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. 2024 Nov;30(13):1598-1608.
doi: 10.1177/13524585241279645. Epub 2024 Oct 8.

Intrathecal immune reactivity against Measles-, Rubella-, and Varicella Zoster viruses is associated with cerebrospinal fluid inflammation in multiple sclerosis

Benjamin Vlad  1 , Stephan Neidhart  2 , Marc Hilty  1   3 , Klara Asplund Högelin  4 , Ina Reichen  1   5 , Mario Ziegler  1 , Mohsen Khademi  4 , Andreas Lutterotti  1   6   5 , Axel Regeniter  7 , Roland Martin  1   6   8 , Faiez Al Nimer  4 , Ilijas Jelcic  1   6   5
Affiliations

Intrathecal immune reactivity against Measles-, Rubella-, and Varicella Zoster viruses is associated with cerebrospinal fluid inflammation in multiple sclerosis

Benjamin Vlad et al. Mult Scler. 2024 Nov.

Abstract

Background/objectives: We aimed to determine in multiple sclerosis (MS) whether intrathecal immunoglobulin G (IgG) production against measles- (M), rubella- (R), and varicella zoster (Z) viruses, which is called MRZ reaction (MRZR) and considered the most specific soluble biomarker for MS, is associated with demographic and basic cerebrospinal fluid (CSF) parameters reflecting inflammation.

Methods: We analyzed the presence of positive MRZR and associations with demographic and clinical routine CSF parameters in 513 patients with MS and 182 non-MS patients.

Results: Comparing MS patients versus non-MS patients, positive MRZR (38.8% versus 2.2%; specificity 97.8%; positive likelihood ratio, PLR 17.7) had a better specificity and PLR for MS than CSF-specific OCB (89.5% versus 22.0%; specificity 78.0%; PLR 4.1). A positive MRZR in MS patients was associated with female sex (p = 0.0001), pleocytosis (p < 0.0001), higher frequency of presence of plasma cells in CSF (p = 0.0248), normal CSF/serum albumin ratio (p = 0.0005), and intrathecal production of total IgG or CSF-specific OCB (both p < 0.0001), but not with intrathecal production of total IgA or IgM.

Conclusions: This study confirms the MRZR as a highly specific marker of MS and shows that MRZR-positive MS patients more frequently are female and show inflammatory changes of basic CSF parameters than MRZR-negative MS patients.

Keywords: Antibodies; Rubella virus/immunology*; biomarkers/cerebrospinal fluid; herpesvirus 3; human/immunology*; humans; measles virus/immunology*; multiple sclerosis/cerebrospinal fluid*; multiple sclerosis/virology; viral/cerebrospinal fluid*.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.M. is employed part-time by Cellerys, a startup company outfounded from the University of Zurich. He is a co-founder and stockholder of Cellerys and a co-founder of Abata Therapeutics. R.M. is listed as an inventor on patents of the University of Zurich about target antigens in multiple sclerosis. R.M. is further listed as an inventor and received remuneration for an NIH-held patent on the use of daclizumab to treat multiple sclerosis. None of which has an impact on the submitted work. I.J. has received speaker honoraria or unrestricted grants from Biogen Idec and Novartis and has received compensation for advice or lecturing by Alexion, Biogen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Neuway, Merck, Novartis, Roche, and Sanofi Genzyme; none of these are related to this study. The other authors report no conflicts of interest related to this work.

Figures

Figure 1.
Figure 1.
Differences in sex proportion and basic CSF parameters between MS patients with positive and negative MRZ reaction. Depicted are the differences between MS patients with positive MRZ reaction (MRZ+) and MS patients with negative MRZ reaction (MRZ-) regarding (A) sex proportion, (B) CSF white cell count (WCC) in cells/µL, (C) frequency of pleocytosis, WCC 0–4/µL, WCC 5–30/µL, WCC > 30/µL (with dashed line delimiting cut-off for normal CSF cell numbers, i.e., 4/µL), (D) frequency of samples with detection of plasma cells in CSF in %, (E) CSF/serum albumin quotient (QAlb x 10-3), and (F) frequency of samples with blood–CSF barrier (BCFSB) dysfunction. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 2.
Figure 2.
Differences in intrathecal production of IgG, IgA, or IgM between MS patients with positive and negative MRZ reaction. Depicted are the differences between MS patients with positive MRZ reaction (MRZ+) and MS patients with negative MRZ reaction (MRZ–) regarding CSF/serum ratios of (A) IgG (QIgG), (C) IgA (QIgA), and (E) IgM (QIgM), and Reiber diagrams showing intrathecal synthesis of (B) IgG, (D) IgA, and (F) IgM. ***p < 0.001, n.s. = not significant.
Figure 3.
Figure 3.
Differences in occurrence of (A) intrathecal synthesis of IgG (IgGIF > 0), IgA (IgAIF > 0), or IgM (IgMIF > 0) and (B) CSF-specific oligoclonal bands (OCB) between MS patients with positive MRZ reaction (MRZ+) and negative MRZ reaction (MRZ–). ***p < 0.001, n.s. = not significant.
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