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1032 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1033

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Myeloperoxidase Deficiency undergoing degradation in a proteasome. In this way, the quality con-
The functional and immunochemical absence of the enzyme MPO from trol system operating in the endoplasmic reticulum retrieves misfolded
granules of neutrophils and monocytes, but not eosinophils, is inherited MPO precursors from the biosynthetic pathway and creates the bio-
as an autosomal recessive trait, with a prevalence of 1:2000. MPO, an chemical phenotype of MPO deficiency. In another patient, a missense
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enzyme that catalyzes the production of HOCl in the phagosome. In mutation resulted in an intact MPO molecule that acquired heme but
MPO deficiency, the microbicidal activity of the neutrophils is reduced failed to undergo proteolytic processing to a mature molecule.
early after ingestion of microorganisms (see Table 66–2). However, Acquired disorders are associated with MPO deficiency. Reported
normal microbicidal activity is observed in approximately 1 hour after states include lead intoxication, ceroid lipofuscinosis, myelodysplastic
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a variety of organisms are ingested. Thus, the MPO-deficient neu- syndromes, and acute myelogenous leukemia. One-half of untreated
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trophil uses an MPO-independent system for killing bacteria that is patients with acute myelogenous leukemia and 20 percent of patients
slower than the MPO–H O –halide system, but that is eventually effec- with CML may have MPO deficiency. 442
2
2
tive in eliminating bacteria. MPO-deficient neutrophils accumulate
more H O than do normal neutrophils; the higher peroxide concen- Deficiencies of Glutathione Reductase and Glutathione
2
2
tration improves the bactericidal activity of the affected neutrophils. In Synthetase
contrast to the retardation of bactericidal activity, candidacidal activity Neutrophils contain enzymes capable of inactivating potentially dam-
in MPO-deficient neutrophils is absent. The most significant clinical aging reduced oxygen byproducts. Disposal of superoxide anion is
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manifestation in a few patients with diabetes mellitus and MPO defi- accomplished through superoxide dismutase, a soluble enzyme that
ciency has been severe infection with C. albicans. Because this is such converts superoxide to a H O . H O is detoxified by catalase and by the
2
2
2
2
a common disorder of phagocytes, it is important to note that the vast glutathione peroxidase–glutathione reductase system, which converts
majority of patients with this genetic disorder have not been unusually H O to water and oxygen. In addition to the soluble enzymes, cellular
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2
2
susceptible to pyogenic infections and do not require therapy. vitamin E serves as an antioxidant to prevent damage to the surface of
The complementary DNA encoding human MPO has been cloned activated neutrophils when releasing H O . Single cases of profound
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2
and the gene structure, including promoter and regulatory elements, deficiencies in glutathione reductase and glutathione synthetase
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delineated. The gene consists of 12 exons and 11 introns and is located have been associated with impaired neutrophil bactericidal activity (see
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on the long arm of chromosome 17, and its expression is finely coor- Table 66–2). Both deficiencies are associated with hemolysis under con-
dinated with expression of genes encoding other lysosomal proteins. ditions of oxidative stress (Chap. 48). Glutathione synthetase deficiency
Expression of genes for human neutrophil elastase and MPO is very also has been associated with intermittent neutropenia during times of
similar; it is low in myeloblasts, peaks during the promyelocyte stage, mild infection. Vitamin E has been employed to ameliorate the hemo-
and eventually drops to low levels in myelocytes. MPO is a symmet- lysis and improve neutrophil function in a patient with glutathione
ric molecule composed of four peptides, where each half consists of a synthetase deficiency. Like patients with MPO-deficient neutrophils,
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heavy- and a light-chain heterodimer. Each heavy- and light-chain the patients with glutathione reductase deficiency and glutathione syn-
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heterodimer starts as a single peptide that is cleaved during the post- thetase deficiency are not unusually susceptible to bacterial infections.
translational process to yield the heavy and light chains that form half
of the mature molecules. The two halves of the molecule are associated
by a disulfide linkage between heavy-subunit residues at their residue DIAGNOSTIC APPROACH TO
C319.
The primary translation product of the gene is a single-chain THE PATIENT WITH SUSPECTED
peptide of 80 kDa that undergoes cotranslational glycosylation at sev- NEUTROPHIL DYSFUNCTION
eral asparagine residues, followed by a series of modifications of these
oligosaccharides. The apopromyeloperoxidase exists for a prolonged An increased susceptibility to pyogenic infections must be viewed
time in the endoplasmic reticulum, where it associates reversibly with in light of a number of factors: (1) adequacy of host defense; (2) the
several endoplasmic reticulum–resident proteins known as molecular microbes to which the host is exposed; and (3) the conditions of the
chaperones. Subsequent to heme insertion, the enzymatically active exposure. It is not always easy to establish a diagnosis of a specific neu-
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promyeloperoxidase undergoes proteolytic cleavage of the pro region. trophil dysfunction on clinical grounds alone. Patients with recurrent
Then, in a prelysosomal compartment, the single peptide is cleaved into pyogenic infections often yield no clues as to why they are afflicted, and
the heavy and light subunits, which remain linked. During final sorting patients with established deficiency of a defense mechanism may have
within the azurophil lysosome compartment, there is dimerization of an unimpressive clinical history. On the other hand, patients may be
half-molecules to form the mature MPO. suspected of having a neutrophil dysfunction if they have a history of
Most patients with MPO deficiency have a missense mutation in frequent bacterial or severe infections. Recurrent pulmonary infections,
the gene that results in replacement of arginine 569 with tryptophan. hepatic abscesses, and perirectal abscesses also should alert the clini-
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The mutation results in a precursor that associates with molecular cian to consider further diagnostic evaluation of neutrophil function.
chaperones, but does not incorporate heme, resulting in a maturational For example, the identification of unusual catalase-positive bacteria and
arrest during processing at the stage of an inactive enzymatic apopro- fungi, such as B. cepacia, S. marcescens, Nocardia, and Aspergillus, could
myeloperoxidase. Other patients are heterozygotes with one allele bear- be indicative of CGD.
ing the common mutation and the other being normal, resulting in a Because many of the tests of neutrophil function are bioassays with
partial deficiency. To date, four genotypes have been reported to cause great variability, the results of the tests must be interpreted in light of the
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inherited MPO deficiency, each of which results in missense mutations. patient’s clinical condition. For instance, isolated chemotactic defects
In the genotype Y173C, a missense mutation results in replacement of usually do not explain the propensity for a patient to have recurrent
a tyrosine at codon 173 with a cysteine residue resulting in the mutant severe infections. Furthermore, variation in bioassays is often intensi-
precursor being retained in the endoplasmic reticulum by virtue of fied by inflammation or infection. Figure 66–8 is an algorithm for eval-
its prolonged interaction with the chaperone calnexin, and eventually uation of the patient with recurrent infection.

Kaushansky_chapter 66_p1005-1042.indd 1033 9/21/15 10:48 AM