Dysregulated B Cells in Relapsing Remitting Multiple Sclerosis and Their Impact on T-Cell Function

Relapsing-remitting multiple sclerosis (MS) is an autoimmune mediated inflammatory demyelinating disorder of the central nervous system. The role of B cells in the pathoetiology of MS is substantiated by cell depletion therapies but is not well understood. We hypothesized that B cells from MS patients would secrete more pro-inflammatory cytokines and support T cell responses to self-antigens and that the therapeutic agent glatiramer acetate (GA) could modulate these aspects of B cell function. To test this hypothesis we interrogated the ability of memory and naive B cells from healthy donors (HD), MS patients, and GA-treated MS patients (GA-MS) to proliferate and secrete cytokines in vitro. We identified a remarkable loss of IL-10 secretion by B cells from MS patients, but a marked increase in the production of IL-6, particularly from naïve B cells. We also found that memory B cells from MS patients exhibited hyperactive proliferation compared to healthy donors and naïve B cells from MS patients. GA had no measurable impact on any of the B cell functions we tested; however, B cells from GA-treated MS patients had a restored ability to produce IL-10, greatly enhanced immunoglobulin production, altered proliferation capacity and a transient diminishment of IL-6 production for patients on therapy for less than 32 months. To address whether memory or naïve B cells from MS patients supported neuro-antigen specific T cell responses, we co-cultured B and T cells in the absence or presence of foreign or neuro-antigens. We found that memory and naïve B cells from MS patients support more CD4+ T cell proliferation and TH1 and TH17 responses to neuro-antigens despite a similar frequency of neuroantigen specific T cells. Together, these data reveal that B cells from MS patients exhibit dysregulated proliferation and cytokine secretion that can be modulated by GA. Furthermore B cells from MS patients support neuroantigen-specific T cell proliferation and pro-inflammatory cytokine production in response to self neuro-antigens.

Author dc:creator

• Ireland, Sara Jean

Contributors dc:contributor

• Monson, Nancy L.
• Farrar, J. David
• Davis, Laurie
• van Oers, Nicolai S. C.
• Kasper, Lloyd

• B-Lymphocytes
• CD8-Positive T-Lymphocytes
• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting

Language dc:language

en

Identifier

988778276

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/4116