https://www.cell.com/trends/immunology/pdf/S1471-4906(12)00126-3.pdf

Capture, crawl, cross: the T cell code to breach the blood-brain barriers

The CNS is an immune-privileged environment, yet the local control of multiple pathogens is dependent on the ability of immune cells to access and operate within this site. However, inflammation of the distinct anatomical sites (i.e., meninges, cerebrospinal fluid, and parenchyma) associated with the CNS can also be deleterious. Therefore, control of lymphocyte entry and migration within the brain is vital to regulate protective and pathological responses. In this review, several recent advances are highlighted that provide new insights into the processes that regulate leukocyte access to, and movement within, the brain.

/pdf/trafficking-of-immune-cells-in-the-central-nervous-system-2lv71jhx98.pdf

Trafficking of immune cells in the central nervous system.

B cells and antibodies account for the most prominent immunodiagnostic feature in patients with multiple sclerosis (MS), namely oligoclonal bands. Furthermore, evidence is accumulating that B cells and antibodies contribute to MS pathogenesis in at least a subset of patients. The CNS provides a B-cell-fostering environment that includes B-cell trophic factors such as BAFF (B-cell-activating factor of the TNF family), APRIL (a proliferation-inducing ligand), and the plasma-cell survival factor CXCL12. Owing to this environment, the CNS of patients with MS is not only the target of the immunopathological process, but also becomes the site of local antibody production. B cells can increase or dampen CNS inflammation, but their proinflammatory effects seem to be more prominent in most patients, as B-cell depletion is a promising therapeutic strategy. Other therapies not primarily designed to target B cells have numerous effects on the B-cell compartment. This Review summarizes key features of B-cell biology, the role of B cells and antibodies in CNS inflammation, and current attempts to identify the targets of pathogenic antibodies in MS. We also review the effects of approved and investigational interventions-including CD20-depleting antibodies, BAFF/APRIL-depleting agents, alemtuzumab, natalizumab, FTY720, IFN-β, glatiramer acetate, steroids and plasma exchange-on B-cell immunology.

B cells and antibodies in multiple sclerosis pathogenesis and therapy

The blood-brain barrier, chemokines and multiple sclerosis

Background B cells are implicated in the pathogenesis of multiple sclerosis. A beneficial effect of B-cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear. Objective To determine the relationship between T and B cells and changes in cerebrospinal fluid (CSF) chemokine levels with rituximab, a monoclonal antibody that targets CD20. Design Phase 2 trial of rituximab as an add-on therapy. Setting The John L. Trotter Multiple Sclerosis Center, Washington University. Participants and Intervention Thirty subjects who had relapsing-remitting multiple sclerosis with clinical and magnetic resonance imaging activity despite treatment with an immunomodulatory drug received 4 weekly doses of rituximab (375 mg/m 2 ). Main Outcome Measures Lumbar puncture was performed before and after rituximab infusions in 26 subjects. Levels of B and T lymphocytes in the CSF were enumerated by flow cytometry, and chemoattractant levels were measured by enzyme-linked immunosorbent assay. Results After rituximab administration, CSF B-cell levels were decreased or undetectable in all subjects, and CSF T-cell levels were reduced in 21 subjects (81%). The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 levels decreased ( P  = .002 and P  = .03, respectively). The proportional decline in CSF T-cell levels correlated with the proportional decrease in CXCL13 levels ( r  = 0.45; P  = .03), suggesting a possible relationship. The CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment. Conclusions In subjects with multiple sclerosis, B cells are critical for T-cell trafficking into the central nervous system and may alter the process by influencing chemokine production within the central nervous system.

https://jamanetwork.com/journals/jamaneurology/articlepdf/800472/noc90105_707_714.pdf

M. Hofbauer

Papers

CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions.