The worst type of primary immunodeficiency
is SCID (severe combined immunodeficiency).
The title tells it all,
doesn’t it really?
It’s severe and it’s combined because it
affects not only T-cells but also B-cells.
It’s due to mutations in one of a number of different genes
involved in controlling cytokine signaling, or T-cell
receptor signaling, or VDJ recombination of the
immunoglobulin and T-cell receptor genes, or in metabolism.
There is a complete and total
failure of T-cell development.
It affects approximately one child
in every 80,000 live births.
There are severe defects in both
cellular and humoral immunity.
The result is severe and recurrent viral,
bacterial and fungal opportunistic infections.
And unfortunately without treatment, this
condition is fatal within the first year of life.
Although there are a number of
treatments that are available.
And the key thing about SCID is that
there is a complete absence of T-cells.
There are a number of different genes that
can cause SCID, and the particular genes that
are involved will determine exactly which
cell types are absent in the immune response.
But the common theme is there
is always a absence of T-cells.
So if there’s a gene defect in the
γC component of the interleukin
receptors or in JAK3, the result is that there are no T-cells.
There are B-cells present,
but there are no NK cells.
So this is referred to as T negative,
B positive, NK negative SCID.
In contrast, if there is mutation in those
other genes that you can see listed there,
RAG1, RAG2 and so forth, then the result is
T negative, B negative, NK positive SCID.
In other words, those children will totally lack
T-cells and B-cells, but they do have NK cells.
The third group of genes that you can see there,
the interleukin-7 receptor α-chain, CD3δ and so
forth; defects in those genes will result in the T
negative, B positive, NK positive phenotype of SCID.
In other words, there are no T-cells,
but there are B-cells and NK cells.
And then the most severe of the severe
immunodeficiency is the ADA and AK2 gene defects.
So defects in those two genes, will result in an absence of
T-cells, an absence of B-cells and an absence of NK cells.
The γC defect and JAK3 defects, account
for approximately 50% of SCID cases.
This results in an inability to
signal through six different interleukin
receptors, because those receptors all use the γC-chain
of the interleukin receptors; it’s called γC, the C stands for
Common, it’s common to six different interleukin receptors.
And they all use JAK3
as a signaling molecule.
And these six receptors are the interleukin-2 receptor,
the interleukin-4 receptor, the interleukin-7
receptor, the interleukin-9 receptor, interleukin-15
receptor, and finally the interleukin-21 receptor.
All six using both the γC common chain of
the receptor, and JAK3 signaling molecule.
So there’s no signaling from any
of these six different cytokines,
and that leads to this severe combined immunodeficiency.