Phagocytic Cell Disorders – Primary Immunodeficiency

00:01 There are a number of gene defects that can affect phagocytic cells, and these are listed here.

00:08 Defective genes for components of the NADPH oxidase can result in chronic granulomatous disease.

00:18 And here we see a number of typical infections, with an increased instance and severity of disease with Staph aureus, Aspergillus fumigatus, Candida albicans and so on.

00:31 A defect in the CD18 β-subunit; CD18 is an integrin adhesion molecule, leads to leukocyte adhesion deficiency type I. We see an increased instance of pyogenic bacteria. In contrast, a defective gene for the GDP-fucose transporter leads to leukocyte adhesion deficiency or LAD II; again, with an increased incidence of pyogenic bacteria. Kindlin 3 deficiency leads to leukocyte adhesion deficiency type III, again with an increased incidence of pyogenic bacteria.

01:11 And then a defect in the LYST gene leads to the disorder called Chediak-Higashi syndrome.

01:17 And a range of Staphylococci and Streptococci, and other species are seen with an increased incidence in this condition.

01:27 Let’s have a look in a little bit more detail at chronic granulomatous disease.

01:32 In the vast majority of patients, this is due to a defect in subunits of the nicotinamide adenine dinucleotide phosphate oxidase, the NADPH oxidase.

01:42 It affects monocytes, macrophages and neutrophils.

01:48 And they fail to produce reactive oxygen intermediates that are required to kill engulfed microorganisms.

01:56 The NADPH oxidase consists of a number of different subunits as you can see here.

02:04 The function of this oxidase is to produce reactive oxygen species that are involved in killing engulfed microorganisms.

02:13 A defect in the gene encoding the gp91-phox component of the NADPH oxidase, is the X-linked form of this disease because that gene is present on the X chromosome.

02:29 The genes for the other components of the NADPH oxidase are found on the non-sex chromosomes, in other words, the autosomes.

02:37 And the autosomal recessive p22-phox, p47-phox, p40-phox or p67-phox variants of chronic granulomatous disease are caused by gene defects in these particular autosomal genes.

02:58 In a minority of patients, rather than having gene defects in components of the NADPH oxidase, there can be genetic mutations in the myeloperoxidase or glucose-6-phosphate dehydrogenase genes.

03:14 This leads to a similar but less severe phenotype in these patients.

03:21 Turning now to leukocyte adhesion deficiency; as we’ve already heard, there are three types.

03:29 LAD type I is due to a lack of the CD18 β subunit of the β2 integrins.

03:36 LAD type II is due to defective GDP-fucose transporter, and therefore an inability to fucosylate sialyl Lewis structures.

03:50 Whereas LAD type III is due to a mutation in the integrin activation molecule, kindlin 3.

03:58 So any one of these three gene defects, in different ways can lead to defective adhesion of leukocytes and compromise the ability to fight infection.

04:12 In Chediak-Higashi syndrome, there’s a defect in the LYST (lysosomal trafficking) gene.

04:19 There’s an accumulation of giant intracytoplasmic granules.

04:23 This is due to defective migration of the late endosomal/lysosomal compartment within the cell, which interferes with the correct function of these cells.

04:34 There is dysfunction of neutrophils, of natural killer cells, and of cytotoxic T-cells.

04:41 And here we can see a neutrophil with these giant granules accumulating within the cell, and this compromises the function of the cell.

04:50 Likewise, in the natural killer cell and in the cytotoxic T-cell, these large granules accumulate in the cytoplasm and interfere with the correct activity of the cell.

05:02 Patients suffer from a range of pyogenic infections, particularly with Staph aureus, Strep pyogenes, Pneumococci, Aspergillus species and Pseudomonas aeruginosa.