Sara J. Ireland
University of Texas Southwestern Medical Center
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Publication
Featured researches published by Sara J. Ireland.
European Journal of Immunology | 2010
Christopher T. Harp; Sara J. Ireland; Laurie S. Davis; Gina Remington; Bonnie Cassidy; Petra D. Cravens; Olaf Stüve; Amy E. Lovett-Racke; Todd N. Eagar; Benjamin Greenberg; Michael K. Racke; Lindsay G. Cowell; Nitin J. Karandikar; Elliot M. Frohman; Nancy L. Monson
Recent evidence suggests that B‐ and T‐cell interactions may be paramount in relapsing‐remitting MS (RRMS) disease pathogenesis. We hypothesized that memory B‐cell pools from RRMS patients may specifically harbor a subset of potent neuro‐APC that support neuro‐Ag reactive T‐cell proliferation and cytokine secretion. To test this hypothesis, we compared CD80 and HLA‐DR expression, IL‐10 and lymphotoxin‐α secretion, neuro‐Ag binding capacity, and neuro‐Ag presentation by memory B cells from RRMS patients to naïve B cells from RRMS patients and to memory and naïve B cells from healthy donors (HD). We identified memory B cells from some RRMS patients that elicited CD4+ T‐cell proliferation and IFN‐γ secretion in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Notwithstanding the fact that the phenotypic parameters that promote efficient Ag presentation were observed to be similar between RRMS and HD memory B cells, a corresponding capability to elicit CD4+ T‐cell proliferation in response to myelin basic protein and myelin oligodendrocyte glycoprotein was not observed in HD memory B cells. Our results demonstrate for the first time that the memory B‐cell pool in RRMS harbors neuro‐Ag specific B cells that can activate T cells.
Autoimmunity | 2012
Sara J. Ireland; Monica Blazek; Christopher T. Harp; Benjamin Greenberg; Elliot M. Frohman; Laurie S. Davis; Nancy L. Monson
The pathogenic role for B cells in the context of relapsing remitting multiple sclerosis (MS) is incompletely defined. Although classically considered a T cell-mediated disease, B cell-depleting therapies showed efficacy in treating the clinical symptoms of RRMS without decreasing plasma cells or total immunoglobulin (Ig) levels. Here, we discuss the potential implications of antibody-independent B cell effector functions that could contribute to autoimmunity with particular focus on antigen presentation, cytokine secretion, and stimulation of T cell subsets. We highlight differences between memory and naïve B cells from MS patients such as our recent findings of hyper-proliferation from MS memory B cells in response to CD40 engagement. We discuss the implications of IL6 overproduction in contrast to limited IL10 production by B cells from MS patients and comment on the impact of these functions on yet unexplored aspects of B cells in autoimmune disease. Finally, we contextualize B cell effector functions with respect to current immunomodulatory therapies for MS and show that glatiramer acetate (GA) does not directly modulate B cell proliferation or cytokine secretion.
Journal of Cerebral Blood Flow and Metabolism | 2014
Nancy L. Monson; Sara J. Ireland; Ann J. Ligocki; Ding Chen; William Rounds; Min Li; Ryan M. Huebinger; C. Munro Cullum; Benjamin Greenberg; Ann M. Stowe; Rong Zhang
Alzheimers disease (AD) is a progressive, neurodegenerative disease that may involve inflammatory responses in the central nervous system (CNS). Our objective was to determine whether patients with amnestic mild cognitive impairment (aMCI), a preclinical stage of AD, have inflammatory characteristics similar to patients with multiple sclerosis (MS), a known CNS inflammatory disease. The frequency of lymphocytes and levels of pro-inflammatory cytokines in the cerebrospinal fluid of aMCI patients was comparable to MS patients or patients at high risk to develop MS. Thus, brain inflammation occurs early at the preclinical stage of AD and may have an important role in pathology.
PLOS Pathogens | 2012
Molly R. Perkins; Caroline F. Ryschkewitsch; Julia Liebner; Maria Chiara Monaco; Danielle Himelfarb; Sara J. Ireland; Annelys Roque; Heather L. Edward; Peter N. Jensen; Gina Remington; Thomas Abraham; Jaspreet Abraham; Benjamin Greenberg; Charles Kaufman; Chris LaGanke; Nancy L. Monson; Xiao-Ning Xu; Elliot M. Frohman; Eugene O. Major
Progressive multifocal leukoencephalopathy (PML) induced by JC virus (JCV) is a risk for natalizumab-treated multiple sclerosis (MS) patients. Here we characterize the JCV-specific T cell responses in healthy donors and natalizumab-treated MS patients to reveal functional differences that may account for the development of natalizumab-associated PML. CD4 and CD8 T cell responses specific for all JCV proteins were readily identified in MS patients and healthy volunteers. The magnitude and quality of responses to JCV and cytomegalovirus (CMV) did not change from baseline through several months of natalizumab therapy. However, the frequency of T cells producing IL-10 upon mitogenic stimulation transiently increased after the first dose. In addition, MS patients with natalizumab-associated PML were distinguished from all other subjects in that they either had no detectable JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production. Additionally, IL-10 levels were higher in the CSF of individuals with recently diagnosed PML. Thus, natalizumab-treated MS patients with PML have absent or aberrant JCV-specific T cell responses compared with non-PML patients, and changes in T cell-mediated control of JCV replication may be a risk factor for developing PML. Our data suggest further approaches to improved monitoring, treatment and prevention of PML in natalizumab-treated patients.
