Dysregulated B Cells in Relapsing Remitting Multiple Sclerosis and Their Impact on T-Cell Function
| dc.contributor.committeeMember | Monson, Nancy L. | en |
| dc.contributor.committeeMember | Farrar, J. David | en |
| dc.contributor.committeeMember | Davis, Laurie | en |
| dc.contributor.committeeMember | van Oers, Nicolai S. C. | en |
| dc.contributor.committeeMember | Kasper, Lloyd | en |
| dc.creator | Ireland, Sara Jean | en |
| dc.date.accessioned | 2017-06-02T15:26:25Z | |
| dc.date.available | 2017-06-02T15:26:25Z | |
| dc.date.created | 2015-05 | |
| dc.date.issued | 2015-03-10 | |
| dc.date.submitted | May 2015 | |
| dc.date.updated | 2017-06-02T15:14:35Z | |
| dc.description.abstract | 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. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 988778276 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/4116 | |
| dc.language.iso | en | en |
| dc.subject | B-Lymphocytes | en |
| dc.subject | CD8-Positive T-Lymphocytes | en |
| dc.subject | Multiple Sclerosis | en |
| dc.subject | Multiple Sclerosis, Relapsing-Remitting | en |
| dc.title | Dysregulated B Cells in Relapsing Remitting Multiple Sclerosis and Their Impact on T-Cell Function | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Immunology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |