Introduction
Myeloperoxidase deficiency (MPD) is an uncommon primary immunodeficiency caused by an innate immune problem characterized by neutrophil and monocyte myeloperoxidase activity that is significantly reduced or nonexistent. Most people are asymptomatic clinically. However, rarely severe infectious issues can develop. Recurrent candida infections are especially harmful when coexisting diabetes mellitus is present.
What Are the Causes of Myeloperoxidase Deficiency?
Different genetic deletions and mutations affect MPO production. MPO is a 150 kDa tetramer encoded by a single gene in the band 17q22–23 and consists of two heavy chains, two light chain subunits, and two iron atoms. The MPO gene encodes for a single translational product, packed as mature MPO in the azurophilic granules following glycosylation and proteolytic processing. In the peroxidation and halogenation cycles, MPO, once produced by activated leukocytes, uses the oxidative potential of its co-substrate hydrogen peroxide to produce the cytotoxic oxidant species and potent bactericidal molecule hypochlorous acid (HOCl), along with other hazardous oxidants that are capable of not only starting lipid peroxidation but also encouraging several post-translational changes, such as halogenation, nitration, and oxidative crosslinking of target proteins at the inflammation sites. HOCl's capacity to transform lipids, DNA (deoxyribonucleic acid), amines, and tyrosine into halohydrins, 5-chlorouracil, chloramines, and 3-chlorotyrosine, respectively, accounts for both its hazardous and bactericidal properties.
What Are the Types of Myeloperoxidase Deficiency?
Myeloperoxidase deficiency is divided into two types based on the cause. The different types of MPD are
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Primary MPD - Primary MPO deficiency is a hereditary autosomal recessive disorder that typically manifests with various clinical characteristics and degrees of severity. Numerous primary forms of point germline mutations causing MPO deficiency have been identified. Some of these mutations are linked to poor post-translational processing of the MPO precursor protein. In contrast, others are related to pre-translational flaws brought on by changes in the MPO gene's regulatory region. The most prevalent mutations linked to the hereditary form are R569W, followed by Y173C, M251T, G501S, R499C, and a 14-base deletion (D14) in exon 9. It is interesting to note that because a different gene expresses eosinophil peroxidase than MPO, eosinophils are never affected by MPO deficiency.
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Secondary MPD - Although less frequent than the hereditary variety, secondary MPO impairment can arise from somatic mutations of the MPO gene. The deficiency often only affects a percentage of neutrophils and is only partial. The acquired form is typically momentary and goes away once the underlying ailment improves. Many conditions can cause acquired or secondary MPO deficiency, such as diabetes mellitus, pregnancy, iron deficiency, renal transplantation, thrombotic diseases, lead poisoning, obstructive jaundice, disseminated cancers, hematologic disorders and neoplasms like acute and chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, Hodgkin lymphoma, severe infections, cytotoxic agents, and some anti-inflammatory drugs like sulfapyridine.
What Is the Pathophysiology of Myeloperoxidase Deficiency?
The different functions of myeloperoxidase enzyme and its impact on deficiency are
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Respiratory Burst - As the initial line of defense against infections, neutrophils undergo a respiratory burst during phagocytosis, where most bacteria are killed and digested in the phagosomes. When the common membrane is torn, the MPO-enriched azurophilic granules in neutrophils fuse with the phagosome and are discharged into the phagosomes. When these neutrophils come into contact with pathogens, NADPH oxidase is activated, causing the generation of superoxide, hydrogen peroxide, and other reactive oxygen derivatives, including HOCI, a main byproduct of MPO activity. Its significance in the innate immune response is shown by the fact that MPO-antimicrobial HOCl's actions are not just limited to killing bacteria but also fungi, viruses, erythrocytes, tumor cells, natural killer (NK) cells, and platelets. Since people with MPO-deficient neutrophils have a prolonged respiratory burst and increased hydrogen peroxide production, reports have also demonstrated that MPO is involved in ending the respiratory burst.
