Severe Combined Immunodeficiency (SCID) – Primary Immunodeficiency

00:01 The worst type of primary immunodeficiency is SCID (severe combined immunodeficiency).

00:10 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.

00:18 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.

00:34 There is a complete and total failure of T-cell development.

00:41 It affects approximately one child in every 80,000 live births.

00:50 There are severe defects in both cellular and humoral immunity.

00:56 The result is severe and recurrent viral, bacterial and fungal opportunistic infections.

01:04 And unfortunately without treatment, this condition is fatal within the first year of life.

01:09 Although there are a number of treatments that are available.

01:13 And the key thing about SCID is that there is a complete absence of T-cells.

01:19 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.

01:30 But the common theme is there is always a absence of T-cells.

01:33 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.

01:46 There are B-cells present, but there are no NK cells.

01:51 So this is referred to as T negative, B positive, NK negative SCID.

01:57 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.

02:12 In other words, those children will totally lack T-cells and B-cells, but they do have NK cells.

02:19 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.

02:35 In other words, there are no T-cells, but there are B-cells and NK cells.

02:39 And then the most severe of the severe immunodeficiency is the ADA and AK2 gene defects.

02:49 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.

03:01 The γC defect and JAK3 defects, account for approximately 50% of SCID cases.

03:17 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.

03:39 And they all use JAK3 as a signaling molecule.

03:44 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.

04:03 All six using both the γC common chain of the receptor, and JAK3 signaling molecule.

04:11 So there’s no signaling from any of these six different cytokines, and that leads to this severe combined immunodeficiency.