Intrathecally produced CXCL13: A predictive biomarker in multiple sclerosis

Abstract

Background Clinicians caring for patients with Multiple Sclerosis (MS) need improved biomarkers to aid them in disease management. Objective We assessed the predictive value of the candidate biomarker CXCL13 index in comparison to oligoclonal bands (OCBs) and CSF neurofilament light (NfL) concentration, examining the ability of each biomarker to predict future disease activity in clinically and radiologically isolated syndromes, relapsing-remitting MS, and progressive MS. Methods Matched serum and CSF samples were obtained from 67 non-inflammatory neurologic disease patients and 67 MS patients. CSF and serum CXCL13 and CSF NfL were analyzed by Luminex and ELISA, respectively. CXCL13 data were also analyzed as CSF/serum ratios and indices. Electronic medical records were accessed to determine diagnosis, CSF profiles, and disease activity after the lumbar puncture. Results Among CXCL13 measures, CXCL13 index was the best predictor of future disease activity in MS patients (AUC = 0.82; CI = 0.69–0.95; p = 0.0002). CXCL13 index values were significantly elevated in activity-positive MS patients compared to activity-negative patients (p < 0.0001). As a single predictor, CXCL13 index outperformed both OCBs and CSF NfL in sensitivity, specificity, and positive and negative predictive value, for future disease activity in MS patients. Moreover, combining CXCL13 index and CSF NfL status improved sensitivity and predictive values for disease activity in MS patients. Conclusions The CXCL13 index is an excellent candidate prognostic biomarker for disease activity in patients with MS.

Cerebrospinal fluid inflammatory profile of cognitive impairment in newly diagnosed multiple sclerosis patients

“…6 In contrast, the dominance of inflammatory CSF molecular pathways linked to B and T lymphocyte chemotaxis and regulation, related to both mCI and sCI patients, probably reflect the increasing involvement of the adaptive immune response as the disease progresses and the GM damage evolves. The fact that high CSF levels of CXCL13, a biomarker predicting disease activity 31 and cortical damage inflammation 17,23 in pwMS, were able to differentiate sCI from mCI pwMS at the time of diagnosis, supports a key role of intrathecal B-cell-mediated damage to disability in MS. 32…”

“…6 In contrast, the dominance of inflammatory CSF molecular pathways linked to B and T lymphocyte chemotaxis and regulation, related to both mCI and sCI patients, probably reflect the increasing involvement of the adaptive immune response as the disease progresses and the GM damage evolves. The fact that high CSF levels of CXCL13, a biomarker predicting disease activity 31 and cortical damage inflammation 17,23 in pwMS, were able to differentiate sCI from mCI pwMS at the time of diagnosis, supports a key role of intrathecal B-cellmediated damage to disability in MS. 32 The results of the gene ontology analysis corroborate our previous longitudinal study 5 in which we showed that a hierarchical cluster analysis, performed on EDSS change and cortical thickness change between baseline and 8-year follow-up, revealed two separate groups of pwMS: the first group was almost exclusively composed of ACN pwMS, while the second group was composed of both mCI and sCI pwMS, suggesting that mCI pwMS performed similarly to sCI patients than to ACN pwMS. In this study, we confirmed and extended this observation by showing that mCI and sCI pwMS share the same molecular profile linked to B and T lymphocyte chemotaxis and regulation with regard to ACN pwMS.…”

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations

“…The use of CSF CXCL13 as a biomarker is not restricted to only CIS patients. In RRMS patients, it was shown to correlate with disease activity and indicators of a more severe disease course, such as the relapse rate, IgG index, intrathecal leukocyte count, cortical atrophy and HLA genotype [ 169 , 171 , 174 , 179 , 180 , 181 ]. Not surprisingly, CSF CXCL13 levels seem to be a robust and sensitive indicator of intrathecal B-cell response, even under the conditions of an intact blood-brain barrier [ 167 , 182 ].…”

“…Furthermore, as a single marker, the CXCL13 index (calculated as CSF CXC13 /serum CXCL13 )/(CSF albumin /serum albumin ) had better specificity, sensitivity, and positive and negative predictive value to forecast future disease activity than OCBs and CSF NFL did. Even higher sensitivity and predictive values were achieved when the CXCL13 index and CSF NFL levels were combined [ 181 ]. In addition, elevated levels of intrathecal CXCL13 were detected in 50% of patients treated with highly active DMTs who seemingly had stable disease (no signs of clinical or ongoing radiological activity on MRI), indicating residual, subclinical disease activity [ 185 ].…”

Mechanisms of brain protection against autoimmune inflammation

“…Показано, что хоминг В-клеток в мозг связан с высоким уровнем В-клеточного хемокина, CXCL13, который продуцируют моноциты при активации Толл-подобных рецепторов 2-го типа [44,45]. Уровень CXCL13 повышен в ЦСЖ пациентов с РС и имеет прогностическую ценность в отношении течения заболевания [46]. З а к л ю ч е н и е Несмотря на существование ГЭБ и гематоликворных барьеров, ЦНС не является полностью изолированной от периферической иммунной системы, и иммунный надзор, в том числе с участием клеток адаптивной иммунной системы, осуществляется в ЦНС непрерывно.…”