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

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.

Keywords: B cell-activating factor (BAFF); MRZ reaction (MRZR); chemokine CXC ligand 13 (CXCL-13); chitinase-3-like protein 1 (CHI3L1); glial fibrillary acidic protein (GFAP); neurofilament light chain (NfL); primary progressive multiple sclerosis (PPMS); soluble B cell maturation antigen (sBCMA); soluble transmembrane activator and CAML interactor (sTACI).

Figure 1

CXCL-13: chemokine CXC ligand 13; CSF: cerebrospinal fluid; BAFF: B cell-activating factor; MRZR-: primary progressive multiple sclerosis patients with no more than one positive MRZ antibody index; MRZR+: primary progressive multiple sclerosis patients with at least two positive MRZ antibody indices.

Figure 2

sBCMA: soluble B cell maturation antigen; CSF: cerebrospinal fluid; sTACI: soluble transmembrane activator and CAML interactor; MRZR-: primary progressive multiple sclerosis patients with no more than one positive MRZ antibody index; MRZR+: primary progressive multiple sclerosis patients with at least two positive MRZ antibody indices.