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Autoimmunity
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in depth highly detailed immunology notes. includes extra reading as-well as the basic lecture material
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AUTOIMMUNITY.Central tolerance.
Autoimmunity- what happens when very tightly controlled processes within the
adaptive immune response, something goes wrong, and we get non-specific
activation of our B or T cells which drive very pro-inflammatory aggressive adaptive
response, which can ultimately lead to the production of autoantibodies.
The adaptive immune response, just like the innate immune response is a very
tightly controlled series of cell-cell interactions, that requires lots of soluble
molecules, surface receptors and the ability of those cells to traffic around the body
in order to drive forward a very synchronized series of steps leading to the
production of antibodies so that we can clear invading pathogens.
For the adaptive response it is important that we only produce T and B cells, these
have receptors on their surface which they use to recognize the pathogens.
We have to be able to produce these cells that don’t contain or express receptors
which recognize self proteins.
If we release T or B cells into the periphery, which had receptors on their surface
which could recognize self tissues then these cells would be constantly being
activated by binding to their peptide or ligand and driving constant bouts of pro-
inflammatory cycles leading to what would eventually become a very pro-
inflammatory state.
Because those T cells would constantly be activated as their ligand or antigen is
constantly being expressed in the body.
One of the most important mechanisms that has been described before:
The adaptive response has to have a series of very controlled checkpoints which
allows deletion of cells which recognize self proteins.
Example:
Development of T cells within thymus.
Central tolerance: process where newly forming T cells are tested for their ability to
bind self proteins.
And if those T cells that recognize self proteins are found then they are given
apoptosis signals and deleted straight away.
So, if you are a member in the thymus, or a developing T cell, upregulates a newly
formed T cell receptor and it undergoes two major checks.
The first is if the T cell receptor is functional
The second process, this mega selection- can that T cell receptor recognize self
peptides.
If it does recognize those self peptides, you will get tight binding of that T cell
receptor to that particular peptide being expressed by MHC molecules within the
thymus and those T cells will be deleted and removed so they cannot be released
into the periphery and therefore we only allow export of newly formed T cells which
have T cell receptors which only recognize non-self proteins/peptides.
This way we make sure that we only release cells into the periphery that will only be
activated upon exposure to foreign invading pathogens and cannot be accidently
activated by binding to a self protein or peptide that the host normally expresses.
, This is important for producing functionally efficient T cells, to be released into the
periphery and maintain our tissue homeostasis so we don’t accidently activate them
driving inflammation.
B cell central tolerance.
Similar process of central tolerance also occurs for B cells.
This time it is happening in our bone marrow as our B cells are developing from B cell
progenitors.
The same B cell progenitors have to mutate and recombine genes to form new B cell
receptors on their surface.
Similarly, to T cells, newly formed B cell receptors are tested for their ability to bind
to self antigens, and this time if they do bind to self antigens then the receptor itself
is reedited and remutated so that it forms a new variant of that B cell receptor,
which we tested.
And this time if it does not recognize self –antigens it can be released into the
periphery.
These very important cells for the adaptive immune response have a mechanism of
making sure that they only release these cells into the periphery if they do not
recognize self-proteins and self-antigen.
Peripheral tolerance- CTLA-4 expression on Tregs.
There is a second major type of tolerance: peripheral tolerance.
This requires a very specific population of T cells, called regulatory T cells within the
peripheral tissues.
These T cells have the ability to recognize or bind to self-antigens on the surface of
antigen presenting cells with mild affinity.
But if they bind to these self-proteins or peptides being expressed by antigen
presenting cells and they recognize the T cell interacting on that same antigen
presenting cell, then the regulatory T cell has the ability to strip of co-stimulatory
molecules from the antigen presenting cell, this means any T cell interacting with
that antigen presenting cell which has the potential to bind self peptide no longer
can get that second co-stimulatory signal that is required to fully activate the T cell.
So instead that T cell will be binding to that antigen presenting cell only through its T
cell receptor, that one signal needs to anergy and subsequent deletion of that T cell.
In the video above, the antigen presenting cells are in green, the regulatory T cells
are in red.
The regulatory T cell is starting to pull of from the surface of the antigen presenting
cell and taking it away.
In this case, these are CTLA-4 molecules, labelled with a green dye.
And it is stripping off those co-stimulatory molecules from the surface of the antigen
presenting cell, preventing that secondary signal to prevent the activation of that T
cell that may go on to form activation against cell proteins.
So we have central and peripheral tolerance mechanisms to try and make sure our
adaptive immune response is kept in check and is only responsible for activation on
exposure to foreign peptides from foreign pathogens.
Autoimmunity.
, We get cases where we get a breakdown on these tolerance mechanisms.
We can get leakage of T cells and B cells into the periphery, that may have a mild
affinity or a stronger affinity for self peptides.
This can subsequently be activated by this peptide within various tissues or organ
and that drives activation of an adaptive response and subsequent inflammation,
this can also ultimately lead to the production of antibodies.
So if the T cells are being activated against the self –peptide, if it finds a B cell which
it interacts with through that T cell-B cell interaction, you might subsequently
generate autoantibodies and that can lead to a persisting chronic disease.
Autoimmunity is the result of a loss of the mechanisms of tolerance and it can
happen in the thymus to release the autoreactive T cells or release of autoreactive B
cells from the bone marrow.
Or we can get defects in the regulatory T cell populations in the periphery so we
loose peripheral tolerance allowing activation of T cells with antigen presenting cells.
Autoimmunity concerns the adaptive arm of the immune system, which will mainly
be T cell driven.
It is the breakdown in our ability to remove B and T cells which recognise self
peptides.
So they're ability to subsequently be activated by self proteins leads to this
imbalance in subsequent autoimmune condition.
Autoimmune diseases can be categorised.
We can breakdown different autoimmune diseases depending on the cell type that is
involved or the organ where this particular reaction can occur in.
It is either a B cell mediated disease or a T cell mediated disease.
But it can also be broken down in which particular organ or anatomical location, this
autoimmune disease is occurring in.
For example, it can be organ or tissue specific, for example in diabetes where we get
an autoimmune reaction in the pancreas, leading to loss of insulin producing cells.
Or it can be systemic, if we have a release of a T or B cell, which recognises a widely
expressed protein then we can get activation of these cells throughout the body.
So it really depends on what the self antigen is that is being expressed or being
recognised by the T and B cell populations.
Is it restricted to one specific tissue.
Or is it spread throughout the body.
Autoimmune conditions are becoming common within the population.
Roughly 3% of the population have some form of an autoimmune disease.
Because they are unregulated inflammation driven by the adaptive response, they
are often described as being chronic in terms of, they never switch off, they are
always on. This leads to cystic fibrosis and loss of tissue function.
These disease can be very debilitating as they can lead to loss of mobility and
skeletal diseases, or specific loss in individual organs, such as kidney failure or in
diabetes a loss of insulin in the pancreas.
They have very big impacts on their hosts, driven by this lack of tolerance and driving
through recognition by our own immune cells.
Autoimmune disease have different frequencies in the population.
The frequency of these cells, varies greatly within the population.
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