Chemokine CXCL13 in serum, CSF and blood–CSF barrier function: evidence of compartment restriction

Abstract

Background and purpose: Elevation of the chemokine CXCL13 in CSF frequently occurs during active and acute CNS inflammatory processes and presumably is associated with B cell-related immune activation. Elevation levels, however, vary a lot and "leaking" of CXCL13 from blood across dysfunctional brain barriers is a possible source. The aim was to clarify the relation between CXCL13 concentrations in CSF, CXCL13 concentrations in serum and blood-CSF barrier (BCSFB) function for a correct interpretation of the intrathecal origin of CXCL13. Methods: We retrospectively analyzed CXCL13 of banked CSF/serum samples (n = 69) selected from patient records and categorized the CSF CXCL13 elevations as CXCL13 negative (< 30 pg/ml), low (30-100 pg/ml), medium (101-250 pg/ml), or high (> 250 pg/ml). CXCL13 concentrations in CSF and serum and the corresponding CSF/serum CXCL13 quotients (Qcxcl13) were compared to CSF/serum albumin quotients (QAlb) as a measure for BCSFB function. The CXCL13 negative category included two subgroups with normal and dysfunctional BCSFB. Results: Serum CXCL13 concentrations were similar across categories with median levels around 100 pg/ml but differed between individuals (29 to > 505 pg/ml). Despite clear evidence in serum, CXCL13 was detectable only at trace amounts (medians 3.5 and 7.5 pg/ml) in CSF of the two CXCL13 negative subgroups irrespective of a normal or pathological QAlb. Moreover, we found no association between CSF and serum CXCL13 levels or between QAlb and CSF CXCL13 levels in any of the CSF CXCL13-delineated categories. CXCL13 apparently does not "leak" from blood into CSF. This implies an intrathecal origin also for low CSF CXCL13 levels and a caveat for analyzing the Qcxcl13, because higher serum than CSF concentrations arithmetically depress the Qcxcl13 resulting in misleadingly low CSF/serum quotients. Conclusion: We demonstrated that CXCL13 does not cross from blood into CSF, not even during severe BCSFB dysfunction. CSF CXCL13 elevations therefore most likely always are CNS-derived, which highlights their relevance as indicator of inflammatory CNS processes. We recommend data should not be corrected for BCSFB permeability (QAlb) and not to calculate CSF/serum quotients for CXCL13 as these may introduce error.

Association of Circulating Follicular Helper T Cells and Serum CXCL13 With Neuromyelitis Optica Spectrum Disorders

“…Given that blood samples are easily available and that CXCL13 in both the central nervous system and blood may reflect immune activation in the central nervous system, routine monitoring of peripheral blood CXCL13 levels in patients with NMOSD is feasible for understanding and evaluating disease progression. Other studies have suggested that co-determination of serum CXCL13 has potential in allocating the focus of the inflammatory process, which may localize to the periphery or to the CNS or co-localize in both compartments with possible therapeutic consequences (24). These results are consistent with our findings.…”

NFL and CXCL13 may reveal disease activity in clinically and radiologically stable MS

“…Both biomarkers were correlated to each other and hence, the contribution from CXCL13 seemed low. Further, although CXCL13 can be determined in both CSF and blood the CXCL13 concentration in these compartments may not reflect similar pathological processes (Pilz et al 2020). Infections or other co-morbidities outside the CNS may influence blood CXCL13 (Kazanietz et al 2019).…”

Highly sensitive quantification of optic neuritis intrathecal biomarker CXCL13

“…Furthermore, even in patients with abnormal Qalb suggesting BCSFB leakiness, there was evidence of CXCL13 not being able to diffuse the BCSFB. Overall, the data suggested a high degree of compartmentalization that argues against the use of serum CXCL13 as a proxy for neuroinflammation (Pilz et al, 2020).…”