Cerebrospinal Fluid Biomarkers in Relation to MRZ Reaction Status in Primary Progressive Multiple Sclerosis.

Ahmed Abdelhak,Tilman Robinson,Uwe K Zettl,Tanima Bose,André Huss,Edgar Meinl,Sebastian Rauer,Rick Dersch,Markus Otto,Hayrettin Tumani

doi:10.3390/cells9122543

Abstract

The MRZ reaction (MRZR) comprises the three antibody indices (AIs) against measles, rubella, and varicella zoster virus, reflecting an intrathecal polyspecific B cell response highly specific for multiple sclerosis (MS). Thus, MRZR can be used to confirm a diagnosis of primary progressive MS (PPMS) but its pathophysiological and wider clinical relevance is unclear. This study aimed to investigate whether PPMS patients with a positive MRZR (MRZR+) differ from those with a negative MRZR (MRZR-) according to cerebrospinal fluid (CSF) biomarkers of B cell activity, neuroaxonal damage or glial activity, and clinical features. (1) Methods: In a multicenter PPMS cohort (n = 81) with known MRZR status, we measured B cell-activating factor (BAFF), chemokine CXC ligand 13 (CXCL-13), soluble B cell maturation antigen (sBCMA), soluble transmembrane activator and CAML interactor (sTACI), and chitinase-3-like protein 1 (CHI3L1) in the CSF with enzyme-linked immunosorbent assays (ELISAs). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were detected in serum and CSF using single molecule array (SIMOA) technology. (2) Results: MRZR+ patients (45.7% of all PPMS patients) revealed higher levels of NfL in CSF compared to MRZR- patients (54.3%). There were positive correlations between each of sBCMA, sTACI, and intrathecal immunoglobin G (IgG) synthesis. Additionally, NfL concentrations in serum positively correlated with those in CSF and those of GFAP in serum. However, MRZR+ and MRZR- patients did not differ concerning clinical features (e.g., age, disease duration, Expanded Disability Status Scale (EDSS) at diagnosis and follow-up); CSF routine parameters; CSF concentrations of BAFF, CXCL-13, sBCMA, sTACI, CHI3L1, and GFAP; or serum concentrations of GFAP and NfL. (3) Conclusions: In PPMS patients, MRZR positivity might indicate a more pronounced axonal damage. Higher levels of the soluble B cell receptors BCMA and transmembrane activator and CAML interactor (TACI) in CSF are associated with a stronger intrathecal IgG synthesis in PPMS.

Highlights

It has been found that 10 to 15% of all multiple sclerosis (MS) patients are suffering from primary progressive multiple sclerosis (PPMS) [1]
Higher levels of the soluble B cell receptors B cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI) in cerebrospinal fluid (CSF) are associated with a stronger intrathecal immunoglobin G (IgG) synthesis in PPMS
This hypothesis is supported by the efficacy of ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells and the only MS drug currently approved for both RRMS and PPMS patients [7,8]

Summary

Introduction

It has been found that 10 to 15% of all multiple sclerosis (MS) patients are suffering from primary progressive multiple sclerosis (PPMS) [1]. In contrast to the more common primary relapsing–remitting type of MS (RRMS), PPMS patients show a more balanced gender distribution, later symptom onset, and gradually increasing neurological disability without discernable relapses [2,3]. B cells and humoral immune mechanisms have been suggested as playing a key role in the pathogenesis of MS [4,5,6]. This hypothesis is supported by the efficacy of ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells and the only MS drug currently approved for both RRMS and PPMS patients [7,8]. Intrathecal immunoglobulin G synthesis was recently found to be associated with disability worsening in MS [11]

Objectives

Results

Discussion

Conclusion