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Quantitative Measurement of Intrathecally Synthesized Proteins in Mice
Published on: November 29, 2019
Free light chain kappa and the polyspecific immune response in MS and CIS - Application of the hyperbolic reference
Marie Süße1, Hansotto Reiber2, Matthias Grothe1
1Departement of Neurology, University Medicine Greifswald, Greifswald, Germany.
Insights
Free light chain kappa (FLC-k) analysis in cerebrospinal fluid (CSF) using hyperbolic reference ranges offers superior diagnostic accuracy for multiple sclerosis (MS) compared to linear indices. This method aids in earlier MS detection and assessing intrathecal immune responses.
Area of Science:
- Neurology
- Immunology
- Biochemistry
Background:
- Intrathecal immune responses involve free light chain kappa (FLC-k) in cerebrospinal fluid (CSF).
- FLC-k is increasingly investigated for its diagnostic sensitivity in neurological conditions.
- Accurate interpretation of FLC-k is crucial for diagnosing conditions like multiple sclerosis (MS).
Purpose of the Study:
- To apply and interpret FLC-k data using quotient diagrams with a hyperbolic reference range.
- To compare the diagnostic performance of the hyperbolic reference range method against other reference methods and cut-off values.
- To analyze the FLC-k quotient diagram's performance in MS and clinically isolated syndrome (CIS) patients, and its relation to polyspecific immune responses.
Main Methods:
- FLC-k was quantified in a control cohort (n=302) and MS/CIS patients (n=98) using nephelometry.
- Intrathecal FLC-k fraction was calculated based on a hyperbolic reference range.
- Comparisons were made with linear FLC-k indices and routine CSF parameters like oligoclonal bands (OCB) and polyspecific antiviral immune response.
Main Results:
- The hyperbolic reference range identified intrathecal FLC-k synthesis in 20/302 OCB-negative controls.
- Sensitivity for definitive MS was 100% with the hyperbolic method, versus 93% for OCB.
- Linear FLC-k indices showed similar MS sensitivity but risked false positives/negatives in controls; hyperbolic method proved superior.
- CIS patients (later MS) showed higher intrathecal FLC-k synthesis than definitive MS patients.
- A positive MRZ reaction in 53% of CIS patients with intrathecal FLC-k synthesis suggested potential for earlier MS diagnosis.
Conclusions:
- FLC-k evaluation with hyperbolic reference ranges in quotient diagrams surpasses linear FLC-k index methods.
- A sequential CSF testing approach including FLC-k Reibergram evaluation is suggested, potentially followed by isoelectric focusing.
- The MRZ reaction demonstrated high specificity for MS diagnosis.
Objectives:
Free light chain kappa (FLC-k) in cerebrospinal fluid (CSF) is involved in intrathecal immune responses and is being investigated frequently for its diagnostic sensitivity. The objective of this study was the application and interpretation of FLC-k data in quotient diagrams with a hyperbolic reference range and to confirm the superior evaluation in comparison with another proposed reference method and cut-off values. Secondly, the performance of the FLC-k quotient diagram was analyzed in respect to MS and CIS patients and in relation to the polyspecific immune response.
Materials And Methods:
FLC-k was analyzed in a control cohort (n = 302) and in patients with MS/CIS (n = 98) using a nephelometric FLC-k kit. The intrathecal fraction of FLC-k based on the hyperbolic reference range was calculated in comparison to various linear FLC-k indices and routine CSF parameters [oligoclonal bands (OCB), polyspecific antiviral immune response].
Results:
Using the new hyperbolic reference range, intrathecal FLC-k synthesis was found in 20 / 302 OCB negative controls. The sensitivity in the definitive MS cohort was 100%, compared to 93% positive OCB. The linear FLC-k Index interpretation with similar sensitivity for MS, however, bares the risk for the control samples,depending on the reference range, of false positive interpretations (up to 7 at low QAlb) or false negative interpretations (up to 17/20 FLC-k positives at high QAlb). The quantitative mean intrathecal FLC-k synthesis in the CIS cohort (later MS) was even slightly higher than in initially definitive MS questioning a pathophysiological difference. A positive MRZ reaction found in 53% percent of CIS patients with intrathecal FLC-k synthesis could have allowed diagnosis of MS immediately, i.e. earlier than with the Mc Donald criteria.
Conclusions:
The evaluation of FLC-k with hyperbolic reference range in quotient diagrams is superior to other analytical methods like the linear FLC-k index. We suggest a sequential CSF testing with FLC-k Reibergram evaluation, potentially followed by isoelectric focusing. With the MRZ reaction we obtain highest specificity for MS diagnosis.
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