Are CSF CXCL13 concentrations solely dependent on intrathecal production? A commentary on \u201cChemokine CXCL13 in serum, CSF, and blood\u2013CSF barrier function\u201d

Krista D Disano,Francesca Gilli,Andrew R Pachner

doi:10.1186/s12987-021-00244-5

Krista D Disano, Francesca Gilli + Show 1 more

Open Access

https://doi.org/10.1186/s12987-021-00244-5

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Abstract

Pilz et al. (Fluids Barriers CNS 17:7; 2020) investigated how CSF CXCL13 concentrations are influenced by CXCL13 serum concentrations and blood-CSF barrier (BCSFB) function, comparing the impact of serum CXCL13 levels and Qalbumin (CSF albumin/serum albumin) on CSF CXCL13 among patients with CNS inflammation categorized as CXCL13 negative, low, medium, or high. Among all CXCL13 groups, their results showed no correlation between CSF CXCL13 concentrations and serum CXCL13 or Qalbumin. The authors argue that, in contrast to other proteins, CXCL13 passage across the BCSFB does not occur, regardless of BCSFB function, and is instead solely influenced by intrathecal production. In contrast to the authors’ findings, in our studies including both non-inflammatory neurological disorders (NIND; n = 62) and multiple sclerosis (MS) patients we observed a significant correlation between serum CXCL13 concentrations and CSF CXCL13 concentrations. We review several observations which may underlie these contrasting results, including (1) the impact of serum CXCL13 concentrations on CSF CXCL13 in patients with lower intrathecal CXCL13 production and thus lower CXCL13 concentrations (i.e. NIND and MS), (2) the proposed diffusion dynamics of the small molecule CXCL13 across the BCSFB, and (3) differing definitions of negative versus elevated CSF CXCL13 concentrations determined by an assay’s relative sensitivity. In conclusion, we argue that for patients with moderately elevated CSF CXCL13 concentrations, serum CXCL13 concentrations influence CSF CXCL13 levels, and thus the appropriate corrections including incorporation of CSF/serum ratios and Qalbumin values should be utilized.

Highlights

Pilz et al.’s conclusion that the blood-cerebrospinal fluid (CSF) barrier (BCSFB) is completely closed to a small protein like CXCL13 runs counter to long experience of neuroscientists with the equilibrium between proteins in the blood and CSF [7], and would represent, if true, a remarkable and surprising exception
These results challenge the use of CSF/serum quotients or index calculations (i.e. (CSF analyte/serum analyte)/(CSF albumin/serum albumin), which are conventionally used to distinguish between passive transfer of proteins from the serum across the blood-CSF-barrier (BCSFB) into the CSF and intrathecal production
The conclusions in the Pilz manuscript were not sufficiently supported by the data presented, especially for inflammatory conditions, such as multiple sclerosis (MS), where there is minimal, if any, blood-CSF barrier (BCSFB) dysfunction, and there are small elevations of intrathecally produced CSF CXCL13 relative to the dramatic elevations seen in diseases such as Lyme neuroborreliosis (LNB) [10–12]

Summary

Background

There has been increased attention to candidate biomarkers in the cerebrospinal fluid (CSF) in neurological diseases. For biomarkers derived from the periphery or CNS, including inflammatory proteins, the relationship between serum and CSF levels of these proteins are an important concept. CXCL13, a 10 kD chemokine, is a candidate CSF biomarker in MS [1].

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