Myeloperoxidase deficiency

Myeloperoxidase deficiency
Classification and external resources
Hypochlorous acid is normally produced by myeloperoxidase
OMIM	254600
DiseasesDB	8662
eMedicine	ped/1530

Myeloperoxidase deficiency is a common genetic disorder featuring deficiency, either in quantity or function, of myeloperoxidase, an enzyme found in certain phagocytic immune cells, especially polymorphonuclear leukocytes.

It can appear similar to chronic granulomatous disease on some screening tests.

Presentation

Although MPO deficiency classically presents with immune deficiency (especially candida albicans infections), the majority of individuals with MPO deficiency show no signs of immunodeficiency.

The lack of severe symptoms suggest that role of myeloperoxidase in the immune response must be redundant to other mechanisms of intracellular killing of phagocytosed bacteria.

Patients with MPO deficiency have a respiratory burst with a normal nitro blue tetrazolium (NBT) test (positive result) because they still have NADPH oxidase activity, but do not form bleach due to their lack of myeloperoxidase activity. This is in contrast to chronic granulomatous disease in which the NBT test is 'Negative' due to the lack of NADPH oxidase activity (positive test result means there is NADPH oxidase activity, and Negative result means that there is no NADPH activity).

Pathophysiology

Normal function of myeloperoxidase

MPO, a heme-containing protein, is found in the azurophilic granules of neutrophils and in the lysosomes of monocytes in humans; however, monocytes contain only about a third of the MPO present in neutrophils. When neutrophils become activated during phagocytosis, they undergo a process referred to as a respiratory burst. This respiratory burst causes production of superoxide, hydrogen peroxide, and other reactive oxygen derivatives, which are all toxic to microbes. During respiratory bursts, granule contents are released into the phagolysosomes and outside the cell, allowing released contents to come into contact with any microbes present. Experiments conducted in the 1960s showed that MPO catalyzes the conversion of hydrogen peroxide and chloride ions (Cl) into hypochlorous acid.[1] Hypochlorous acid is 50 times more potent in microbial killing than hydrogen peroxide.

MPO also directly chlorinates phagocytosed bacteria; thus, the MPO-hydrogen peroxide-Cl system seems to have an important role in microbial killing. Although the exact mechanism by which microbial killing occurs is controversial, researchers are fairly certain that MPO is important for the process to optimally occur.

In addition to killing bacteria, the products of the MPO-hydrogen peroxide-Cl system are believed to play a role in killing fungi, parasites, protozoa, viruses, tumor cells, natural killer (NK) cells, red cells, and platelets. The MPO-hydrogen peroxide-Cl system is also believed to be involved in terminating the respiratory burst, because individuals with MPO deficiency have prolonged respiratory bursts. It may play a role in downregulating the inflammatory response by regulating NK cells, decreasing peptide binding to chemotactic receptors, and auto-oxidizing and inactivating products of polymorphonuclear leukocytes (PMNs), such as a1-proteinase inhibitor and chemotaxins.

Other functions of MPO include tyrosyl radical production and chlorination, generation of tyrosine peroxide, mediation of the adhesion of myeloid cells via b2-integrins, and oxidation of serum lipoproteins. MPO may have a role in atherosclerosis. Researchers have demonstrated that patients with stable coronary artery disease had an increased cardiovascular risk if plasma MPO levels were elevated.[2] A small study demonstrated that MPO deficiency may protect against cardiovascular disease.[3] MPO may also have a role in carcinogenesis and degenerative neurological diseases. The understanding of MPO biology remains incomplete; much more remains to be discovered.

Normal myeloperoxidase production

MPO is a dimeric molecule, consisting of a pair of heavy-chain and light-chain protomers and 2 iron atoms. MPO is encoded by a single gene located on band 17q22-23. The mature enzyme is synthesized from a single polypeptide product. Therefore, the expression of the gene and the synthesis of MPO primarily occurs during the promyelocytic stage of myeloid development, concurrent with development of the azurophilic granules. The MPO gene encodes for a primary translational product, which is glycosylated to yield an enzymatically inactive precursor, apopro-MPO.

