Intrathecal chitotriosidase and the outcome of multiple sclerosis

Abstract

Activated macrophages are major effectors at all stages of lesion formation in multiple sclerosis (MS) brain. Here, we report that the macrophage enzyme chitotriosidase (Chit) is significantly elevated both in plasma and cerebrospinal fluid (CSF) of patients with MS as compared to healthy controls and other neurological patients (P<0.001). Furthermore, the Chit activity in blood significantly associates with the MS clinical course (higher in secondary progressive relative to relapsing-remitting, P=0.01) and the clinical severity as measured by Kurtkze's Expanded Disability Status Scale (P<0.001). Also, we found that Chit activity is compartmentalized in the central nervous system of early MS patients and that its CSF/plasma quotient, in the presence of a preserved albumin quotient, correlates with the extent of future clinical deterioration (r=0.91; P<0.001). These findings confirm that innate immunity, here represented by Chit, is clinically relevant in MS and allows, if confirmed, reconsidering novel MS therapeutic strategies specifically aimed at this branch of the immune response.

Microglia and Chitotriosidase in Multiple Sclerosis

“…This study 48 not only confirms the important role of the innate immune response in MS phenomenology, but also allows Chit determination in CSF and plasma to be proposed as a diagnostic and monitoring method in an MS laboratory. As a result of our analysis, plasma and, to a larger extent, CSF Chit levels better correlate with the extent of CNS damage compared with the previously proposed macrophage-derived markers such as TNF-α, IL-6, IL-1, NO and ROS.…”

“…33,34,43 The markedly augmented glucose metabolism occurring during inflammation in the MS brain could induce a spontaneous increase of glucosamine-derived chitinlike substances. In this context, the microglia-derived Chit activity 48 could counterbalance the naturally occurring glucosamine aggregation as well as its transformation into detrimental chitin, thus having a protective rather than a detrimental role within the CNS. In contrast, deposition of chitin-like substances in the AD brain could result from a reduced immune response that characterises the most severe clinical expression of disease, 58 or from an impaired chitin cleavage in relation to the advanced age of AD patients.…”

“…19 For the first time, we described that such enzymatic activity is also present in the CSF of patients with MS and that it is compartmentalised within the CNS, and therefore is of intrathecal origin. 48 The question remained open for a couple of years as to whether such…”

“…45,46 TNF-α, IL-6, NO, reactive oxygen species (ROS) and other macrophage-derived products unfortunately show only a modest correlation with clinical activity in MS, and are as yet of very limited usefulness in clinical routine. 47 Through a case-control study, we demonstrated that Chit activity is increased in the blood and, particularly, in the cerebrospinal fluid (CSF) of MS patients, 48 and that this activity correlates well with the extent of CNS damage as scored by the Extended Disability Status Scale (EDSS) at follow-up 49 (see Figures 2 and 3). …”

“…Chit was determined according to published methods 38,48 in the supernatant of microglial cell cultures: briefly, after 24 hours of culture, cell-free supernatants were collected; 30µl were incubated with 22µlmol/l 4-methylumelliferyl-β-d-N,N',N''triacetylchitotriose in 0.5M citrate-phosphate buffer at pH 5.2, and fluorescence was measured on a fluorimeter. Chit activity was calculated as nanomoles of substrate hydrolysed per ml per hour (nmol/ml/h).…”