Cytokine | 2015
Sara J. Ireland; Nancy L. Monson; Laurie S. Davis
The cytokines IL-6 and IL-10 are produced by cells of the adaptive and innate arms of the immune system and they appear to play key roles in genetically diverse autoimmune diseases such as relapsing remitting multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Whereas previous intense investigations focused on the generation of autoantibodies and their contribution to immune-mediated pathogenesis in these diseases; more recent attention has focused on the roles of cytokines such as IL-6 and IL-10. In response to pathogens, antigen presenting cells (APC), including B cells, produce IL-6 and IL-10 in order to up-or down-regulate immune cell activation and effector responses. Evidence of elevated levels of the proinflammatory cytokine IL-6 has been routinely observed during inflammatory responses and in a number of autoimmune diseases. Our recent studies suggest that MS peripheral blood B cells secrete higher quantities of IL-6 and less IL-10 than B cells from healthy controls. Persistent production of IL-6, in turn, contributes to T cell expansion and the functional hyperactivity of APC such as MS B cells. Altered B cell activity can have a profound impact on resultant T cell effector functions. Enhanced signaling through the IL-6 receptor can effectively inhibit cytolytic activity, induce T cell resistance to IL-10-mediated immunosuppression and increase skewing of autoreactive T cells to a pathogenic Th17 phenotype. Our recent findings and studies by others support a role for the indirect attenuation of B cell responses by Glatiramer acetate (GA) therapy. Our studies suggest that GA therapy temporarily permits homeostatic regulatory mechanisms to be reinstated. Future studies of mechanisms underlying dysregulated B cell cytokine production could lead to the identification of novel targets for improved immunoregulatory therapies for autoimmune diseases.
JAMA Neurology | 2014
Sara J. Ireland; Alyssa A. Guzman; Dina E. O’Brien; Samuel Hughes; Benjamin Greenberg; Angela Flores; Donna Graves; Gina Remington; Elliot M. Frohman; Laurie S. Davis; Nancy L. Monson
IMPORTANCE This 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.
Multiple Sclerosis International | 2011
Sara J. Ireland; Nancy L. Monson
Multiple sclerosis is a chronic debilitating autoimmune disease of the central nervous system. The contribution of B cells in the pathoetiology of MS has recently been highlighted by the emergence of rituximab, an anti-CD20 monoclonal antibody that specifically depletes B cells, as a potent immunomodulatory therapy for the treatment of MS. However, a clearer understanding of the impact B cells have on the neuro-inflammatory component of MS pathogenesis is needed in order to develop novel therapeutics whose affects on B cells would be beneficial and not harmful. Since T cells are known mediators of the pathology of MS, the goal of this review is to summarize what is known about the interactions between B cells and T cells, and how current and emerging immunotherapies may impact B-T cell interactions in MS.
Journal of Immunology | 2014
Ding Chen; Monica Blazek; Sara J. Ireland; Sterling B. Ortega; Xiangmei Kong; Anouk Meeuwissen; Ann M. Stowe; Laura Carter; Yue Wang; Ronald Herbst; Nancy L. Monson
Plasma cells and the autoreactive Abs they produce are suspected to contribute to the pathogenesis of multiple sclerosis, but recent attempts to target these components of humoral immunity have failed. MEDI551, an anti-CD19 Ab that depletes mature B cells including plasma cells may offer a compelling alternative that reduces pathogenic adaptive immune responses while sparing regulatory mechanisms. Indeed, our data demonstrate that a single dose of MEDI551, given before or during ongoing experimental autoimmune encephalomyelitis, disrupts development of the disease. Leukocyte infiltration into the spinal cord is significantly reduced, as well as short-lived and long-lived autoreactive CD138+ plasma cells in the spleen and bone marrow, respectively. In addition, potentially protective CD1dhiCD5+ regulatory B cells show resistance to depletion, and myelin-specific Foxp3+ regulatory T cells are expanded. Taken together, these results demonstrate that MEDI551 disrupts experimental autoimmune encephalomyelitis by inhibiting multiple proinflammatory components whereas preserving regulatory populations.
Journal of Immunology | 2016
Ding Chen; Sara J. Ireland; Laurie S. Davis; Xiangmei Kong; Ann M. Stowe; Yue Wang; Wendy I. White; Ronald Herbst; Nancy L. Monson
The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein–specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb–treated mice, but they remained detectable in the CD20 mAb–treated mice. Interestingly, residual disease severity in the CD20 mAb–treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19+CD20− plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19+CD20− plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19+CD20− B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.
Journal of Neuroimmunology | 2016
Sara J. Ireland; Alyssa A. Guzman; Elliot M. Frohman; Nancy L. Monson
B cells are highly potent antigen presenting cells of their cognate antigens. However, it remains unknown whether B cells can orchestrate Th17-mediated responses against neuro-antigens. We report that MS patients and healthy donors had a similar frequency of antigen-specific Th1 and Th17 cells, and distribution of T effector and T central memory cells. Notwithstanding these similarities, the application of an in vitro assay demonstrated that the B cells derived from a subset of MS patients exhibited the capability of coordinating Th17 responses directed toward neuro-antigens. These observations underscore the B cells contribution to the putative underpinnings of multiple sclerosis.