Myeloperoxidase deficiency is a

disorder Disorder may refer to randomness, non-order, or no intelligible pattern. Disorder may also refer to: Healthcare * Disorder (medicine), a functional abnormality or disturbance * Mental disorder or psychological disorder, a psychological pattern ...

featuring lack in either the quantity or the function of

myeloperoxidase Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the ''MPO'' gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry ...

–an iron-containing protein expressed primarily in

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

granules. There are two types of myeloperoxidase deficiency: primary/inherited and secondary/acquired. Lack of functional myeloperoxidase leads to less efficient killing of intracellular pathogens, particularly ''

Candida albicans ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usu ...

'', as well as less efficient production and release of

neutrophil extracellular traps Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. Neutrophils are the immune system's first line of defense against infection and have conventionally be ...

(NETs) from the neutrophils to trap and kill extracellular pathogens. Despite these characteristics, more than 95% of individuals with myeloperoxidase deficiency experience no symptoms in their lifetime. For those who do experience symptoms, the most common symptom is frequent infections by Candida albicans. Individuals with myeloperoxidase deficiency also experience higher rates of chronic inflammatory conditions. Myeloperoxidase deficiency is diagnosed using flow cytometry or cytochemical stains. There is no treatment for myeloperoxidase deficiency itself. Rather, in the rare cases that individuals experience symptoms, these infections should be treated. Myeloperoxidase_Function

Pathophysiology

The innate immune system responds quickly to infection, with neutrophils (a type of white blood cells) being the first responders. Neutrophils enter the site of infection and begin to

phagocytose Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

(take up) pathogens. Once engulfed, the neutrophils must then degrade the captured pathogens–a process known as intracellular killing. One method of intracellular killing which takes place in the

phagolysosomes In biology, a phagolysosome, or endolysosome, is a cytoplasmic body formed by the fusion of a phagosome with a lysosome in a process that occurs during phagocytosis. Formation of phagolysosomes is essential for the intracellular destruction of micr ...

of neutrophils involves the reaction of myeloperoxidase with hydrogen peroxide (H₂O₂) acquired in the cells from

NADPH oxidase NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white ...

through the respiratory bursts. This reaction generates several acidic products including hypochlorous acid (HClO), which can break down pathogens. Bacteria such as ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerug ...

'' and fungi such as ''

'' are killed in this manner. Neutrophils are also involved in killing extracellular pathogens (pathogens outside of the cell) through the release of NETs. These NETs contain myeloperoxidase, among other antimicrobial proteins. Once released outside of the cell, NETs trap pathogens and may in some cases kill them. Although myeloperoxidase is not required for all NET formation/release, NETs are only formed and released in response to ''Candida albicans'' when myeloperoxidase is present. Myeloperoxidase proteins in NETs can still react with H₂O₂ to form HClO and break down some extracellular pathogens. In myeloperoxidase deficient individuals, this extracellular pathogen killing doesn’t typically occur. Finally, during infection, neutrophils can migrate to the lymph nodes, where they deposit myeloperoxidase. Although the mechanisms of this process aren’t well understood, there is evidence that this extracellular myeloperoxidase interacts with

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

(cells of the

adaptive immune system The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...

) in the

lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...

, leading to a decrease in adaptive immune system activity in response to infection.

Presentation

About 1:1,000 to 1:4,000 individuals in the United States and Europe and 1:55,000 individuals in Japan experience myeloperoxidase deficiency. The most common symptom of myeloperoxidase deficiency is frequent infections, particularly by the fungus ''Candida albicans''. This symptom is especially frequent in individuals who also experience

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

. The majority of myeloperoxidase-deficient individuals, however, do not display any significant tendencies towards chronic infections from most bacteria. This is likely due to the fact that the absence of myeloperoxidase leads to increased neutrophil phagocytosis and degranulation as well as increased development of the adaptive immune system. That is, other aspects of the immune system typically compensate for the lack of myeloperoxidase, leading to relatively mild symptoms. Nonetheless, myeloperoxidase-deficient individuals have been found to experience more chronic inflammatory conditions (such as

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

, pulmonary/skin inflammation, kidney/heart disease, etc.) than individuals with sufficient myeloperoxidase. Researchers hypothesize this may be a result of heightened adaptive immune system activity in individuals with myeloperoxidase deficiency. There is also some evidence that congenital myeloperoxidase deficiency is correlated with higher rates of malignant tumors.

Types

MPO deficiency is broken down into two categories: primary/congenital and secondary/acquired. Primary MPO deficiency is an autosomal recessive genetic disorder, which is caused by mutations in the myeloperoxidase gene on chromosome 17q23. There are several different known mutations of this gene which all lead to myeloperoxidase deficiency. Secondary MPO deficiency, on the other hand, occurs in various clinical situations as a result of hematological neoplasm, disseminated cancers, some drugs,

iron deficiency Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...

, lead intoxication, thrombotic disease,

renal transplantation Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...

, severe infectious disease,

, neuronal lipofuscinosis, or pregnancy. Secondary MPO deficiency is typically partial, meaning only a portion of the affected individual’s neutrophils lack functional myeloperoxidase.

Diagnosis

Myeloperoxidase deficiency can be diagnosed via flow cytometry and cytochemical stains. Various devices can divide up leukocyte (white blood cell) populations based on their size and

peroxidase Peroxidases or peroxide reductases ( EC numberbr>1.11.1.x are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides. Functionality Peroxidases typically ca ...

activity. Specific stains bind to myeloperoxidase, and individuals who display large, granulated cells without this stain through flow cytometry typically have myeloperoxidase deficiency. In this way, it’s apparent when neutrophils are present in an individual but peroxidase activity is absent. Note, myeloperoxidase deficiency can cause false positives in the diagnosis of

chronic granulomatous disease Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reacti ...

, a condition which includes dysfunctional NADPH oxidase. Both disorders interfere with neutrophils’ abilities to kill pathogens through reaction with oxidative species. However, chronic granulomatous disease leads to inadequate H₂O₂ production, while myeloperoxidase deficiency is characterized by a lack of myeloperoxidase to interact with present H₂O₂. Testing with NADPH oxidase-specific assays can lead to positive results for chronic granulomatous disease and negative results for myeloperoxidase deficiency.

Treatment

Most individuals with myeloperoxidase deficiency do not need regular treatment, as they experience only mild symptoms, if any at all. Continued antibiotic use is not recommended in myeloperoxidase-deficient patients who don’t experience recurrent infections. Acquired myeloperoxidase deficiency typically goes away when the underlying condition is treated. In particular, when myeloperoxidase deficiency is caused by severe iron deficiency, treatment with iron returns myeloperoxidase function to normal.

References

External links

{{Myeloid and complement immunodeficiency Enzyme defects Congenital defects of phagocyte number, function, or both Noninfectious immunodeficiency-related cutaneous conditions