What is the role of myeloperoxidase (MPO) in chronic granulomatous disease (CGD)?

Myeloperoxidase in Chronic Granulomatous Disease

Myeloperoxidase (MPO) is NOT deficient in chronic granulomatous disease (CGD) and plays no role in the pathophysiology of this condition—the fundamental defect in CGD is in NADPH oxidase, not MPO. 1, 2

The Fundamental Distinction

MPO Activity is Normal in CGD

• CGD patients have completely normal myeloperoxidase activity in their neutrophils, as demonstrated by direct biochemical measurements of MPO-mediated systems including peroxidase assays, protein iodination, and amino acid decarboxylation 2
• The defect in CGD lies in NADPH oxidase, which is responsible for generating superoxide (O2-) during the respiratory burst—this is the enzyme system that is absent or dysfunctional in CGD 3, 2
• MPO requires hydrogen peroxide (H2O2) as a substrate to produce hypochlorous acid (HOCl), and since H2O2 is derived from superoxide produced by NADPH oxidase, MPO cannot function in CGD due to lack of substrate, not because MPO itself is defective 3

Why This Matters Clinically

• CGD patients present with severe, life-threatening infections early in life due to defective NADPH oxidase, whereas individuals with isolated MPO deficiency are usually healthy and asymptomatic 4, 5
• The clinical severity difference is striking: CGD requires aggressive prophylaxis with trimethoprim-sulfamethoxazole, itraconazole, and interferon-gamma 1, while MPO-deficient individuals rarely need any intervention unless they have concurrent conditions like diabetes mellitus 5

Comparative Importance of Oxidative Systems

NADPH Oxidase vs. MPO in Host Defense

• NADPH oxidase is more critical than MPO for antifungal defense: In experimental models, NADPH oxidase-deficient (CGD) mice showed 10- to 100-fold increased fungal outgrowth and shorter survival compared to MPO-deficient mice when infected with Candida albicans or Aspergillus fumigatus 3
• However, both systems contribute to host defense: MPO-deficient mice still showed significantly reduced cytotoxicity against fungi compared to normal mice, demonstrating that MPO does play a supportive role when NADPH oxidase is functional 4
• At high infectious inocula, mortality in MPO-deficient mice approached that of CGD mice, suggesting MPO becomes more important when pathogen burden is overwhelming 4

The Hierarchical Relationship

• MPO is completely dependent on NADPH oxidase for function: Double knockout mice (lacking both MPO and NADPH oxidase) showed the same susceptibility as CGD mice alone, proving that MPO cannot contribute to host defense without the superoxide/hydrogen peroxide generated by NADPH oxidase 3
• This creates a hierarchical system where NADPH oxidase is the primary enzyme, and MPO amplifies the antimicrobial effect when substrate is available 3

Clinical Implications for CGD Management

Standard CGD Treatment (Not MPO-Related)

• Antimicrobial prophylaxis: Trimethoprim-sulfamethoxazole (5 mg/kg daily or twice daily based on trimethoprim component in children) to prevent bacterial infections 1
• Antifungal prophylaxis: Itraconazole is strongly recommended (A-II evidence) 1
• Immunotherapy: Recombinant interferon-gamma (rIFN-γ) decreases severe infections by approximately 70% (A-II recommendation) 1
• Acute invasive aspergillosis: Voriconazole is first-line treatment (AII) 1

Genetic Modifiers Involving MPO

• While MPO itself is not defective in CGD, MPO gene polymorphisms can modify disease severity: Specific MPO genotypes are strongly associated with increased risk for gastrointestinal complications in CGD patients (P = 0.003) 6
• Patients with variant MPO genotypes combined with FcγRIIIb and FcγRIIa polymorphisms had the highest risk for GI complications (P < 0.0001), suggesting that even though MPO is functionally normal, genetic variations affecting its expression or activity can influence inflammatory complications 6

Common Pitfalls to Avoid

• Do not confuse MPO deficiency with CGD: These are completely separate conditions with different pathophysiology, clinical presentations, and management strategies 5, 2
• Do not assume MPO testing is useful for CGD diagnosis: The diagnostic test for CGD is the nitroblue tetrazolium (NBT) test or dihydrorhodamine (DHR) flow cytometry assay, which measure NADPH oxidase function, not MPO activity 1
• Recognize that MPO is irrelevant to CGD pathophysiology but MPO polymorphisms may predict complications: The enzyme itself works normally, but genetic variants can modify inflammatory responses 6