00:01
At the heart of the development of autoimmune disease
is a breakdown in immunological tolerance.
00:06
In fact, the immunological tolerance mechanisms
have evolved to prevent harmful autoimmunity.
00:14
Whilst T-cells are developing in the thymus and B-cells are
developing in the bone marrow, they
can undergo central tolerance.
Recognition of self antigen in these
primary lymphoid organs can lead
to apoptotic cell death, with
deletion of those particular cells.
00:34
Or in the case of B-cells, there is also the possibility for
the B-cell to change the specificity of its antigen receptor.
00:43
This is referred to
as receptor editing.
00:47
And regulatory lymphocytes can develop that
can suppress unwanted autoimmune responses.
00:54
Central tolerance is not 100% efficient, so it is backed
up with a number of peripheral tolerance mechanisms.
01:05
These can involve the induction of anergy, non-responsiveness in
lymphocytes when antigen is seen
in the absence of co-stimulation.
01:16
Usually during an infection, co-stimulatory molecules
such as CD80 and CD86 are up-regulated on dendritic cells.
01:25
But when autoantigens are being
shown to lymphocytes by dendritic
cells, there is no co-stimulation and this results in anergy.
01:36
Apoptosis can also occur as a
mechanism of peripheral tolerance.
01:41
And finally suppressor cells can suppress
these responses in the periphery.
01:47
An important discovery a few years ago was that in the thymus,
there is a transcription factor called the autoimmune regulator.
01:59
The function of AIRE, the autoimmune regulator
is to cause expression of what are normally
tissue-restricted antigens so that these antigens are
also expressed in the thymus to facilitate tolerance.
02:17
There will be negative selection
of the self-reactive T-cells and
apoptotic cell death leading to
deletion of those autoreactive T-cells.
02:29
In the absence of AIRE which can occur due to
mutations, individuals will fail to delete tissue
specific T-cells resulting in autoimmunity and
this can lead to pathology - autoimmune disease.
02:52
In fact, autoimmunity is not
in itself necessarily harmful.
02:59
If I was to take some blood from you and use a sensitive
enough assay, I would find autoantibodies in your circulation.
03:05
We all have some level
of autoimmunity.
03:09
But in most of us it is not
pathological, it doesn’t cause disease.
03:14
So a low level of autoimmunity
seems to be the norm.
03:18
Now whether that’s a kind of just noise in the
system if you like, or whether there is actually some
physiological function of autoantibodies in getting rid
of dead and dying cells is still a matter of debate.
03:31
But just beware that autoimmunity
does not equal autoimmune disease.
03:37
Clearly you have to have autoimmunity
in order to develop autoimmune
disease, but 95% of people don’t develop autoimmune disease.
03:46
But virtually all of us have
some level of autoimmunity.
03:50
So why is it that in around about 5% of individuals,
this normal autoimmunity becomes pathogenic?
Well it’s a mixture of genetic factors,
environmental factors such as infections.
04:05
And other environmental factors such as
diet and stress and so forth, that lead to a
breakdown of tolerance which affects the T-cells
and B-cells that are potentially pathogenic.
04:19
And that breakdown in tolerance
affecting those particular clones of
T and B-cells can precipitate the
development of autoimmune disease.