The Effect of Glatiramer Acetate Therapy on Functional Properties of B Cells From Patients With Relapsing-Remitting Multiple Sclerosis

Abstract

IMPORTANCEThis study describes what is, to our knowledge, the previously unknown effect of glatiramer acetate therapy on B cells in patients with relapsing-remitting multiple sclerosis (MS).OBJECTIVE To determine whether glatiramer acetate therapy normalizes dysregulated B-cell proliferation and cytokine production in patients with MS. DESIGN, SETTING, AND PARTICIPANTS Twenty-two patients with MS who were receiving glatiramer acetate therapy and 22 treatment-naive patients with MS were recruited at The University of Texas Southwestern Medical Center MS clinic. Cell samples from healthy donors were obtained from HemaCare (Van Nuys, California) or Carter Blood Bank (Dallas, Texas). Treatment-naive patients with MS had not received any disease-modifying therapies for at least 3 months before the study.EXPOSURES Glatiramer acetate therapy for at least 3 months at the time of the study. MAIN OUTCOMES AND MEASURES B-cell phenotype and proliferation and immunoglobulin and cytokine secretion.RESULTS A restoration of interleukin 10 production by peripheral B cells was observed in patients undergoing glatiramer acetate therapy as well as a significant reduction of interleukin 6 production in a subset of patients who received therapy for less than 32 months. Furthermore, proliferation in response to high-dose CD40L was altered and immunoglobulin production was elevated in in vitro-activated B cells obtained from patients who received glatiramer acetate.CONCLUSIONS AND RELEVANCE Glatiramer acetate therapy remodels the composition of the B-cell compartment and influences cytokine secretion and immunoglobulin production. These data suggest that glatiramer acetate therapy affects several aspects of dysregulated B-cell function in MS that may contribute to the therapeutic mechanisms of glatiramer acetate.

CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics

“…We have recently demonstrated that B cells from RRMS patients, but not healthy donors (HD), are hyper-responsive to CD40 stimulation as measured by proliferation (19, 20, 22, 30). Based on this data, we hypothesized that dysregulation of CD40 signaling contributes to the hyperactivity of B cells from RRMS patients.…”

“…In fact, B cells from glatiramer acetate (Copaxone) treated MS patients no longer display hyper-responses to low-dose CD40 stimulation (20). To understand why B cells from MS patients exhibit a hyperactive response to CD40, we asked whether key signaling intermediates downstream of CD40 displayed enhanced activity.…”

Efficacy of glatiramer acetate in neuromyelitis optica spectrum disorder: a multicenter retrospective study

“…Wilcoxon rank-sum test AQP4-IgG sero-positive and -negative NMOSD are similar in their immunopathogenesis and clinical course, or whether AQP4-IgG seronegative cases belong to a distinct subtype of NMOSD with features closer to MS [15,19]. In our patients with AQP4-IgG seropositive NMOSD, GA therapy was clearly not effective, indicating that modulation of autoimmune mechanisms by GA, as demonstrated in experimental autoimmune encephalomyelitis [13,14] and MS patients, [20] may be insufficient to suppress the immune process in NMOSD. Our findings are in agreement with a small case series of five AQP4-IgG seropositive NMOSD patients, who failed to respond to GA therapy [21].…”

Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent to Oral Intervention in Experimental Autoimmune Encephalomyelitis

“…The role of B cells in MS and EAE has generated increasing interest (12, 46, 51-55). Distinct B cell subtypes have recently been associated with EAE disease progression and regulation (6, 7, 16, 53, 56-59), and are at least partially dependent on the choice of antigen (protein or peptide) used to induce the disease (18). A role for B cells has also been suggested in different models of recombinant MOG (rMOG)-induced EAE (18, 60-62).…”

“…Bregs also have a role in the mechanism of action by Copaxone ® , a glatiramer acetate copolymer, approved for the treatment of relapsing-remitting MS (5, 12, 25, 52, 56). In a recent clinical trial, Ireland et al showed that treatment of relapsing-remitting MS patients with glatiramer acetate restored IL-10 production while reducing lymphotoxin-α production by peripheral B cells, thus contributing to the therapeutic effects of glatiramer acetate (53). This finding further supports our contention that IL-10-producing Bregs contribute to suppression of autoimmunity.…”