body
Immunologically ———- sites can tolerate the introduced ——–.
This is in the eyes, testes, placenta, fetus and parts of the CNS.
Diseases can occur when you get trauma at these sites that causes the release of ——- that then go onto engage with the ———- immune system.
Example - Sympathetic Ophthalmia
Trauma to one eye results in the release of ———- intraocular protein ——. The released —— are carried to the —— —– and activates —- cells. ———- – cells return via the —— and encounter —— in both eyes.
This is when you have self antigen that have the potential to drive an autoimmune response that never engage with the adaptive immune system because they are serquestered to immunologically privileged sites in the body
Immunologically privileged sites can tolerate the introduced antigens.
This is in the eyes, testes, placenta, fetus and parts of the CNS.
Diseases can occur when you get trauma at these sites that causes the release of antigen that then go onto engage with the adaptive immune system.
Example - Sympathetic Ophthalmia
Trauma to one eye results in the release of serquestered intraocular protein antigens. The released antigens are carried to the lymph nodes and activates T cells. Effector T cells return via the bloodstream and encounter antigens in both eyes.
