{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T11:39:37Z","timestamp":1780745977641,"version":"3.54.1"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T00:00:00Z","timestamp":1625529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian MS Foundation (FISM)","award":["FISM 16\/17\/F14"],"award-info":[{"award-number":["FISM 16\/17\/F14"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-na\u00efve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines\/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p &lt; 0.001), sTNF-R1 (fold change: 1.693; p &lt; 0.001) and sTNF-R2 (fold change: 2.189; p &lt; 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p &lt; 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-\u03b3, IL-1\u03b2, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-\u03b2, IFN-\u03bb2, sIL-6R\u03b1) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1\/2 pathways associates with specific clinical\/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome.<\/jats:p>","DOI":"10.3390\/cells10071712","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T11:36:44Z","timestamp":1625571404000},"page":"1712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Na\u00efve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8284-7763","authenticated-orcid":false,"given":"Roberta","family":"Magliozzi","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy"},{"name":"Department of Brain Sciences, Department of Medicine, Imperial College London, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1590-4558","authenticated-orcid":false,"given":"Francesco","family":"Pezzini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mairi","family":"Pucci","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8854-7072","authenticated-orcid":false,"given":"Stefania","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Higher Institute of Health Care, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Facchiano","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Higher Institute of Health Care, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Marastoni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8999-0001","authenticated-orcid":false,"given":"Martina","family":"Montagnana","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9523-9054","authenticated-orcid":false,"given":"Giuseppe","family":"Lippi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4622-4694","authenticated-orcid":false,"given":"Richard","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Brain Sciences, Department of Medicine, Imperial College London, London W12 0NN, UK"},{"name":"Centre for Molecular Neuropathology, Lee Kong Chian School of Medicine, Singapore 308232, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3362-7403","authenticated-orcid":false,"given":"Massimiliano","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.4049\/jimmunol.179.6.4239","article-title":"Interaction between Transmembrane TNF and TNFR1\/2 Mediates the Activation of Monocytes by Contact with T Cells","volume":"179","author":"Rossol","year":"2007","journal-title":"J. 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