Apopro-MPO reversibly binds to chaperone proteins, calreticulin and calnexin, during protein maturation. This results in the subsequent binding of heme.[4] Heme insertion induces conformational changes in the protein yielding pro-MPO, an enzymatically active precursor.[5] Pro-MPO undergoes several complex conversions and eventually becomes mature MPO in the azurophilic granules, but the exact mechanisms are still poorly understood.

MPO should be distinguished from eosinophilic peroxidase (EPO), a different enzyme produced by a different gene. Although patients with MPO deficiency have decreased MPO activity in the neutrophils and monocytes, these patients usually have normal levels of EPO in eosinophils.

Pathophysiology of hereditary myeloperoxidase deficiency

Hereditary MPO deficiency was initially thought to follow the classic autosomal recessive pattern. A number of genetic mutations resulting in MPO deficiency have been identified, and many others may still be undiscovered. Researchers now believe that most patients are compound heterozygotes, which means that they have a different mutation on each allele, one from each parent. As with several other genetic diseases, numerous allele combinations can lead to the phenotype of MPO deficiency, which partially explains the variability of clinical features. Some mutations result in posttranslational defects; others (which are not yet clearly defined) seem to cause pretranslational defects, possibly due to structural alterations in the regulatory parts of the MPO gene. See Causes for a discussion of individual mutations that have been identified and their effects.

Some authors have proposed a bigenic model involving the interaction of 2 genes, such as a production gene and a regulatory gene. Overall, the genetic basis of this condition is now thought to be quite heterogeneous and complex. Undoubtedly, much remains to be discovered.

Pathophysiology of acquired myeloperoxidase deficiency

MPO deficiency in acquired cases is usually transient and generally resolves once the inciting condition improves. In addition, acquired MPO deficiency is usually partial and involves only a fraction of the PMNs.[6] The following conditions can lead to acquired MPO deficiency:

Pregnancy

Lead intoxication - Inhibits heme synthesis (a component of mature MPO) Iron deficiency Severe infection - Secondary to PMN activation and "consumption" of MPO Thrombotic diseases Renal transplantation Diabetes mellitus Neuronal lipofuscinosis Drugs - Cytotoxic agents and some anti-inflammatory agents such as dapsone, 5-aminosalicylic acid, and sulfapyridine Disseminated cancers - Probably related to administration of cytostatic agents Several hematologic disorders and neoplasms especially those involving the maturation of granulocytes: Acute myeloid leukemia (AML) Chronic myeloid leukemia (CML) Polycythemia vera Hodgkin disease Refractory megaloblastic anemia Aplastic anemia Myelofibrosis with myeloid metaplasia Myelodysplastic syndromes Microbial killing in myeloperoxidase deficiency MPO-deficient neutrophils are normally able to phagocytose most microbes. However, the ability of MPO-deficient neutrophils to kill bacteria seems impaired to varying degrees. For organisms such as Staphylococcus aureus, Serratia species, and Escherichia coli, killing is initially impaired but then reaches normal levels after a period of time. This suggests that an apparently slower, alternative mechanism of killing can take over in MPO-deficient neutrophils.

The capacity to kill certain fungi, however, seems completely absent in MPO-deficient neutrophils. In vitro studies have shown that Candida albicans, Candida krusei, Candida stellatoidea, and Candida tropicalis cannot be killed by MPO-deficient PMNs. In contrast, an MPO-independent mechanism can kill Candida glabrata, Candida parapsilosis, and Candida pseudotropicalis. Even more interesting is that the hyphal elements of Aspergillus fumigatus and C albicans cannot be killed, but the spores of A fumigatus and the yeast phase of C albicans can be killed by an independent mechanism. This leads to the conclusion that bacterial killing may not necessarily be a problem for patients with MPO deficiency, but the killing of certain fungi may be a problem, depending on the severity of the deficiency.