Abstract
BackgroundThe chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels.MethodsCytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n = 20), clinically isolated syndrome (CIS, n = 30), multiple sclerosis (MS, n = 20), Lyme neuroborreliosis (LNB, n = 8) and patients with other inflammatory neurological diseases (OIND, n = 30). Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry.ResultsCXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in the CSF of all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with CSF B cells, plasmablasts and intrathecal Ig synthesis.ConclusionsCXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity.
Highlights
The chemokines and cytokines CXCL13, CXCL12, Chemokine ligand 19 (CCL19), Chemokine ligand 21 (CCL21), B cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation
In the subgroup of other inflammatory neurological diseases (OIND) patients, highest cerebrospinal fluid (CSF) CXCL13 levels were similar to those observed in patients with acute Lyme disease
In contrast to previous studies, which had already shown an impact of different cytokines/chemokines on the fraction of B cells in the CSF compartment, we aimed to investigate the full repertoire of relevant chemokines/cytokines to understand the contribution and importance of each of them for humoral immune responses across different neuroinflammatory diseases
Summary
The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation. Recruitment, clonal selection and expansion of B cells require a specialized milieu of secondary lymphoid organ chemokines and cytokines [1]. Chemokines, such as CCL19 (MIP-3β, Macrophage Inflammatory Protein-3), CCL21 (SLC, secondary lymphoid-tissue chemokine), CXCL12 (SDF-1, stromal cellderived factor-1) and CXCL13 (BCA-1, B cell attracting chemokine-1), are known to influence migration of B cells [2]. These chemokines are constitutively expressed in lymphoid organs and regulate the migration and CXCL13 is produced by stromal cells, binds to the CXCR5 receptor and regulates homing of B cells and subsets of T cells to lymphoid follicles [5,6,7]. Based on the observation that high CXCL13 levels are found in the CSF of patients with acute neuroborreliosis, CXCL13 was proposed as a specific diagnostic marker and a key regulator for B cells in acute Lyme neuroborreliosis [11,15,16,17]
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