Methylation-dependent PAD2 upregulation in multiple sclerosis peripheral blood

Area of Science:

• Neuroimmunology
• Epigenetics
• Enzymology

Background:

• Peptidylarginine deiminase 2 (PAD2) and PAD4 are over-expressed in the multiple sclerosis (MS) brain.
• PAD2 converts myelin basic protein (MBP) arginines to citrullines, potentially promoting autoimmunity.
• PAD4 is implicated in chromatin remodeling.

Purpose of the Study:

• To investigate if altered epigenetic control of PAD2, observed in the MS brain, is also present in peripheral blood mononuclear cells (PBMCs) of MS patients.
• To explore the link between PAD2 expression and epigenetic modifications in peripheral immune cells of individuals with MS.

Main Methods:

• Quantitative Polymerase Chain Reaction (qPCR) was used to assess PAD2 and PAD4 gene expression.
• DNA methylation analysis was performed using the bisulfite sequencing method.
• Expression of reference genes was evaluated for accurate normalization.

Main Results:

• PAD2 was significantly upregulated in PBMCs of MS patients compared to healthy donors, mirroring findings in the MS brain.
• Analysis of a CpG island in the PAD2 promoter revealed that its overexpression is associated with promoter demethylation.
• PAD4 expression levels were also assessed in the context of MS.

Conclusions:

• Defective peripheral regulation of PAD2, without the blood-brain barrier's protection, may contribute to the development of autoimmune responses in MS.
• Epigenetic alterations, specifically promoter demethylation, are linked to PAD2 dysregulation in MS.
• These findings highlight PAD2 as a potential peripheral biomarker and therapeutic target in multiple sclerosis.