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Autoimmune Inflammation - It has been demonstrated that MPO-derived HOCl is the essential source of ROS for neutrophil extracellular traps (NETs), DNA structures released from chromatin formation de-condensation that traps bacteria and regulates the innate and adaptive immune response in a variety of ways. According to two models of heightened T cell-mediated delayed-type cutaneous hypersensitivity and antigen-induced arthritis in Mpo/+ mice, MPO is thought to dampen the adaptive immune response. By reducing IL-12 production and CD86 expression, MPO produced from neutrophils blocks LPS-induced DC activation, which, in turn, reduces the proliferation of T cells and the generation of pro-inflammatory cytokines. However, MPO-deficient animals showed lower disease severity in the K/BxN arthritis and collagen-induced arthritis (CIA) models, indicating a harmful role for MPO in triggering autoimmune inflammation. Additionally, elevated MPO levels and activity have been seen in various inflammatory disorders and autoimmune diseases, such as rheumatoid arthritis (RA) and multiple sclerosis (MS).
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Vascular Function - MPO modulates the functioning of the vasculature, which is linked to chronic vascular disorders, including atherosclerosis. MPO functions as a nitric oxide (NO)-scavenger in the extracellular matrix (ECM), consuming NO to impede endothelial relaxation. By selectively modulating apolipoprotein A-I (apoA-I), MPO and its oxidative species, which are present in atherothrombotic tissue, promote lipid peroxidation, the conversion of LDL to a highly-uptake atherogenic form, the generation of dysfunctional HDL particles that are more prone to degradation, and the impairment of apoA-I’s ability to promote cholesterol efflux. Moreover, greater cardiovascular risk is linked to elevated systemic levels of MPO and its oxidation products. However, unlike the more standardized test for susceptible C-reactive protein, the detection of MPO as a cardiovascular risk factor has not primarily been acknowledged.
What Are the Symptoms of Myeloperoxidase Deficiency?
Most MPO-deficient patients have no symptoms and no increase in infections. However, repeated, severe Candida albicans infections have only been noted in patients who simultaneously had other illnesses, like diabetes mellitus. It is, therefore, unclear in these patients whether the conditions were solely caused by MPO deficiency or if additional MPO-independent processes were also at fault. In a study conducted by European researchers, only 50 % of patients with total MPO deficiency experienced infectious issues; the other 50 % were asymptomatic, and only 10 % of patients experienced potentially fatal consequences. MPO-deficient patients experience fewer serious infections than CGD (chronic granulomatous disease) patients highlights the significance of reactive oxygen species, such as enhanced hydrogen peroxide formation, acting as a potent bactericidal agent that safeguards MPO deficiency patients. However, the inability to treat fungal infections like candidiasis is directly related to the absence of MPO-mediated species like HOCl.
How Is MPD Diagnosed?
The first step in the diagnosis of MPO deficiency is
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The evaluation of peroxidase activity by
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Histochemical labeling of leukocytes.
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Immunocytochemistry.
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Flow cytometry, which enables the assessment of functional MPO inside neutrophils.
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An additional source of information on the molecular causes of the reported absence of a functional enzyme independent of its enzymatic activity comes from immunoblotting isolated leukocytes for the MPO protein.
How Is MPD Treated?
Prophylactic antibiotics are typically avoided and unnecessary because most people with MPO deficiency are asymptomatic and do not usually get sick. However, quick and aggressive antimicrobial treatment is generally required to control infections in individuals with concurrent diabetes mellitus and a high incidence of localized and systemic diseases. Therefore, avoiding therapies like extended use of antibiotics or steroids that can make fungal infections more likely is wise and prudent.
Conclusion:
In conclusion, myeloperoxidase (MPO) deficiency is a rare hereditary condition that increases susceptibility to specific infections due to a lack of or deficiency in the enzyme. Despite the fact that there is no treatment, people with MPO deficiency can live healthy lives with the help of proper management and preventive measures.
