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

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.

Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination

“…The source of the T-cells in progressive MS lesions is unclear given that the BBB remains largely intact despite the enriched lymphocytic trafficking [ 72 , 73 ]. These lymphocytes may be remainders from lesions formed earlier in the disease or they may migrate from prominent intrathecal inflammation – a characteristic of progressive MS [ 74 ]. With cuprizone exposure, the recruitment of T-cells to the lesion site [ 70 ] may result from the decreased BBB integrity induced by cuprizone [ 75 , 76 ]…”

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

“…We call this “lesional” inflammation. But there are other inflammatory processes in MS that are not captured by CELs, such as formation of cortical lesions not typically associated with BBB opening and more diffuse inflammation compartmentalized to CNS tissue, often seen in progressive MS. We call this “non-lesional” inflammation ( Frischer et al, 2009 ; Androdias et al, 2010 ; Komori et al, 2015 ; Milstein et al, 2019 ).…”

Molecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms

“…Intrathecally compartmentalized inflammation 6 , associated with the tertiary lymphoid follicles, may be pathogenic based on correlations with rates of disability progression in a limited number of autopsy cases 7 . We recently validated relationship between intrathecal inflammation and MS severity in a prospectively acquired MS patients ( N = 244); where CSF biomarkers of intrathecal inflammation positively, but weakly (i.e., Rho = 0.18-0.24; p = 0.044-0.002) correlate with the rates of disability progression 8 .…”