Next Generation Sequencing of Cerebrospinal Fluid B Cell Repertoires in Multiple Sclerosis and Other Neuro-Inflammatory Diseases—A Comprehensive Review

Abstract

During the last few decades, the role of B cells has been well established and redefined in neuro-inflammatory diseases, including multiple sclerosis and autoantibody-associated diseases. In particular, B cell maturation and trafficking across the blood–brain barrier (BBB) has recently been deciphered with the development of next-generation sequencing (NGS) approaches, which allow the assessment of representative cerebrospinal fluid (CSF) and peripheral blood B cell repertoires. In this review, we perform literature research focusing on NGS studies that allow further insights into B cell pathophysiology during neuro-inflammation. Besides the analysis of CSF B cells, the paralleled assessment of peripheral blood B cell repertoire provides deep insights into not only the CSF compartment, but also in B cell trafficking patterns across the BBB. In multiple sclerosis, CSF-specific B cell maturation, in combination with a bidirectional exchange of B cells across the BBB, is consistently detectable. These data suggest that B cells most likely encounter antigen(s) within the CSF and migrate across the BBB, with further maturation also taking place in the periphery. Autoantibody-mediated diseases, such as neuromyelitis optica spectrum disorder and LGI1 / NMDAR encephalitis, also show features of a CSF-specific B cell maturation and clonal connectivity with peripheral blood. In conclusion, these data suggest an intense exchange of B cells across the BBB, possibly feeding autoimmune circuits. Further developments in sequencing technologies will help to dissect the exact pathophysiologic mechanisms of B cells during neuro-inflammation.

Peripheral memory B cells in multiple sclerosis vs. double negative B cells in neuromyelitis optica spectrum disorder: disease driving B cell subsets during CNS inflammation

“…An alternative function of B cells could be centered around antigen presentation and T cell stimulation. Our group ( Kowarik et al, 2021 ) and other studies ( Stern et al, 2014 ; Ruschil et al, 2021 ) have demonstrated that B cells not only traverse the blood-brain barrier but also recirculate in the peripheral blood through cervical lymph node drainage ( Figure 1 .). B cells, potentially primed against antigens in the CNS compartment during relapse, could thus possess the capacity to re-enter germinal centers in the periphery and perpetuate autoimmune circuits ( Ruschil et al, 2021 ).…”

“…Double negative (DN) B cells constitute another B cell population that lacks expression of immunoglobulin D and CD27 surface markers and has shown to be associated with autoimmune diseases ( Sanz et al, 2019 ; Ruschil et al, 2021 ). The class-switched IgD- phenotype may indicate an antigen-specific maturation.…”

Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients

“…In addition, we could show that multiple treatments including dimethyl fumarate, interferon beta and fingolimod all lead to a significantly decreased peripheral blood memory B cell fraction ( 36 ) pointing at a pathophysiologic role of memory B cells in MS. An overall pathophysiological role of peripheral blood B cells is strongly supported by the high efficacy of peripheral B cell depleting anti CD20 antibodies that are supposed to enter the CNS in limited concentrations ( 35 , 37 ). Given the strong evidence for an intrathecal B cell activation and expansion ( 4 ), it was surprising that intrathecal rituximab treatment did not show substantial better effects than peripheral B cell depletion ( 37 ). However, it has to be noted that intrathecal effects of rituximab might be hampered by the lack of intrathecal complement and the consecutively limited effects regarding B cell depletion.…”

“…During the last decade, B cells have been proven to play an important pathophysiological role in multiple sclerosis (MS) and B cells have more and more entered into the focus of therapeutic approaches ( 1 , 2 ). Although several targets including recent work on possible Epstein-Barr virus (EBV) antigens have been suggested as potential B cell antigens during MS pathophysiology ( 3 ), the exact role of B cells in MS remains inconclusive ( 4 ). Besides a primary antigen driven role of B cells in MS it has to be taken into consideration that B cells might also serve as antigen presenting cells, produce proinflammatory cytokines and thus might feed autoimmune circuits in the periphery ( 5 – 7 ).…”

“…This hypothesis is - to a certain point- supported by studies on B cell migration between the periphery and the central nervous system (CNS) which showed a bidirectional exchange of B cells across the blood-brain barrier and suggested that B cell germinal centers may be active on both sides of the blood-brain barrier ( 8 ). Furthermore, CSF B cells are clonally connected with B cells in the meninges, and parenchyma of the CNS ( 4 , 8 , 9 ).…”