Review: NGS Reveals Migration Patterns of B Cells Across Blood-Brain Barrier for MS

Using next-generation sequencing (NGS) helped investigators outline the migration patterns and maturation of B cells in multiple sclerosis (MS), revealing that there is an intense exchange of B cells across the blood-brain barrier (BBB), according to a systemic review.

The results of the review, which was published in Diagnostics, suggested that B-cell migration across the BBB at such an intense rate may contribute to autoimmune circuits and that further developments in sequencing technologies may help to accurately decipher the pathophysiologic mechanism of B cells during neuro-inflammation.

“The development of high-throughput next-generation sequencing has further contributed to push the boundaries of B cell immunology and helped to representatively assess peripheral blood B cell repertoires…thus allowing insights in B cell maturation processes and trafficking patterns across the blood-brain barrier,” wrote the investigators.

B cells are essential to the adaptive immune system and play a critical role in the pathogenesis of several neuro-inflammatory diseases. Central nervous system (CNS) inflammation can either be modulated or initiated by B cells. B cells can enter the CNS through the BBB, blood-cerebrospinal fluid (CSF), or surface barriers of the brain.

During neuro-inflammation, B cells can be found in CSF in infectious and autoimmune diseases, including MS. Research has suggested that an orchestrated reaction between T and B cells causes inflammation in the CNS, resulting in demyelination and damage to the neurons. Despite B cell levels presenting higher in the CSK of patients with MS, there is still no defined antigen target for CSK antibodies has not been consistently identified in MS.

The investigators conducted a data base search for published reports and articles published up to May 2021. To be included, the studies had to include data on human research, did not report on previously published data, and had to state sequencing of the B cell receptor. Of the 135 papers identified, 38 were selected for the analysis.

Additionally, it had been suggested that B cells in CSF may recirculate in the peripheral blood, potentially through draining of cervical lymph nodes, where they interact with other immune cells and further maturation and interaction can occur.

The investigators said that the most striking result they found was that there was an intense exchange B cell trafficking across the BBB, demonstrating an involvement of additional compartments outside of the CNS in regard to B cell migration.

Results of the analysis demonstrated that B cell receptors had a high variability because of the recombination of V-D-J segments, affinity maturation, class-switch recombination, and somatic hypermutations. As a result, B cell immunoglobulin transcript that contain the same segments and highly similar somatic hypermutation profiles are considered to be clonally related.

Applying NGS allowed for representative sequencing of CSF and peripheral blood B cell repertoires, which can enable examination of B cell trafficking across the BBB. Some studies showed that there was a substantial clonal overlap between peripheral blood and CSF B cells. The investigators said that their analysis provided evidence that B cells migrate freely across the tissue barrier and that a lot of B cell maturation occurs outside of the CNS.

Furthermore, the studies showed that CSF transcriptome and proteome B cell repertoires revealed that intrathecal immunoglobulin (Ig) is produced by CSF B cells and B cell clones. Intrathecal Ig synthesis is associated with MS disease severity and progression.

The investigators said that NGS could be established as a powerful tool for studying B cell trafficking and maturation between different compartments and can help to understand B cell-related pathologies within the CNS.

Reference

Ruschil C, Kemmerer CL, Beller L, Baretnet G, Kowarik MC. Next generation sequencing of cerebrospinal fluid B cell repertoires in multiple sclerosis and other neuro-inflammatory diseases—a comprehensive review. Diagnostics. Published online October 11, 2021. doi:10.3390/diagnostics11101871