Molecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms

Barbour, Christopher; Kósa, Péter; Varosanec, Mihael; Greenwood, Mark C.; Bielekova, Bibiana

doi:10.1101/2020.05.18.20105932

Cited by 9 publications

(10 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To derive adjustment equations, we pooled all cNfL, sNfL, and CHI3L1 HD subjects’ data available in our research database ( Table 3 and Supplementary Data File 1 ). As described previously ( Barbour et al, 2020 ), linear regression models for the logarithmic value of biomarker concentrations with age as an independent variable were used to predict the healthy, age-related levels of these biomarkers for all MS patients according to their age at time of sample collection; Then to exclude the effect of healthy aging, these predicted biomarker levels due to healthy aging were subtracted from true, measured biomarker levels.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…To differentiate biomarkers specific for MS biology from physiological age- and gender-differences, CSF SOMAscan values for all subjects were adjusted for age and gender dependency within HD subgroup as described (21).…”

Section: Methodsmentioning

confidence: 99%

“…The copyright holder for this this version posted September 18, 2020. ; https://doi.org/10.1101/2020.09.15.20195016 doi: medRxiv preprint To differentiate biomarkers specific for MS biology from physiological age-and genderdifferences, CSF SOMAscan values for all subjects were adjusted for age and gender dependency within HD subgroup as described (21).…”

Section: Statistical Analysesmentioning

confidence: 99%

Drug library screen identifies inhibitors of toxic astrogliosis

Masvekar

Kósa

Barbour

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Objective: Multiple sclerosis is a chronic neuroinflammatory disorder, in which activated immune cells directly or indirectly induce demyelination and axonal degradation. Inflammatory stimuli also change the phenotype of astrocytes, making them neurotoxic. The resulting toxic astrocyte phenotype has been observed in animal models of neuroinflammation and in multiple sclerosis lesions. Proteins secreted by toxic astrocytes are elevated in the cerebrospinal fluid of multiple sclerosis patients and reproducibly correlate with the rates of accumulation of neurological disability and brain atrophy. This suggests a pathogenic role for neurotoxic astrocytes in multiple sclerosis. Methods: Here, we applied a commercially available library of small molecules that are either Food and Drug Administration-approved or in clinical development to an in vitro model of toxic astrogliosis to identify drugs and signaling pathways that inhibit inflammatory transformation of astrocytes to a neurotoxic phenotype. Results: Inhibitors of three pathways related to the endoplasmic reticulum stress: 1) proteasome, 2) heat shock protein 90 and 3) mammalian target of rapamycin reproducibly decreased inflammation-induced conversion of astrocytes to toxic phenotype. Dantrolene, an anti-spasticity drug that inhibits calcium release through ryanodine receptors expressed in the endoplasmic reticulum of central nervous system cells, also exerted inhibitory effect at in vivo achievable concentrations. Finally, we established cerebrospinal fluid SERPINA3 as a relevant pharmacodynamic marker for inhibiting toxic astrocytes in clinical trials. Interpretation: Drug library screening provides mechanistic insight into the generation of toxic astrocytes and identifies candidates for immediate proof-of-principle clinical trial(s).

show abstract

“…All cell proportions and absolute numbers were correlated with age separately in CSF, blood, and as CSF/blood ratios using Spearman correlation in HD cohort. Features that demonstrated significant correlation defined as p -value ≤ 0.05 adjusted for multiple comparisons using false discovery rate (FDR) were subsequently adjusted in patient samples using linear regressions derived from HD cohort: specifically, the measured values were re-calculated as residuals from HD linear regressions as previously described (20).…”

Section: Methodsmentioning

confidence: 99%

Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis through Immunophenotyping

Hannikainen

Kósa

Barbour

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in neuroimmunological disorders such as multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological diseases (OIND) controls to identify MS specific changes. The goals of this blinded, training and validation study of MS patients and embedded controls, representing 1240 prospectively-acquired paired CSF/blood samples from 588 subjects was: 1. To define physiological age/gender-related changes in CSF cells; 2. To define/validate cellular abnormalities in blood and CSF of untreated MS through disease duration (DD) and determine which are MS-specific; 3. To compare effect(s) of low-efficacy (i.e., interferon-beta [IFN-beta] and glatiramer acetate [GA]) and high-efficacy drugs (i.e., natalizumab, daclizumab and ocrelizumab) on MS-related cellular abnormalities using propensity score matching. Physiological gender differences are less pronounced in the CSF compared to blood, while age-related changes suggest decreased immunosurveillance of CNS by activated, HLA-DR+ T cells associated with natural aging. Results from patient samples support concept of MS being immunologically single disease evolving in time. Initially, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. With progression, T cells (CD8+ > CD4+), NK cells and myeloid dendritic cells are depleted from blood as they continue to accumulate, together with B cells, in the CSF and migrate to CNS tissue forming compartmentalized inflammation. All MS drugs inhibit non-physiological accumulation of immune cells in the CSF. While low efficacy drugs tend to normalize it, high efficacy drugs overshoot some aspects of CSF physiology suggesting impairment of CNS immunosurveillance. Comparable inhibition of MS-related CSF abnormalities advocates changes within CNS parenchyma responsible for differences in drug's efficacy on MS disability progression. Video summarizing all results may become useful educational tool.

show abstract

Molecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms

Cited by 9 publications

References 46 publications

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

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

Drug library screen identifies inhibitors of toxic astrogliosis

Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis through Immunophenotyping

Contact Info

Product

Resources

About