Association of cerebrospinal fluid kappa free light chains with the intrathecal polyspecific antiviral immune response in multiple sclerosis
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).
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Free light chain kappa and the polyspecific immune response in MS and CIS – Application of the hyperbolic reference range for most reliable data interpretation
2020, Journal of NeuroimmunologyCitation Excerpt :As already reported (Reiber, 2016; Rocha et al., 2013), the detection of the MRZ response may be superior to the diagnostic value of imaging techniques. The MRZ antibody response is the only specific laboratory parameter for the indication of a chronic disease either as MS or as an autoimmune disease involving the central nervous system (Jarius et al., 2017; Reiber, 2017; Huss et al., 2019). The higher frequency of the MRZ reaction in patients with CIS (higher mean FLC-kloc value) compared to the MS group supports the observation made for total IgG that the detection frequency of the MRZ reaction increases with increasing intrathecal immune response (Reiber et al., 1998; Reiber, 2016).
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