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.
The lecture Phagocytic Cell Disorders – Primary Immunodeficiency by Peter Delves, PhD is from the course Immunodeficiency and Immune Deficiency Diseases. It contains the following chapters:
X-linked chronic granulomatous disease (XL-CGD) arises due to mutations in which of the following genes?
Which of the following conditions is caused by mutations in the lysosomal trafficking regulator (LYST) gene?
Which of the following defects causes leukocyte adhesion deficiency type 3?
Chediak-Higashi syndrome most strongly affects which types of immune cells?
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