Amit Bar-Or, University of Pennsylvania, USA
Amit Bar-Or is the Melissa and Paul Anderson Professor of Neurology and Presidential Endowed Chair at the Perelman School of Medicine, University of Pennsylvania. Here he Directs the age-span Centre for Neuroinflammation and Experimental Therapeutics, and serves as Chief of the Division of Multiple Sclerosis and Related Disorders. He is former Professor in the Department of Neurology and Neurosurgery, and Associate Director of the Montreal Neurological Institute and Hospital, McGill University. Bar-Or’s clinical focus is Multiple Sclerosis (MS) and related disorders in both adults and children, for which he is cross appointed at the Children’s Hospital of Philadelphia (CHOP). He also runs a cellular and molecular Neuroimmunology lab studying principles of immune regulation and immune-neural interaction in the context of injury and repair of the human central nervous system (CNS). Ongoing themes involve elucidation of effector and regulatory mechanisms by which distinct human immune cell subsets (principally T cells, B cells, myeloid cells) interact with one another and with CNS (glial and neuronal) cells, contributing to both ‘Neuroimmune Health’ and to a range of CNS inflammatory diseases across the age-span. Of particular interest are human immune-monitoring studies, studies of immune reconstitution, design and implementation of mechanism-of-action and biological proof-of-principle studies of emerging therapies, and development of clinically meaningful biomarkers as part of advancing precision medicine in autoimmune and CNS-inflammatory diseases. He is past President of the Canadian Network of MS Clinics (CNMSC); past member of the Board of Directors and currently serving on the Education Committee of the Federation of Clinical Immunology Societies (FOCIS); member of the Board of Directors of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the Steering Committee of the NIH Immune Tolerance Network (ITN). Bar-Or is also a long-standing member of the Scientific Advisory Board, and now President-Elect of the International Society of Neuroimmunology (ISNI).
Antibody independent Contributions of B cells to CNS Inflammation
Professor Amit Bar-Or, MD, FRCPC
Melissa and Paul Anderson President’s Distinguished Professor
Director, Center for Neuroinflammation and Experimental Therapeutics
Chief, Multiple Sclerosis Division, Department of Neurology
Research Scientist, Children’s Hospital of Philadelphia
Perelman School of Medicine, University of Pennsylvania
Adjunct Professor of Neurology, Montreal Neurological Institute, McGill University
Perelman Center for Advanced Medicine (PCAM), South Pavilion
3400 Civic Center Blvd., Philadelphia, Pennsylvania, USA, 19104
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B-cell contributions to CNS inflammation in multiple sclerosis (MS) may be both antibody-dependent and antibody independent Elucidating B cell roles in both the periphery and within the CNS of patients is of considerable interest.
This study aims to Investigate interactions between disease-implicated B-cell subsets and other immune cells (T cells and myeloid cells) involved in peripherally-mediated relapsing MS biology, as well as B cell interactions with CNS glial cells that may reveal novel mechanisms underlying the propagation of ongoing CNS-inflammation and injury contributing to progressive disease.
Anti-CD20 therapy (which depletes large B-cell populations) substantially decreases new MS disease activity, without altering abnormal profiles of cerebrospinal-fluid antibodies. This highlights a key role for B cells in triggering new MS relapses, yet one that is mediated by non-antibody dependent B-cell functions. Rigorously-applied multi-parametric assessment of functional immune cell-subset responses reveals that MS-patient memory B cells can produce exaggerated amounts of pro-inflammatory cytokines (IL-6, TNFa, LT, GM-CSF), while their naïve B cells are deficient in producing down-regulatory cytokine (IL-10). This abnormal cytokine response-profile induces aberrant pro-inflammatory activation of T cells (Th1/Th17) and myeloid cells, both of which are normalized following B-cell depletion in patients. The aberrant MS B-cell cytokine responses are partly regulated by STAT5/6 signaling and particular miRNAs. Astrocytes can support B-cell survival and activation, while MS B-cells, in turn, induce pro-inflammatory microglia responses as well as oligodendrocyte and neuronal toxicity through (non-antibody) secreted products.
B cells of MS patients may contribute through antibody-independent mechanisms to both peripheral cascades of cellular (B cell, T cell, myeloid cell) interactions that underlie disease relapses, and to CNS-compartmentalized interactions (B-cell and glial-cell cross-talk). The compartmentalized interactions may contribute to fostering long-term B-cell survival within the disease target-organ, where they may participate in propagating inflammation and injury involved in progressive disease.
Funding: Canadian Institutes of Health Research (CIHR), MS Society of Canada Research Foundation, National MS Society (NMSS); Melissa and Paul Anderson Endowed Chair in Neuroinflammation.
Conflicts of Interest: Dr. Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from: Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MAPI, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme.
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