The chemokine C-X-C- ligand 13 (CXCL13) is a major B cell chemoattractant to B cell follicles in secondary lymphoid organs (SLO) that proposedly recruits B cells to the cerebrospinal fluid (CSF) during neuroinflammation. CXCR5, the cognate receptor of CXCL13, is expressed on B cells and certain T cell subsets, in particular T follicular helper cells (Tfh cells), enabling them to follow CXCL13 gradients towards B cell follicles for spatial proximity, a prerequisite for productive T cell–B cell interaction. Tfh cells are essential contributors to B cell proliferation, differentiation, and high-affinity antibody synthesis and are required for germinal center formation and maintenance. Circulating Tfh cells (cTfh) have been observed in the peripheral blood and CSF. Furthermore, CXCL13/CXCR5-associated immune activities organize and shape adaptive B cell-related immune responses outside of SLO via the formation of ectopic lymphoid structures in inflamed tissues, including the central nervous system (CNS). This review summarizes the recent advances in our understanding of the CXCL13/CXCR5 immune axis and its role in vaccination, autoimmunity, and infection with a special focus on its relevance for intrathecal B cell activities in inflammatory CNS diseases.

Introduction Sphingosine-1-phosphate receptor (S1PR) modulators are effective therapies for multiple sclerosis (MS) that block lymphocyte egress from secondary lymphoid organs. This migration inhibition carries the risk of reduced infection-control as reported for the non-selective S1PR modulator, fingolimod. CXCL13:CXCR5-associated immune activities play a key role in protective antibody-based immunity but are also linked to inflammation in MS. Utilizing the ongoing SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, we aimed to determine whether selective S1PR modulation with ozanimod acts on the CXCL13:CXCR5 axis for modulating MS activity and whether this impacts anti-viral immune responses. Methods This 1-year observational study included 20 patients with MS receiving ozanimod and 10 healthy probands. CXCR5⁺ T cells, B cells, serum CXCL13, anti-SARS-CoV-2 serostatus, and SARS-CoV-2-spike protein (ProtS)-reactive T cell responses were measured at 3-month intervals. Results CXCR5⁺ T and B cell frequencies and serum CXCL13, but not anti-SARS-CoV-2 responses, declined after ozanimod initiation. Anti-SARS-CoV-2 antibody and ProtS-reactive T cell responses peaked after recall vaccinations and break-through infections. Notably, ProtS-reactive T cell frequencies shifted from CD4⁺ to CD8⁺ T cell responses in patients treated with ozanimod compared to controls. Conclusion Selective S1P receptor modulation with ozanimod affects the CXCL13:CXCR5 axis by reducing circulating CXCR5⁺ lymphocytes and serum CXCL13, which may contribute to reduce meningeal inflammation in MS. Moreover, the anti-SARS-CoV-2 immune defense appeared to be preserved during treatment with SARS-CoV-2-reactive CD8⁺ T cells, possibly compensating the lack of CD4⁺ T cell responses. Our immunological data may well apply to other viral infections and underscore the favorable safety and efficacy profile of ozanimod.

Objective: To describe long‐term outcomes after anti‐CD20 discontinuation in selected patients with secondary progressive multiple sclerosis (SPMS) who remained without subsequent disease‐modifying therapy (DMT). Methods: We retrospectively analyzed data from four centers in Austria and Switzerland. Inclusion criteria were SPMS, ≥ 2 anti‐CD20 cycles, discontinuation without subsequent DMT, and ≥ 36 months follow‐up. The primary endpoint was time to first confirmed Expanded Disability Status Scale (EDSS) worsening, defined as a ≥ 0.5‐point increase after discontinuation documented at a subsequent routine visit. Secondary endpoints were relapses, MRI activity, and severe infections. No continuation cohort was available. Results: Fifty‐five patients were included (61% female). Mean age at anti‐CD20 start was 53.5 ± 6.6 years, disease duration 19.3 ± 10.1 years, treatment duration 32.8 ± 16.1 months, and post‐discontinuation follow‐up 55.1 ± 14.1 months. Mean EDSS increased from 5.9 ± 1.3 before anti CD20, to 6.3 ± 1.3 at discontinuation and 6.9 ± 1.2 at last follow‐up. Confirmed EDSS worsening occurred in 31 patients (56%). Hazard analysis suggested an exploratory late increase between 48 and 60 months ( p = 0.043) based on small numbers at risk. Relapses occurred in 6 patients (10.9%), MRI activity in 4/35 (11%), and severe infections in 17 (31%). Conclusions: In this selected SPMS cohort, focal inflammatory activity was uncommon, whereas confirmed EDSS worsening accumulated over long‐term follow‐up. Because inclusion required ≥ 36 months untreated follow‐up, early disease activity may have been underestimated, and apparent stability may have been overestimated. Findings are descriptive and hypothesis‐generating and do not establish safety or optimal timing of anti‐CD20 discontinuation.

Background: Spastic movement disorders (SMD) are commonly treated with botulinum toxin, however, many patients who may benefit from treatment remain unrecognized in routine clinical practice. Early identification is particularly challenging in non-specialized settings. This study evaluated the diagnostic performance of interprofessional screening tools for identifying patients with clinically relevant SMD requiring referral for specialist assessment. Methods: In this prospective, two-phase, single-center study, 124 patients who received care by departments of neurology and geriatrics were included. In phase 1, the Spastic Movement Disorder decision tree (SMD-DT) was applied independently by nurses, physiotherapists, and occupational therapists and compared with the clinical assessment of an experienced neurologist as the reference standard. Based on the findings, a simplified nursing screening tool, the Salzburg Nursing Questionnaire (SNQ), was developed and subsequently evaluated in independent cohorts in phase 2 of the study. Results: The SMD-DT demonstrated high agreement with the reference standard in neurological rehabilitation settings, with a high degree of consistency across all professional groups compared with the expert, but showed substantially lower performance among nurses in non-specialized geriatric settings. In contrast, the SNQ consistently achieved high diagnostic accuracy in these settings (sensitivity of 1.00 and specificity of 0.96) considering treatment recommendation. Conclusion: The diagnostic performance of screening instruments for SMD depends strongly on both clinical context and professional background. These findings support the implementation of profession-specific screening strategies to improve early recognition of clinically relevant SMD, facilitating timely referral for specialist evaluation, and optimize access to botulinum toxin therapy in routine clinical practice.