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Here, we analyzed the most specific biomarker for MS, that is, the polyspecific intrathecal IgG antibody production against measles, rubella, and varicella zoster virus (MRZ reaction), for possible HLA associations in MS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed MRZ reaction from 184 Swiss patients with MS and clinically isolated syndrome (CIS) and 89 Swiss non\u2010MS\/non\u2010CIS control patients, and performed HLA sequence\u2010based typing, to check for associations of positive MRZ reaction with the most prevalent HLA alleles. We used a cohort of 176 Swedish MS\/CIS patients to replicate significant findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Whereas positive MRZ reaction showed a prevalence of 38.0% in MS\/CIS patients, it was highly specific (97.7%) for MS\/CIS. We identified HLA\u2010DRB1*15:01 and other tightly linked alleles of the HLA\u2010DR15 haplotype as the strongest HLA\u2010encoded risk factors for a positive MRZ reaction in Swiss MS\/CIS (odds ratio [OR], 3.90, 95% confidence interval [CI] 2.05\u20137.46, <jats:italic>p<\/jats:italic><jats:sub>adjusted<\/jats:sub>\u2009=\u20090.0004) and replicated these findings in Swedish MS\/CIS patients (OR 2.18, 95%\u2010CI 1.16\u20134.02, <jats:italic>p<\/jats:italic><jats:sub>adjusted<\/jats:sub>\u2009=\u20090.028). In addition, female MS\/CIS patients had a significantly higher probability for a positive MRZ reaction than male patients in both cohorts combined (<jats:italic>p<\/jats:italic><jats:sub>adjusted<\/jats:sub>\u2009&lt;0.005).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>HLA\u2010DRB1*15:01, the strongest genetic risk factor for MS, and female sex, 1 of the most prominent demographic risk factors for developing MS, predispose in MS\/CIS patients for a positive MRZ reaction, the most specific CSF biomarker for MS. ANN NEUROL 2024;95:1112\u20131126<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26921","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T10:18:29Z","timestamp":1711707509000},"page":"1112-1126","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["HLA Associations of Intrathecal <scp>IgG<\/scp> Production against Specific Viruses in Multiple Sclerosis"],"prefix":"10.1002","volume":"95","author":[{"given":"Stephan","family":"Neidhart","sequence":"first","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8830-0173","authenticated-orcid":false,"given":"Benjamin","family":"Vlad","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Hilty","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara Asplund","family":"H\u00f6gelin","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Berenjeno\u2010Correa","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Reichen","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-0039","authenticated-orcid":false,"given":"Pernilla","family":"Stridh","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Jelcic","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Khademi","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0867-4726","authenticated-orcid":false,"given":"Ingrid","family":"Kockum","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia","family":"Sospedra","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"},{"name":"Clinical Research Priority Program MS (CRPP) Precision<sup>MS<\/sup> of the University of Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiez","family":"Al Nimer","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Martin","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University of Zurich and University Hospital  Zurich Switzerland"},{"name":"Clinical 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