00:01
So there’s a genetic susceptibility,
in the vast majority of cases.
00:07
This is many different genes acting
together resulting in a failure
of self tolerance and the development
of self reactive lymphocytes.
00:17
Coupled with these multiple genetic factors, are environmental
stimuli such as tissue injury,
inflammation, infection and so on.
00:26
This can lead to the activation of
tissue antigen presenting cells.
00:31
And these antigen presenting cells can activate
self reactive lymphocytes, which then become self
reactive effector lymphocytes that are actually
going to carry out the damage that is occurring.
00:45
There’ll be tissue injury, and the
result will be autoimmune disease.
00:50
So let's have a look at some of the
genes that have been implicated.
00:55
In animal studies, it’s quite clear
that maybe in a given autoimmune
disease, perhaps as many as 20 or
30 different genes can contribute.
01:06
And the genes that have been identified
both in animal studies and in human
patients include the following - The
MHC is nearly always implicated.
01:19
And the MHC of course is involved
in antigen presentation to T-cells.
01:25
And this is a gene that virtually all
polygenic autoimmune diseases, which
is 99% of autoimmune diseases, have a
MHC influence on their development.
01:38
CTLA4 which is a molecule that you find on
the surface of T-cells, and actually acts
as a kind of negative regulator of T-cells,
and stops excessive T-cell responses.
01:52
This gene or polymorphisms of this
gene have been implicated in thyroid
autoimmune diseases, in type I
diabetes and in rheumatoid arthritis.
02:04
A molecule called PTPN22, which is involved in antigen receptor
signaling has also been implicated in those particular diseases.
02:16
In other words, thyroid autoimmune disease,
type I diabetes and rheumatoid arthritis.
02:21
Polymorphisms of complement
components, particularly C1q, C2 and
C4 are involved in the development
of systemic lupus erythematosus.
02:35
Meanwhile, polymorphisms in the interleukin-2 gene;
interleukin-2 is involved in stimulating lymphocytes.
02:42
This gene is implicated in rheumatoid arthritis,
type I diabetes and multiple sclerosis.
02:49
Another cytokine, in this case an
immunosuppressive cytokine IL-10.
02:54
Polymorphisms of the IL-10 gene have been
implicated in SLE and type I diabetes.
03:02
And the BLK molecule involved in B-cell signaling has also
been implicated in SLE as well as in rheumatoid arthritis.
03:11
So this is just a few examples of many genes that have
been implicated in the development of autoimmune diseases.
03:19
Let’s have a look at some of the MHC
associations in autoimmune disease.
03:25
Looking at MHC Class I, in this example
we can see that individuals that are
HLA-B8 have a relative risk of three for
the development of myasthenia gravis.
03:39
This means that if an individual happens
to be HLA-B8 rather than other HLA-B
variants, they are three times more
likely to develop myasthenia gravis.
03:52
So for example, this individual may be HLA-B6
and B8, and they would be three times more
likely to develop myasthenia gravis than somebody
that was for example HLA-B1 and HLA-B14.
04:08
Ankylosing spondylitis - the relative
risk is 87 for individuals with HLA-B27.
04:17
So a huge relative risk.
04:22
Let me share a little bit of confidential
medical information with you.
04:26
I know that I am HLA-B27, but I
don’t have ankylosing spondylitis.
04:33
In fact only around about 10% of individuals
that are HLA-B27 develop ankylosing spondylitis.
04:41
So although the relative risk is really
pretty high, you need other genes and
you need environmental factors in order
to develop ankylosing spondylitis.
04:51
So it’s an important contributory factor, but
it requires several other contributory factors
for the disease process to occur and for the
individual to develop ankylosing spondylitis.
05:02
So 90% of individuals that are HLA-B27
positive do not develop ankylosing spondylitis.
05:09
Turning to MHC Class II, these genes are also
implicated in the development of autoimmune disease.
05:14
So for example, individuals with Hashimoto’s
disease, an autoimmune disease of the thyroid
gland, HLA-DR5 is more commonly seen in these
individuals, giving a relative risk of three.
05:28
In type I diabetes, HLA-DQ8
confers a relative risk of 14.
05:35
If an individual has both HLA-DQ8 and
HLA-DQ2, the relative risk goes up to 20.
05:45
Some MHC genes are actually
protective against autoimmune disease.
05:51
And here we see an example where
DQ6 gives a relative risk of 0.2
In other words, an individual that has HLA-DQ6 is
protected against the development of type I diabetes.
06:06
One of the non-genetic factors that has been implicated
in the development of autoimmune disease is infection.
06:14
Usually, encounter with self antigens will lead to tolerance,
because there is an absence of co-stimulatory molecules.
Here we see a resting dendritic cell
that isn’t expressing CD80 and CD86 at
any great level, and therefore will not
provide co-stimulation to the T-cell.
And this will result in self
tolerance usually by anergy.
However, microorganisms contain Pathogen
Associated Molecular Patterns that
will be recognized by the Pattern
Recognition Receptors on dendritic cells.
06:53
And that recognition will cause the up-regulation
of co-stimulatory molecules on the dendritic cell.
07:00
For example the B7 molecules, B7.1
CD80, B7.2 CD86.
07:06
These will interact with the molecule CD28 on the surface
of the T-cell causing this self reactive T-cell to become
activated leading to autoimmunity, which in some cases may
be pathogenic autoimmunity, leading to autoimmune disease.
07:24
There are a number of ways in which infection may
lead to the development of autoimmune disease.
07:31
One of them is a phenomenon
referred to as molecular mimicry.
07:37
This is caused by a sharing of either structures or
sequence between self antigens and microbial antigens.
07:47
So here we have a self reactive T-cell that is
also capable of recognizing a microbial peptide,
because there’s a sequence in the microbial peptide
that is similar to a sequence in a self antigen.
08:01
Therefore there will be activation
of T-cells due to this sharing
of sequence between the microbial protein and the self protein.
08:10
So the peptide sequence sitting in the MHC
will be the same between the microbe and self.
08:17
So a normal immune response if you like,
is developed against an infection.
08:22
But unfortunately, some self peptides
have the same sequence and therefore
the T-cells will recognize not only
the foreign microbial proteins
but also self proteins again leading
to the development of autoimmunity
which in some cases may be pathogenic
and lead to autoimmune disease.