Abstract
Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflammatory activity is currently unknown. Reliable and simultaneous measurements of both lesional and non-lesional MS activity is necessary to understand their contribution to CNS tissue destruction in individual patients. We previously demonstrated that CNS compartmentalized inflammation can be measured by combined quantification of cerebrospinal fluid (CSF) immune cells and cell-specific soluble markers. The goal of this study is to develop and validate a CSF-biomarker-based molecular surrogate of MS lesional activity. The training cohort was dichotomized into active (CELs > 1 or clinical relapse) and inactive lesional activity (no CELs or relapse) groups. Matched CSF and serum samples were analyzed for 20 inflammatory and axonal damage biomarkers in a blinded fashion. Only the findings from the training cohort with less than 0.1% probability of false positive (i.e., p < 0.001) were validated in an independent validation cohort. MS patients with lesional activity have elevated IL-12p40, CHI3L1, TNFα, TNFβ, and IL-10, with the first two having the strongest effects and validated statistically-significant association with lesional activity in an independent validation cohort. Marker of axonal damage, neurofilament light (NfL), measured in CSF (cNfL) was also significantly elevated in MS patients with active lesions. NfL measured in serum (sNfL) did not differentiate the two MS subgroups with pre-determined significance, (p = 0.0690) even though cCSF and sNfL correlated (Rho = 0.66, p < 0.0001). Finally, the additive model of IL12p40 and CHI3L1 outperforms any biomarker discretely. IL12p40 and CHI3L1, released predominantly by immune cells of myeloid lineage are reproducibly the best CSF biomarkers of MS lesional activity. The residuals from the IL12p40/CHI3L1-cNfL correlations may identify MS patients with more destructive inflammation or contributing neurodegeneration.
Highlights
The multiple sclerosis (MS) lesional inflammatory activity is associated with blood brain barrier (BBB) breakdown and transmigration of immune cells from periphery to central nervous system (CNS) (Lassmann, 2018)
IL-12p40 is mostly produced by activated cells of myeloid lineage, such as monocytes, macrophages, microglia, neutrophils and myeloid dendritic cells, and induces Th1 polarization of T cells (Kanangat et al, 1996; Kichian et al, 1996; Cooper and Khader, 2007), while CHI3L1 is mostly produced by neutrophils and activated astrocytes in the CNS and plays a role in Th2 T cell polarization (Boesen et al, 2018)
We can’t make any determination of causality from our study, the indirect evidence for pathogenicity of CHI3L1 does exist in the literature: subjects with clinically isolated syndrome (CIS) who had high cerebrospinal fluid (CSF) levels of CHI3L1 had greater and faster transition to clinically definite Multiple sclerosis (MS) and a four-fold increased risk for the development of neurological disability compared to CIS subjects with low CSF CHI3L1 levels (Comabella et al, 2010; Canto et al, 2015)
Summary
The multiple sclerosis (MS) lesional inflammatory activity is associated with blood brain barrier (BBB) breakdown and transmigration of immune cells from periphery to central nervous system (CNS) (Lassmann, 2018). CELs only reflect the perivascular inflammation associated with the opening of the BBB and influx of immune cells from blood to form MS lesion. 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)
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