The intrathecal polyspecific antiviral immune response (MRZ reaction): A potential cerebrospinal fluid marker for multiple sclerosis diagnosis

Feki, S.; Gargouri, Saba; Mejdoub, Sabrina; Dammak, Mariem; Hachicha, H.; Hadiji, Olfa; Feki, Lamia; Hammami, A.; Mhiri, Chokri; Karray, H.; Masmoudi, Hatem

doi:10.1016/j.jneuroim.2018.05.015

Cited by 19 publications

(12 citation statements)

References 41 publications

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“…MRZR was found positive more frequently in MS than in RDwCNS, despite a high frequency of autoantibodies, hypergammaglobulinemia and positive OCBs in RDwCNS. This is in accordance with findings described before in MS-patients independently of their ANA-status (14, 16, 17). Especially in combination with the absence of specific autoantibodies to nuclear antigens or lack of ANCA-reactivity against PR3 or MPO, MRZR-1 yielded a high specificity and a good sensitivity for diagnosis of MS.…”

Section: Discussionsupporting

confidence: 93%

The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA-Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement

et al. 2019

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Objective: Rheumatic diseases with involvement of the central nervous system (RDwCNS) may mimic multiple sclerosis (MS). Inversely, up to 60% of MS-patients have antinuclear autoantibodies (ANAs) and may be misdiagnosed as RDwCNS. The detection of antibodies against extractable nuclear antigens (ENA) and oligoclonal bands (OCB) are established valuable diagnostic tools in the differential diagnosis of RDwCNS and MS. The MRZ-reaction (MRZR) is defined by three antibody indices (AIs) against neurotropic viruses and is frequently positive in MS. To investigate the added value of MRZR combined with testing for antibodies against ENAs and OCB detection to distinguish RDwCNS from ANA positive MS.Methods: MRZR was evaluated in RDwCNS (n = 40) and 68 ANA positive MS-patients. Two stringency levels, MRZR-1 and MRZR-2 (at least one respectively two of three AIs positive) were applied. Autoantibody testing included ANA plus ENA and anti-dsDNA antibodies, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies.Results: Most of the RDwCNS patients (n = 32; 80%) suffered from systemic lupus erythematosus. Within the RDwCNS group 20% had a positive MRZR-1 and 8.5% a positive MRZR-2 compared to 80.9 and 60%, respectively within the MS-group (p < 0.0001 for both comparisons). Oligoclonal bands were found in 28.6% of the RDwCNS patients and 94.3% of the MS-patients (p < 0.0001). Conversely, autoantibodies to specific nuclear antigens or phospholipids were found more frequently in RDwCNS. A positive MRZR in conjunction with the absence of ENA autoantibodies distinguished MS from RDwCNS with high specificity (97.5%).Conclusions: We suggest combining MRZR, OCBs, and specific autoantibody diagnostics to differentiate RDwCNS from MS.

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Section: Discussionsupporting

confidence: 93%

The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA-Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement

et al. 2019

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“…In this multicentric PPMS cohort, we report a positive MRZR in around half of PPMS patients overall and in each treatment center. Our finding that a considerable proportion (66.7%) among the few OCB-PPMS patients were MRZR+ is in line with earlier reports predominantly concerning RRMS patients [25,26]. Furthermore, in all MRZR+OCB-PPMS patients, positive MRZR was the only available sign of CSF inflammation, highlighting its diagnostic value in those rare cases of suspected MS without OCB.…”

Section: Csf Biomarkers For Ms Diagnosissupporting

confidence: 91%

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

Robinson

Abdelhak

Bose

et al. 2020

Cells

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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.

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“…In MS, much evidence indicates a role for EBV and specifically that EBV-infected B cells have entered the CNS at some point of disease development ( Table 1) (11)(12)(13)(14)(15)(16). EBV AIs are also elevated, however, not necessarily to the same extent as other AIs, despite the presence of high levels of Abs to EBV in serum of MS patients (15,124).…”

Section: Ebv and Msmentioning

confidence: 99%

“…These criteria include detection of active inflammatory foci in the CNS as seen by positron emission tomography (PET) and magnetic resonance imaging (MRI) and intrathecal production of immunoglobulins (Igs), measured as an elevated cerebrospinal fluid (CSF)/serum IgG index, as a free light chain index or as the occurrence of oligoclonal bands (OCBs) of IgG in CSF (6)(7)(8)(9)(10). Each oligoclonal band is a result of intrathecal antibody (Ab) synthesis by single B cell clones and therefore, specific CSF/ serum Ab indices (AIs) may also be elevated, e.g., Abs to various viruses, corresponding to the specificity of some of the OCBs (11)(12)(13)(14)(15). Accordingly, the OCB Abs show evidence of antigen (Ag) exposure, somatic hypermutation and affinity maturation (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus and Multiple Sclerosis

2020

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Multiple sclerosis (MS) is a neurologic disease affecting myelinated nerves in the central nervous system (CNS). The disease often debuts as a clinically isolated syndrome, e.g., optic neuritis (ON), which later develops into relapsing-remitting (RR) MS, with temporal attacks or primary progressive (PP) MS. Characteristic features of MS are inflammatory foci in the CNS and intrathecal synthesis of immunoglobulins (Igs), measured as an IgG index, oligoclonal bands (OCBs), or specific antibody indexes. Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). Many of the clinical signs of MS described above can be explained by chronic/recurrent EBV infection and current models of EBV involvement suggest that RRMS may be caused by repeated entry of EBV-transformed B cells to the CNS in connection with attacks, while PPMS may be caused by more chronic activity of EBV-transformed B cells in the CNS. In line with the model of EBV’s role in MS, new treatments based on monoclonal antibodies (MAbs) targeting B cells have shown good efficacy in clinical trials both for RRMS and PPMS, while MAbs inhibiting B cell mobilization and entry to the CNS have shown efficacy in RRMS. Thus, these agents, which are now first line therapy in many patients, may be hypothesized to function by counteracting a chronic EBV infection.

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The intrathecal polyspecific antiviral immune response (MRZ reaction): A potential cerebrospinal fluid marker for multiple sclerosis diagnosis

Cited by 19 publications

References 41 publications

The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA-Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement

The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA-Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement

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

Epstein-Barr Virus and Multiple Sclerosis

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