Increased CSF Level Of Monocyte/Microgrial Activation Maker In Progressive- Multiple Sclerosis (S53.003)

OBJECTIVE: To assess the pathophysiogical involvement of intrathecal monocytes/microglia in multiple sclerosis (MS). BACKGROUND: In the central nervous system (CNS), an abundant existence of activated macrophages/microglia has been reported in inflammatory MS lesions. These macrophages are involved in repair process by removing myelin debris, which is required for the efficient remyelination. Surprisingly, cerebrospinal fluid (CSF) immunophenotyping by flow cytometry suggested proportional decrease of monocytes in relapsing-remitting MS (RRMS) patients. Because CSF immunophenotyping enumerates only mobile pool of immune cells in the intrathecal compartment, we wanted to assess its relationship to soluble biomarker that may reflect both mobile and stationary macrophages/microglia present in the CNS tissue. DESIGN/METHODS: CSF and clinical data of 425 subjects, including RRMS, secondary-progressive MS (SPMS), primary-progressive MS (PPMS), non-inflammatory neurological disorders (NIND), and other inflammatory neurological disorders (OIND), were collected and processed in a blinded fashion using standard protocol. ELISA assay was optimized to quantify soluble CD14 (sCD14) in the CSF supernatant as biomarker of monocytes and microglia. Number of CD14 expressing monocytes was enumerated by combination of flow cytometry and counting of cells in 25-fold concentrated CSF and was compared with sCD14 concentrations. RESULTS: CSF sCD14 level was significantly elevated in SPMS and PPMS subjects compared to RRMS and NINDS subjects. OIND subjects had the highest levels of sCD14, significantly elevated in comparison to NIND and RRMS subjects, but not in comparison to PPMS or SPMS patients. As reported previously, RRMS patients had significantly lower proportion of monocytes in the CSF, as compared to PPMS, SPMS, but also NIND patients. These inter-group differences disappeared when absolute numbers of CSF monocytes were enumerated. CONCLUSIONS: The observed discrepancy between absolute numbers of mobile monocytes and soluble marker of macrophages/microglia in the CSF indicates that activation of resident microglia is important and easily measurable difference between RRMS and progressive MS subtypes. Disclosure: Dr. Komori has nothing to disclose. Dr. Blake has nothing to disclose. Dr. Romm has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Bielekova has received royalty payments from the National Institutes of Health for patents related to the use of daclizumab and other CD25-blocking agents for the treatment of MS.