YKL-40 is a CSF biomarker of intrathecal inflammation in secondary progressive multiple sclerosis

Highlights

• The YKL-40 level in CSF is increased in SPMS patients and patients with active MS to a similar degree.

• The YKL-40 levels correlate with the number of gadolinium enhancing lesions and are higher during relapses than in remission.

• The YKL-40 levels correlate with the number of T1 lesions, but are inversely correlated with the signal intensity of normal appearing white matter.

Abstract

YKL-40 (CHI3L1) is a glycoprotein predominantly produced by reactive astrocytes in chronic active MS lesions, which are common in secondary progressive MS. In this study, YKL-40 was investigated in different stages of MS and in relation to MRI findings. YKL-40 levels in CSF samples from two independent patient cohorts of MS patients were determined with ELISA. CSF YKL-40 was increased in patients with active relapsing–remitting MS and correlated with the number of gadolinium enhancing lesions. Patients with secondary progressive MS had similar high levels of YKL-40, whereas not active relapsing–remitting MS patients had YKL-40 levels comparable to healthy controls.

Introduction

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. At onset, 85% of patients will have a relapsing remitting form (RRMS), with periods of worsening followed by periods of recovery and stable disease. Eventually, most patients will develop a secondary progressive form (SPMS), characterized by fewer and milder relapses (Lublin and Reingold, 1996, Sospedra and Martin, 2005), less radiological activity (Filippi et al., 1997, Koziol et al., 1998), but continuous deterioration of neurologic function (Confavreux et al., 2003). Treatments targeting adaptive immunity have largely been unsuccessful in SPMS (Rovaris et al., 2006) and at present there is no effective therapy for SPMS. The cause of SPMS is still unknown, but there is an on-going and lively debate over the relative importance of inflammation vis-a-vis neurodegeneration in this phase of MS (Frischer et al., 2009).

The copious treatment failures with anti-inflammatory drugs suggest that if inflammation is still important to the pathogenesis of SPMS, it must be of a fundamentally different form. Chronically active white matter lesions are thought to be characteristic of progressive forms of MS. They contain a demyelinated core with few T cells, which is surrounded by a rim of microglia nodules and enlarged astrocytes (Prineas et al., 2001, Frischer et al., 2009). This type of lesion is also called slowly expanding lesion and is believed to increase in size over time, contributing to demyelination and axonal damage.

YKL-40 (also known as chitinase 3-like-1 or CHI3L1) is a member of the chitinase-like glycoprotein family and is predominantly produced by reactive astrocytes (Bonneh-Barkay et al., 2010, Canto et al., 2015), but also by microglia to some extent. In brain tissue from MS patients, YKL-40 is expressed in reactive astrocytes and microglia at the rim of chronically active lesions (Canto et al., 2015). The physiological role of YKL-40 is not known, but it has been hypothesized to be involved in tissue remodeling during inflammation (Bonneh-Barkay et al., 2010). Increased levels have been found in CSF from patients with clinically isolated syndrome (CIS) and MS (Bonneh-Barkay et al., 2010, Correale and Fiol, 2011, Modvig et al., 2013, Modvig et al., 2015, Malmestrom et al., 2014, Martinez et al., 2015, Canto et al., 2015).

The purpose of this study was to further characterize YKL-40 in different stages of MS; to investigate the relation between YKL-40 and other biomarkers of astrocyte and microglia activation; and to explore its potential as a biomarker of inflammation in SPMS.