Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis.

Joshua L Milstein,Christopher R Barbour,Bibiana Bielekova,Peter Kosa,Kayla Jackson

doi:10.3389/fneur.2019.01232

Abstract

Objective: To test the hypothesis that Multiple Sclerosis (MS) patients have increased peripheral inflammation compared to healthy donors and that this systemic activation of the immune system, reflected by acute phase reactants (APRs) measured in the blood, contributes to intrathecal inflammation, which in turn contributes to the development of disability in MS.Methods: Eight serum APRs measured in a prospectively-collected cross-sectional cohort with a total of 51 healthy donors and 291 untreated MS patients were standardized and assembled into related biomarker clusters to derive global measures of systemic inflammation. The resulting APR clusters were compared between diagnostic categories and correlated to equivalently-derived cerebrospinal fluid (CSF) biomarkers of innate and adaptive immunity. Finally, correlations were calculated between biomarkers of systemic and intrathecal inflammation and MS severity measures, which predict future rates of disability progression.Results: While two blood APR clusters were elevated in MS patients, only one exhibited a weak correlation with MS severity. All CSF inflammation clusters, except CSF albumin, correlated with at least one measure of MS severity, with biomarkers of humoral adaptive immunity exhibiting the strongest correlations, especially in Progressive MS.Conclusion: Systemic inflammation does not appear to be strongly associated with intrathecal inflammation in MS. Positive correlations between markers of intrathecal inflammation, especially of humoral immunity, with MS severity measures support a pathogenic role of intrathecal (compartmentalized) inflammation in central nervous system tissue destruction, including in Progressive MS.

Highlights

Multiple Sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system (CNS)
After accounting for these effects, we found that MS patients had an elevated amount of ferritin (Figures 1A,C; p = 0.0182) and cerebrospinal fluid (CSF) chitinase-3-like 1 (CHI3L1), soluble B cell maturation antigen (sBCMA), CSF immunoglobulin G (IgG), IgG index, and sCD27 (Figures 1B,D; p = 0.0028 for sBCMA and p < 0.0001 for all other markers) as well as diminished levels of the negative blood acute phase reactant (APR) serum albumin and transferrin (Figure 1C; p = 0.0278 and p = 0.0093, respectively)
We assessed the differences of adjusted blood and CSF biomarker Z score residuals between healthy donors (HD), Relapsing-Remitting MS (RRMS), and Progressive MS (PMS) and found that all of these biomarkers were significantly different between HD and both MS groups, with the exception of serum albumin, which was only decreased in PMS patients (Supplementary Figure 1)

Summary

Introduction

Multiple Sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system (CNS). Unbiased proteomic analysis of cerebrospinal fluid (CSF) biomarkers identified proteins that change with MS evolution (from early RRMS stage to late progressive MS stages), but none that could reproducibly differentiate PPMS and SPMS on a molecular level [3]. These data are consistent with extensive genetic studies that were unable to identify reproducible differences in MS susceptibility alleles between clinical subtypes of MS [4]. The overlapping biology justifies merging PPMS and SPMS patients into a single Progressive MS (PMS) category, as is done in this study

Methods

Results

Discussion

Conclusion