Elsevier

Clinica Chimica Acta

Volume 498, November 2019, Pages 148-153
Clinica Chimica Acta

Association of cerebrospinal fluid kappa free light chains with the intrathecal polyspecific antiviral immune response in multiple sclerosis

https://doi.org/10.1016/j.cca.2019.08.016Get rights and content

Highlights

  • CSF immunoglobulin kappa and lambda free light chains are quantitative B-cell response markers.

  • The MRZ reaction is the most specific neurochemical marker for multiple sclerosis.

  • MRZ reaction is associated with kappa but not lambda free light chains.

  • CSF immunoglobulin kappa free light chains might be a helpful marker in multiple sclerosis.

Abstract

The polyspecific B-lymphocyte response to neurotropic viruses such as measles (M), rubella (R) and varicella zoster (Z), known as MRZ reaction, is to-date the most specific neurochemical marker for multiple sclerosis (MS). The aim of this study was to investigate a possible association of immunoglobulin (Ig) kappa (κ-) and lambda (λ-) free light chains (FLC) with the presence of the MRZ reaction in multiple sclerosis.

Immunoglobulin κ- and λ-FLC, MRZ reaction, oligoclonal IgG bands (OCB), and cerebrospinal fluid (CSF) routine parameters were measured in 65 MS patients.

OCB were detected in 97% of MS patients, intrathecal IgG synthesis according to Reiber was detectable in 57%, an elevated IgG index (>0.7) in 66% and the MRZR was positive in 45%. All investigated κ-values (CSF κFLC, CSF-serum ratio of κFLCs (QκFLC), and κFLC index (κFLC/QAlbumin)) were significantly higher in patients with positive MRZ reaction as compared to MRZ negative MS patients. In contrast, λ-values showed no significant differences.

Additionally to the putative diagnostic sensitivity and prognostic value of κFLC, the association of κFLC with a highly specific neurochemical marker for MS – the MRZ reaction, especially the determination of κFLCs is an informative tool to assess the B-cell response and determine its extent in MS patients.

Introduction

Detection of intrathecal B-lymphocyte activation is one of the most important tools to establish the diagnosis of Multiple Sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). The diagnostic criteria of MS evolved over the past decades and underwent the latest revisions in 2005 [1], 2010 [2] and recently in 2017 [3]. One main adjustment of the last revision is the inclusion of cerebrospinal fluid (CSF) specific oligoclonal IgG bands (OCB) as an addition to dissemination in space detected by MRI to fulfil the diagnostic criteria of MS [3]. A positive OCB finding indicates chronic inflammation in the CNS and can be detected in approximately 95% of MS patients [[4], [5], [6]]. However, OCB are not specific for MS but are also frequently detected in other autoimmune/inflammatory CNS diseases [7,8]. The determination of OCB requires technical expertise to lead to reliable results [9,10]. In recent years, immunoglobulin kappa (κ) and lambda (λ) free light chains (FLC), both produced by terminal B lymphocytes, have been discussed as quantitative parameters for intrathecal IgG synthesis with similar diagnostic precision for MS as OCB [[11], [12], [13], [14], [15]]. Furthermore, they could serve as a prognostic marker in patients with a first clinical event suggestive of MS [[16], [17], [18]].

As for OCB, κ- and λ-FLC show high sensitivity for MS but are elevated in other inflammatory CNS disorders as well [14]. To evaluate whether κ- and λ-FLC have an added diagnostic value over OCB for MS, its diagnostic specificity needs to be studied. Up to now the most specific neurochemical marker for MS is the so-called MRZ reaction (MRZR), which in more detail is the detection of intrathecally produced IgG antibodies against measles (M), rubella (R) and varicella zoster (Z), whereof at least two out of the three have to be positive [19,20].

As a new aspect in contrast to previous studies which investigated the diagnostic sensitivity of FLC compared to OCB [15,18,[21], [22], [23]], we aimed to investigate a possible association of CSF immunoglobulin κ- and λ-FLC with the presence of the MRZ reaction in multiple sclerosis.

Section snippets

Patients

This study included 65 MS patients who were seen at the Department of Neurology of the University of Ulm and fulfilled the revised McDonald criteria 2017 [3]. CSF and serum samples were obtained in parallel for diagnostic purposes and were handled accordingly to the consensus protocol for CSF analysis [24].

Determination of CSF and serum parameters

CSF leukocyte count (cells/μl) was determined using the Fuchs Rosenthal Counting Chamber. CSF total protein (g/l), CSF lactate (mmol/l), the albumin CSF-serum concentration ratio (QAlb), CSF

Subject description

Demographic data, main CSF characteristics, and both qualitative (OCB) and quantitative (IgG index, intrathecal IgG synthesis, κ- and λ-FLC) parameters of intrathecal B-cell response are shown in Table 1.

