Background: MicroRNAs
(miRNAs) have emerged as a family of post-transcriptional regulators of
gene expression that mediate diverse aspects of immunity. MiRNA
dysregulation has been found in multiple sclerosis (MS), reflecting the
growing need to identify disease-specific miRNA expression signatures.
Our previous low-density array studies reveal differential miR-126
expression in the CD4+T
cells of untreated relapsing–remitting MS (RRMS) patients. Here, we
investigated miR-126 expression in natalizumab-treated patients.
Methods: We isolated CD4+ T cells from untreated (n = 12) and natalizumab-treated MS patients (n = 24), and from healthy volunteers (n =
12). We analyzed the expression of miRNAs and potential targets by real
time reverse transcription polymerase chain reaction (RT-PCR). We
assessed specific inhibition of miR-126, in vitro.
Results: MiR-126
was down-regulated in cells of patients under natalizumab treatment and
up-regulated during relapse, supporting a regulatory role in MS
immunopathogenesis. MiR-126 expression correlated with the expression of
POU2AF1, a regulator of Spi-B that binds to the promoter/enhancer
sequences of JC virus (JCV), the pathogen of progressive multifocal
leukoencephalopathy (PML), a rare complication of natalizumab treatment.
The same trend was found for Spi-B. Strong up-regulation of both genes
appeared to be treatment duration-dependent. Specific inhibition
experiments supported the link between the expression of miR-126 and
POU2AF1/Spi-B.
Conclusions: Our
findings provided deeper insight into the mode of action of
natalizumab, with possible implications for understanding both the
effects of natalizumab on MS activity and its specific adverse event
profile.
