Rather paradoxically, some primary immunodeficiencies
are associated with autoimmune disease.
Autoimmune disease is where the immune system starts
reacting in a harmful way against our own body components.
So it’s an overreaction of the
immune response if you like.
But we’re discussing immunodeficiency at the
moment, so it’s rather odd isn’t it, that a
immunodeficiency can lead to an excessive or
unwanted immune response against self antigens?
But that is the case.
Mutations in Foxp3 result in IPEX (immune dysregulation
polyendocrinopathy, enteropathy, X-linked) syndrome.
And that is because Foxp3 is a transcription factor
that’s required for the activity of regulatory T-cells.
And what regulatory T-cells do is
they suppress autoimmune responses.
So in the situation we have here, there’s
a mutation in the gene encoding Foxp3.
There’s no Foxp3 produced, so you don’t
have any regulatory T-cell activity.
So there’s unregulated T-cell activity leading to
multisystemic and often fatal autoimmune disease.
There’s no regulatory T-cells to suppress the
other potentially pathogenic autoimmune T-cells.
There can be other gene defects
that result in autoimmune disease.
Mutations in AIRE can result in
autoimmune polyendocrine syndrome-1.
AIRE is the autoimmune regulator.
What the autoimmune regulator does, is it causes expression of
genes that normally would be restricted to an individual tissue.
For example, a gene that perhaps you’d
only ever see in the pancreas, or
you’d only ever see in the thyroid,
because it needs to do a specific job.
The protein product needs to do
a particular job and that’s only
required in the pancreas, perhaps involved in making insulin.
But in order to get negative selection of T-cells in the
thymus, these genes also need to be expressed in the thymus.
And the AIRE gene is involved in that.
So in the absence of the AIRE gene,
there’s no expression of these normally
tissue restricted genes in the thymus,
and there’s no negative selection.
This could end up with giving conditions such as
the autoimmune polyendocrine syndrome-1 or APS-1,
sometimes referred to as APECED (autoimmune polyendocrinopathy
with candidiasis and ectodermal dystrophy).
And this results in defective
central tolerance of T-cells.
Fas, which is also known as CD95, and
Fas ligand which is also known as CD95
ligand mutations, can result in autoimmune
lymphoproliferaitive syndrome (ALPS).
This is due to defective