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The worst type of primary immunodeficiency
is SCID (severe combined immunodeficiency).
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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.
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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.
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There is a complete and total
failure of T-cell development.
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It affects approximately one child
in every 80,000 live births.
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There are severe defects in both
cellular and humoral immunity.
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The result is severe and recurrent viral,
bacterial and fungal opportunistic infections.
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And unfortunately without treatment, this
condition is fatal within the first year of life.
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Although there are a number of
treatments that are available.
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And the key thing about SCID is that
there is a complete absence of T-cells.
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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.
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But the common theme is there
is always a absence of T-cells.
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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.
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There are B-cells present,
but there are no NK cells.
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So this is referred to as T negative,
B positive, NK negative SCID.
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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.
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In other words, those children will totally lack
T-cells and B-cells, but they do have NK cells.
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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.
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In other words, there are no T-cells,
but there are B-cells and NK cells.
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And then the most severe of the severe
immunodeficiency is the ADA and AK2 gene defects.
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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.
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The γC defect and JAK3 defects, account
for approximately 50% of SCID cases.
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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.
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And they all use JAK3
as a signaling molecule.
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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.
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All six using both the γC common chain of
the receptor, and JAK3 signaling molecule.
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So there’s no signaling from any
of these six different cytokines,
and that leads to this severe combined immunodeficiency.