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Microwave & magnetic (M2) proteomics reveals CNS-specific protein expression waves that precede clinical symptoms of experimental autoimmune encephalomyelitis.

ABSTRACT: Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave &magnetic (M(2)) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M(2) proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M(2) proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and ?-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M(2) proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE.

SUBMITTER: Raphael I

PROVIDER: S-EPMC4152753 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Microwave & magnetic (M2) proteomics reveals CNS-specific protein expression waves that precede clinical symptoms of experimental autoimmune encephalomyelitis.

Raphael Itay I Mahesula Swetha S Purkar Anjali A Black David D Catala Alexis A Gelfond Jonathon A L JA Forsthuber Thomas G TG Haskins William E WE

Scientific reports 20140903

Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave &magnetic (M(2)) proteomics of CSPs in brain tissue might be an effective m ...[more]

PMID: 25182730

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Project description:BackgroundMultiple sclerosis (MS) is a debilitating neurological disease caused by autoimmune destruction of the myelin sheath. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for the pathogenesis of MS. We and others have previously demonstrated that IL-17 is critical for the pathogenesis of EAE. The concentration of IL-17 is significantly higher in the sera of MS patients than in healthy controls and correlates with disease activity. Moreover, anti-IL-17 neutralizing antibody demonstrated promising efficacy in a phase II trial in MS patients, further substantiating a key pathogenic role for IL-17 in MS. While Th17 and IL-17 are emerging as a bona fide drivers for neuroinflammation, it remains unclear what effector molecule executes the inflammatory tissue destruction in Th17-driven EAE.MethodsBy microarray analysis, we found STEAP4 is a downstream molecule of IL-17 signaling in EAE. We then used STEAP4 global knockout mice and STEAP4 conditional knockout mice to test its role in the pathogenesis of EAE.ResultsHere, we report that the metalloreductase, STEAP4, is a key effector molecule that participates and contributes to the pathogenesis of Th17-mediated neuroinflammation in experimental autoimmune encephalomyelitis. STEAP4 knockout mice displayed delayed onset and reduced severity of EAE induced by active immunization. The reduced disease phenotype was not due to any impact of STEAP4 deficiency on myelin reactive T cells. In contrast, STEAP4 knockout mice were resistant to passively induced EAE, pointing to a role for STEAP4 in the effector stage of EAE. Notably, STEAP4 was only induced the spinal cord of EAE mice that received Th17 cells but not Th1 cells. Consistently, STEAP4 deficiency protected from only Th17 but not Th1-induced EAE. Finally, using Nestin-Cre STEAP4fl/fl mice, we showed that ablation of STEAP4 expression in the resident cells in the central nervous system attenuated disease severity in both active immunization and passive Th17 transfer-induced EAE.ConclusionIn this study, we identified STEAP4 as a Th17-specific effector molecule that participates and contributes to the pathogenesis of neuroinflammation, thus potentially provide a novel target for MS therapy.

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Microwave & magnetic (M2) proteomics reveals CNS-specific protein expression waves that precede clinical symptoms of experimental autoimmune encephalomyelitis.

Publications

Microwave & magnetic (M2) proteomics reveals CNS-specific protein expression waves that precede clinical symptoms of experimental autoimmune encephalomyelitis.

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