There are a number of gene defects that can affect
phagocytic cells, and these are listed here.
Defective genes for components of the NADPH oxidase
can result in chronic granulomatous disease.
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.
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.
And then a defect in the LYST gene leads to
the disorder called Chediak-Higashi syndrome.
And a range of Staphylococci and Streptococci, and other
species are seen with an increased incidence in this condition.
Let’s have a look in a little bit more
detail at chronic granulomatous disease.
In the vast majority of patients,
this is due to a defect in subunits of
the nicotinamide adenine dinucleotide
phosphate oxidase, the NADPH oxidase.
It affects monocytes,
macrophages and neutrophils.
And they fail to produce reactive oxygen intermediates
that are required to kill engulfed microorganisms.
The NADPH oxidase consists of a number of
different subunits as you can see here.
The function of this oxidase is to produce reactive oxygen
species that are involved in killing engulfed microorganisms.
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.
The genes for the other components of the NADPH oxidase are
found on the non-sex chromosomes, in other words, the autosomes.
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.
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.
This leads to a similar but less
severe phenotype in these patients.
Turning now to leukocyte adhesion deficiency;
as we’ve already heard, there are three types.
LAD type I is due to a lack of the
CD18 β subunit of the β2 integrins.
LAD type II is due to defective GDP-fucose transporter, and
therefore an inability to fucosylate sialyl Lewis structures.
Whereas LAD type III is due to a mutation in
the integrin activation molecule, kindlin 3.
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.
In Chediak-Higashi syndrome, there’s a defect
in the LYST (lysosomal trafficking) gene.
There’s an accumulation of giant
This is due to defective migration of
the late endosomal/lysosomal compartment
within the cell, which interferes with
the correct function of these cells.
There is dysfunction of neutrophils, of natural
killer cells, and of cytotoxic T-cells.
And here we can see a neutrophil with
these giant granules accumulating
within the cell, and this compromises the function of the cell.
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.
Patients suffer from a range of pyogenic
infections, particularly with Staph aureus,
Strep pyogenes, Pneumococci, Aspergillus
species and Pseudomonas aeruginosa.