Cerebral Spinal Fluid levels of Cytokines are elevated in Patients with Metachromatic Leukodystrophy.

Kathryn A Thibert,Gerald V Raymond,Jakub Tolar,Weston P Miller,Troy C Lund,Paul J Orchard

doi:10.1038/srep24579

Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulfatase A causing an accumulation of cerebroside sulfate, a lipid normally abundant in myelin. Sulfatide accumulation is associated with progressive demyelination and a clinical presentation in severe disease forms that is dominated by motor manifestations. Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported. The objective of this study was to evaluate the concentration of inflammatory cytokines in the CSF of patients with MLD and to compare these levels to unaffected controls. Of 22 cytokines evaluated, we documented significant elevations of MCP-1, IL-1Ra, IL-8, MIP-1b and VEGF in the MLD patients compared to unaffected controls. The elevated cytokines identified in this study may play a significant role in the pathophysiology of MLD. Better understanding of the inflammatory and neurodegenerative process of MLD may lead to improved targeted therapies.

Highlights

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A, a lysosomal enzyme required for the degradation of cerebroside sulfate, a membrane lipid normally abundant in myelin[1]
We found significantly elevated levels of the following cytokines in the CSF of MLD patients compared to controls as shown in Table 2: monocyte chemotactic protein 1 (MCP-1) at 1006 ± 264 pg/mL vs 330 ± 29 pg/mL (p = 0.0005), IL-1 receptor antagonist (IL-1Ra) at 51.7 ± 19.7 pg/mL vs. 7.4 ± 5.6 pg/mL (p = 0.009), IL-8 at 79.3 ± 12.3 pg/mL vs. 13.9 ± 1.3 pg/mL (p < 0.0001), macrophage inflammatory protein (MIP)-1b at 15.1 ± 5.8 pg/mL vs. 1.7 ± 1.2 pg/mL (p = 0.003), and vascular endothelial growth factor (VEGF) at 1.7 ± 0.4 pg/mL vs. undetectable (p = 0.001)
MCP-1, IL-1Ra, IL-8, MIP-1b and VEGF were found to be elevated in the CSF and plasma of patients with MLD compared to controls

Summary

Introduction

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A, a lysosomal enzyme required for the degradation of cerebroside sulfate, a membrane lipid normally abundant in myelin[1]. Hematopoietic cell transplant (HCT) has been shown to slow the disease and appears beneficial in pre-symptomatic juvenile and adult MLD patients, but remains ineffective for the late infantile form[5,6,7,8]. In vitro and mouse model experiments have shown inflammatory reactions within the central nervous system, including microglial activation, astrogliosis, recruitment of peripheral macrophages, and the secretion of pro-inflammatory cytokines to be hallmarks of several lysosomal storage diseases[10]. In vitro sulfatide loading triggers the synthesis and secretion of inflammatory cytokines including TNF-a, IL-1b and IL-811,12. These cytokines are thought to amplify tissue damage associated with MLD12. For this first time, we describe inflammatory cytokine levels in the cerebrospinal fluid and plasma of untreated MLD patients and compare them to healthy controls

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