Abstract
Natalizumab (NTZ) can reactivate human polyomavirus John Cunningham polyomavirus (JCPyV) latent infection and lead to progressive multifocal leukoencephalopathy (PML). NTZ modulates the expression of microRNA-126-3p (miR-126-3p) and its target genes, Spi-B, POU2AF1, and vascular cell adhesion molecule-1 (VCAM-1); Spi-B protein binds the JCPyV regulatory region, initiating early gene transcription. This paper is aimed to evaluate the miR-126-3p and soluble (s)VCAM-1 concentration, Spi-B/POU2AF1 gene expression, and JCPyV activity in patients with multiple sclerosis (MS) before and during 2-years NTZ. Serum miR-126-3p and sVCAM-1 concentration was measured before NTZ and after 1, 12, and 24 months of treatment in 22 MS subjects, 1 patient who developed PML, and 29 healthy controls (HCs). The Spi-B and POU2AF1 expression in blood was analyzed at baseline and at month 24 in 13 patients with MS; results were clusterized based on JCPyV activity. miR-126-3p was significantly downregulated in MS before and during NTZ but was greatly increased in the PML patient. sVCAM-1 concentration was comparable in MS and HCs, and was reduced by NTZ in MS and PML. Spi-B/POU2AF1 expression was significantly increased in MS at baseline and was upregulated by NTZ, particularly in JCPyV-infected patients in whom JCPyV reactivation was detected. Taken together, the results suggest that the modulation of the miR-126-3p/POU2AF1/Spi-B axis associates with JCPyV activity in NTZ-treated patients with MS.
Highlights
Epigenetic mechanisms regulating gene expression, such as microRNA, are critical factors in complex human neurological diseases. miRNAs are highly conserved short non-coding RNAs that bind to complementary sequences on 3’ untranslated region (3’UTR) of mRNAs resulting in translational repression or target degradation [1]
Analyses performed on the patient who developed progressive multifocal leukoencephalopathy (PML) showed a >9-fold increase of miR-126-3p serum concentration at the time of PML diagnosis compared with the values seen in healthy controls (HCs); interestingly, miR-126-3p serum concentration was significantly decreased when a clinical partial recovery was observed, it remained well above the concentration observed in either HC or relapsing remitting MS (RRMS) (Figure 1)
John Cunningham polyomavirus serostatus, antibodies index, previous immunosuppressive therapies, and duration of NTZ treatment are currently used for PML risk stratification in patients with multiple sclerosis (MS) undergoing NTZ [22]; these biomarkers, have a very limited ability to predict the risk of developing PML
Summary
Epigenetic mechanisms regulating gene expression, such as microRNA (miRNAs), are critical factors in complex human neurological diseases. miRNAs are highly conserved short non-coding RNAs that bind to complementary sequences on 3’ untranslated region (3’UTR) of mRNAs resulting in translational repression or target degradation [1]. Multiple sclerosis is the most common demyelinating disorder of the central nervous system (CNS) and still only has a partially understood pathogenesis that includes environmental and genetic factors [2]. Biological agents, such as monoclonal antibodies (mAbs), are currently considered as therapeutic options for MS [3]; among such mAbs natalizumab (NTZ) [4] is a humanized anti-α4 integrin antibody. NTZ results in a decrease of soluble (s)VCAM-1 and of intrathecal immune cells [6], and in the upregulation of the transcription regulators, POU domain class 2 associating factor 1 (POU2AF1) and Spi-B in lymphocytes [7]
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