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Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis
R M Nagra1, B Becher, W W Tourtellotte
1Neurology Research Service, West Los Angeles VA Medical Center and Brain Research Institute, CA 90073, USA.
Abstract:
The myeloperoxidase enzyme (MPO) is expressed specifically in myeloid cells and catalyzes the formation of hypochlorous acid and other cytotoxic oxidants. We previously reported that two alleles of MPO exist which differ in promoter strength due to a base difference in an Alu-encoded hormone response element. The present study shows that the higher expressing MPO genotype is overrepresented in early onset multiple sclerosis in females, implicating MPO in this demyelinating disease. Contrary to the general conception that macrophages lack MPO, immunohistochemical analysis shows that MPO is present in microglia/macrophages in and around MS lesions as shown by colocalization with major histocompatibility antigens HLA-DR and phagocytized myelin. Also, MPO mRNA sequences are detected in cDNA derived from isolated human adult microglia. This is the first evidence that MPO is present in microglia/macrophages at MS lesions, that MPO gene expression occurs in microglia and that MPO plays a role in MS pathogenesis as shown by the allelic disequilibrium in early onset disease.
Insights
Myeloperoxidase (MPO) genotype is linked to early-onset multiple sclerosis (MS) in females. MPO is present in microglia at MS lesions, suggesting its role in this demyelinating disease.
Area of Science:
- Biochemistry
- Immunology
- Neuroscience
Background:
- Myeloperoxidase (MPO) is an enzyme in myeloid cells, crucial for forming cytotoxic oxidants.
- Two MPO alleles exist, differing in promoter strength due to a genetic variation.
- Previous research identified MPO allele variations affecting enzyme expression levels.
Purpose of the Study:
- To investigate the association between MPO genotype and early-onset multiple sclerosis (MS).
- To determine the presence and role of MPO in microglia within MS lesions.
- To explore MPO's contribution to the pathogenesis of multiple sclerosis.
Main Methods:
- Genotyping analysis to identify MPO alleles and their frequencies in MS patients.
- Immunohistochemical staining to detect MPO expression in microglia/macrophages at MS lesions.
- Messenger RNA (mRNA) sequencing to confirm MPO gene expression in isolated human microglia.
Main Results:
- A higher-expressing MPO genotype was found to be overrepresented in females with early-onset MS.
- Immunohistochemistry confirmed MPO presence in microglia/macrophages co-localizing with HLA-DR and myelin debris in MS lesions.
- MPO mRNA sequences were detected in cDNA from isolated human adult microglia, indicating gene expression.
Conclusions:
- The MPO enzyme is present and expressed in microglia/macrophages within MS lesions.
- Allelic imbalance in MPO suggests a significant role for this enzyme in the pathogenesis of early-onset MS, particularly in females.
- These findings implicate MPO as a potential factor in the development and progression of multiple sclerosis.