Original article
Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6–infected infants with or without febrile seizures

https://doi.org/10.1016/j.jiac.2014.07.017Get rights and content

Abstract

Human herpesvirus-6 (HHV-6) is a cause of exanthema subitum and, sometimes, of febrile seizures. However, the pathogenesis of febrile seizures associated with HHV-6 infection remains unclear. We investigated serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in infants with HHV-6 infection. Serum levels of both MMP-9 and TIMP-1 were significantly higher in infants with HHV-6 infection than in controls. Serum TIMP-1 levels were significantly higher in infants with febrile seizures than in infants without febrile seizures. Serum MMP-9/TIMP-1 ratios were significantly lower in infants with febrile seizures than in infants without febrile seizures. In infants with HHV-6 infection, positive correlations were found between serum MMP-9 concentrations and the white blood cells (WBC) count, and between serum TIMP-1 concentrations and the WBC count. Positive correlations were also found between the amounts of HHV-6 DNA and the ratios of MMP-9/TIMP-1 in infants with HHV-6 infection. In conclusion, we suggest that high serum levels of MMP-9 and TIMP-1 in infants with HHV-6 infection may induce dysfunction of the blood–brain barrier, eventually causing febrile seizures.

Introduction

Human herpesvirus-6 (HHV-6) is one of the causative agents of exanthema subitum, a common infectious disease in infants [1], [2]. Exanthema subitum is characterized by an abrupt rise in temperature to as high as 40 °C, followed by a rapid drop in temperature within the next 2–4 days that coincides with the appearance of an erythematous maculopapular rash that persists for 1–3 days [3].

During an HHV-6 infection, infants sometimes experience febrile seizures (FS) [4]. However, the pathogenesis of FS associated with HHV-6 infection is still unclear. Matrix metalloproteinases (MMPs) are a family of enzymes that mediate the degradation of extracellular matrix proteins [5]. MMPs have been reported to play important roles in normal and pathological processes, including embryogenesis; wound healing; inflammation; and the development of arthritis, cardiovascular diseases, pulmonary diseases, and cancer [2]. MMP-9 is a major component of the basement membrane of the cerebral endothelium. It degrades collagen IV and promotes the migration of cells through tissues and across the blood–brain barrier (BBB) [6]. The activity of MMPs is controlled by specific tissue inhibitors of metalloproteinases (TIMPs) [7]. One such inhibitor, TIMP-1, has high avidity for MMP-9. TIMP-1 protects BBB function by inhibition of MMP-9 activity and reduction of brain damage after ischemia [8], [9], [10].

To investigate the roles of MMP-9 and TIMP-1 in the pathogenesis of FS associated with HHV-6 infection, we determined serum MMP-9 and TIMP-1 levels, and compared them between HHV-6–infected infants with or without FS. In addition, we investigated the correlations between serum MMP-9 and TIMP-1 and the amounts of HHV-6 DNA in infants with HHV-6 infection.

Section snippets

Subjects

Informed consent was obtained from the parents of infants enrolled in this study. The protocol was approved by the Institutional Review Board of Yamaguchi University Hospital (No. H22-40). Serum samples were obtained from 29 infants with exanthema subitum who visited our hospital or 1 of 6 collaborating hospitals from January 2008 to December 2010. The diagnosis of exanthema subitum was based on characteristic clinical symptoms and the detection of HHV-6 DNA in the serum. Subjects comprised 16

Results

To investigate the roles of MMP-9 and TIMP-1 in the pathogenesis of HHV-6–associated FS, we first determined serum MMP-9 and TIMP-1 levels in HHV-6–infected and control infants (Fig. 1). The serum MMP-9 levels were significantly higher in infants with HHV-6 infection (median, 232.4 ng/ml; range, 144.6–342.9 ng/ml) than in the control group (median, 81.8 ng/ml; range, 32.1–211.9 ng/ml) (P < 0.05). The serum TIMP-1 levels were significantly higher in infants with HHV-6 infection (median,

Discussion

The pathogenesis of neurologic complications associated with HHV-6 infection remains unclear. In this study, we showed that extracellular matrix regulators MMP-9 and TIMP-1 might be involved in the mechanism underlying FS in HHV-6 infection.

The balance of MMP-9 and TIMP-1 is thought to be important in BBB function against brain damage [9], [14], and increased MMP-9/TIMP-1 ratios may induce dysfunction of the BBB. We have previously reported serum MMP-9 and TIMP-1 levels in other neurological

Conflict of interest

None.

References (28)

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