OCB were detected in 97% of MS patients, intrathecal IgG synthesis according to Reiber was detectable in 57%, an elevated IgG index (>0.7) in 66% and the MRZR was positive in 45%.

In MRZR positive MS patients, 100% showed positive OCB, 86% showed elevated IgG index (>0.7) and 72% showed

Discussion

Chronic inflammation of the CNS is a major hallmark of MS [30] and can be demonstrated by the detection of an intrathecal IgG production. Here, the detection of oligoclonal IgG bands is the gold standard for an intrathecal IgG production, which can be found in approximately 95% of MS patients [[4], [5], [6]]. Furthermore, κ- and λFLC are discussed as putative markers for the detection of intrathecal IgG production, while in particular κFLC performs almost as well as OCB in terms of diagnostic

Conclusion

We conclude that additionally to the putative diagnostic sensitivity and prognostic value of κFLC, the association of κFLC with a highly specific neurochemical marker for MS – the MRZ reaction, especially the determination of κFLCs is an informative and particularly quantitative tool to assess B-cell response in MS patients. The utility of κFLC analysis as a marker for the differentiation of a persistent/chronic B-cell activation and a serological scar should be systematically investigated with

Contributors

MS, AH and HT were involved in the conception and design of the study. Data were acquired by AH, FMY, FB, TF, JL, MO, MS and HT. AH, FMY, HT and MS were involved in the statistical methods and analysis. The first draft of the manuscript was designed by AH and MS, followed by a critical revision of all authors. The final version for submission was approved by all authors.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declaration of Competing Interest

AH has nothing to declare.

FMJ has nothing to declare.

FB has nothing to declare.

TF has nothing to declare.

JL has received honoraria for speaking and travel grants from Bayer, TEVA, CHDI and the Movement Disorders Society.

MO has nothing to declare.

HT received funding for research projects, lectures and travel from Bayer, Biogen, Genzyme, Fresenius, Merck, Mylan, Novartis, Roche, Siemens Health Diagnostics, Teva, and received research support from Hertie-Stiftung, DMSG, BMBF, University of Ulm and

Acknowledgements

We would like express our greatest gratitude to all patients for participating in this study. Furthermore, we would like to thank all technicians of our CSF lab for their great work and expertise.

This study was supported by the German Federal Ministry of Education and Research (KKNMS).

References (44)

  • C.H. Polman et al.

    Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”

    Ann. Neurol.

    (2005)
  • C.H. Polman et al.

    Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria

    Ann. Neurol.

    (2011)
  • P. Schwenkenbecher et al.

    McDonald criteria 2010 and 2005 compared: persistence of high oligoclonal band prevalence despite almost doubled diagnostic sensitivity

    Int. J. Mol. Sci.

    (2016)
  • M.S. Freedman et al.

    Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement

    Arch. Neurol.

    (2005)
  • D. Cerrato et al.

    CFS Oligoclonal bands in MS and other neurological diseases detected by agarose isoelectric focusing and electrophoresis

    Ital. J. Neurol. Sci.

    (1984)
  • A.B. Chu et al.

    Oligoclonal IgG bands in cerebrospinal fluid in various neurological diseases

    Ann. Neurol.

    (1983)
  • F. Sellebjerg et al.

    Qualitative assessment of intrathecal IgG synthesis by isoelectric focusing and immunodetection: interlaboratory reproducibility and interobserver agreement

    Scand. J. Clin. Lab. Invest.

    (1996)
  • D. Franciotta et al.

    Interlaboratory reproducibility of isoelectric focusing in oligoclonal band detection

    Clin. Chem.

    (2007)
  • G. Passerini et al.

    Free light chains and intrathecal B cells activity in multiple sclerosis: a prospective study and meta-analysis

    Mult. Scler. Int.

    (2016)
  • S. Presslauer et al.

    Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: a multicenter study

    Mult. Scler. J.

    (2016)
  • M. Christiansen et al.

    Cerebrospinal fluid free kappa light chains and kappa index perform equal to oligoclonal bands in the diagnosis of multiple sclerosis

    Clin. Chem. Lab. Med.

    (2018)
  • M. Senel et al.

    CSF free light chains as a marker of intrathecal immunoglobulin synthesis in multiple sclerosis: a blood-CSF barrier related evaluation in a large cohort

    Front. Immunol.

    (2019)
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