Impact of Glatiramer Acetate on B Cell-Mediated Pathogenesis of Multiple Sclerosis

Abstract

Growing evidence indicates that B cells play a key role in the pathogenesis of multiple sclerosis (MS). B cells occupy distinct central nervous system (CNS) compartments in MS, including the cerebrospinal fluid and white matter lesions. Also, it is now known that, in addition to entering the CNS, B cells can circulate into the periphery via a functional lymphatic system. Data suggest that the role of B cells in MS mainly involves their in situ activation in demyelinating lesions, leading to altered pro- and anti-inflammatory cytokine secretion, and a highly effective antigen-presenting cell function, resulting in activation of memory or naïve T cells. Clinically, B cell-depleting agents show significant efficacy in MS. In addition, many disease-modifying therapies (DMTs) traditionally understood to target T cells are now known to influence B cell number and function. One of the earliest DMTs to be developed, glatiramer acetate (GA), has been shown to reduce the total frequency of B cells, plasmablasts, and memory B cells. It also appears to promote a shift toward reduced inflammation by increasing anti-inflammatory cytokine release and/or reducing pro-inflammatory cytokine release by B cells. In the authors’ opinion, this may be mediated by cross-reactivity of B cell receptors for GA with antigen (possibly myelin basic protein) expressed in the MS lesion. More research is required to further characterize the role of B cells and their bidirectional trafficking in the pathogenesis of MS. This may uncover novel targets for MS treatments and facilitate the development of B cell biomarkers of drug response.

Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

“…It has been reported that GLAT reduces the relative frequency of B cells, plasmablasts and memory B cells in the peripheral blood of MS patients [31,32]. We could only detect slight differences in relative B cell subset frequencies and GLAT seems to have a less profound effect on B cell subsets when compared to other DMDs.…”

Differential Effects of MS Therapeutics on B Cells—Implications for Their Use and Failure in AQP4-Positive NMOSD Patients

“…While some studies reported no relevant modulation by glatiramer acetate regarding the overall lymphocyte and B cell count [ 90 , 98 , 137 ], others described an absolute and relative decrease of B cells in patients treated with glatiramer acetate [ 138 , 139 ]. Despite these discrepancies, several studies agree that glatiramer acetate treatment increases the proportion of interleukin-10 producing regulatory B cells and reduces the amount of memory B cells and plasmablasts [ 138 , 140 , 141 ]. Only one study reports that B cells of glatiramer acetate-treated patients produced higher amounts of interleukin-6 the longer they had been treated [ 138 ].…”

“…Only one study reports that B cells of glatiramer acetate-treated patients produced higher amounts of interleukin-6 the longer they had been treated [ 138 ]. Furthermore, total IgG and IgM levels were shown to be elevated upon glatiramer acetate treatment [ 138 ], probably due to the observation that the majority of treated patients generate non-neutralizing anti-glatiramer acetate IgG antibodies [ 140 ]. While one study observed similar blood BAFF levels in patients with or without glatiramer acetate, two other reports that MS patients treated with glatiramer acetate had significantly higher serum BAFF levels [ 52 , 98 , 142 ].…”

The influence of glatiramer acetate on Th17-immune response in multiple sclerosis

“…It has also been shown that GA can influence the function of B cells which may modulate inflammation in CNS by producing antibodies, pro-inflammatory cytokines and presenting antigen to effector T cells [ 6 ]. Glatiramer acetate modulates B cells functions by converting memory B cells known to contribute to the T cell-dependent inflammatory response into B regulatory cells and reduce the production of the pro-inflammatory cytokines IL-6 and tumor necrosis alpha factor (TNF-α) by B cells [ 7 ].…”