SHORT COURSE 1 Intersections Between Brain and Immune System in Health and Disease
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SHORT COURSE 1 Intersections Between Brain and Immune System in Health and Disease Organizers: Carla Shatz, PhD, and Beth Stevens, PhD Short Course 1 Intersections Between Brain and Immune System in Health and Disease Organized by Carla Shatz, PhD, and Beth Stevens, PhD Please cite articles using the model: [AUTHOR’S LAST NAME, AUTHOR’S FIRST & MIDDLE INITIALS] (2017) [CHAPTER TITLE] In: Intersections Between Brain and Immune System in Health and Disease. (Shatz C, Stevens B, eds) pp. [xx-xx]. Washington, DC: Society for Neuroscience. All articles and their graphics are under the copyright of their respective authors. Cover graphics and design © 2017 Society for Neuroscience. SHORT COURSE 1 Intersections Between Brain and Immune System in Health and Disease NEUROSCIENCE Organized by Carla Shatz, PhD and Beth Stevens, PhD Friday, November 10, 2017 2017 8:30 a.m.–6 p.m. Location: Washington, DC Convention Center • Room: Ballroom A TIME TOPIC SPEAKER 8 – 8:30 a.m. CHECK-IN Carla Shatz, PhD • Stanford University 8:30 – 8:40 a.m. Opening Remarks Beth Stevens, PhD • Harvard University 8:40 – 9:30 a.m. Multiple Sclerosis: From Bench to Bedside and Back Again Stephen Hauser, MD • University of California, San Francisco 9:30 – 10:20 a.m. What Do Reactive Astrocytes Do, and How Should We Study Them? Shane Liddelow, PhD • Stanford University 10:20 – 10:50 a.m. MORNING BREAK 10:50 – 11:40 a.m. Glymphatic–Lymphatic Connections Maiken Nedergaard, PhD • University of Rochester 11:40 a.m. – 12:30 p.m. Microbiota, CNS Development, and the Enternic Nervous System Dan Littman, PhD • New York University 12:30 – 1:30 p.m. LUNCH — ROOM 151 AB 1:30 – 2:20 p.m. Innate Immune Receptors in Microglia Biology Marco Colonna, MD • Washington University in St. Louis 2:20 – 3:10 p.m. Microglia: Synaptic Sculptors and Saboteurs Beth Stevens, PhD • Harvard University Surprise at the Synapse: Developmentally Critical Periods and 3:10 – 4 p.m. Carla Shatz, PhD • Stanford University Alzheimer’s Disease 4 – 4:15 p.m. AFTERNOON BREAK AFTERNOON BREAKOUT SESSIONS • PARTICIPANTS SELECT DISCUSSION GROUPS AT 4:15 AND 5:15 P.M. TIME BREAKOUT SESSIONS SPEAKERS ROOM Group 1: 4:15 – 5 p.m. Modeling Human Disease: Revising Assumptions About Molecules Carla Shatz, Stephen Hauser, & Shane Liddelow 143A and Mechanisms Group 2: Maiken Nedergaard & Dan Littman 143B What Are the Interactions Between the Brain and the Periphery? Group 3: How Normal Immune Processes Go Awry in Brain Disease: Implications for Beth Stevens & Marco Colonna 143C New Therapies and Biomarkers 5 – 5:15 p.m. AFTERNOON BREAK 5:15 – 6 p.m. Repeat sessions above. Select a second breakout group. Table of Contents Introduction Carla Shatz, PhD, and Beth Stevens, PhD .............................................5 Multiple Sclerosis: From Bench to Bedside and Back Again Stephen L. Hauser, MD ...........................................................6 Purification and Culture Methods for Astrocytes Shane Liddelow, PhD .....................................................19 The Glymphatic System Nadia Aalling, MSc, Anne Sofie Finmann Munk, BSc, Iben Lundgaard, PhD, and Maiken Nedergaard, MD, DMSc .............................................27 The Maternal Interleukin-17a Pathway in Mice Promotes Autism-Like Phenotypes in Offspring Gloria B. Choi, PhD, Yeong S. Yim, PhD, Helen Wong, PhD, Sangdoo Kim, PhD, Hyun Ju Kim, PhD, Sangwon V. Kim, PhD, Charles A. Hoeffer, PhD, Jun R. Huh, PhD, and Dan R. Littman, MD, PhD ..............................................37 TREM2 Variants: New Keys to Decipher Alzheimer’s Disease Pathogenesis Marco Colonna, MD, and Yaming Wang, PhD .........................................49 Microglia: Phagocytosing to Clean, Sculpt, and Destroy Soyon Hong, PhD, and Beth Stevens, PhD .......................................64 Synapse Elimination and Learning Rules Coregulated by Major Histocompatibility Class I Protein H2-Db Hanmi Lee, PhD, Lowry A. Kirkby, PhD, Barbara K. Brott, PhD, Jaimie D. Adelson, PhD, Sarah Cheng, BS, Marla B. Feller, PhD, Akash Datwani, PhD, and Carla J. Shatz, PhD ........70 Introduction Communication between brain cells and immune system cells plays a critical role in neural development, homeostasis, and disease. The intersections between the nervous and immune systems are complex and can have either beneficial or detrimental impacts on brain function, depending on the context. The nervous and immune systems share an array of molecules that have both specialized and analogous functions in the other system. Many immune-related molecules are expressed in the healthy brain and have homeostatic and physiological functions. For example, molecules traditionally associated with adaptive and innate immunity regulate circuit development and plasticity. Microglia, resident immune cells, and phagocytes actively signal along with neurons and astrocytes and sculpt developing synapses. Conversely, aberrant regulation of neural–immune interactions can damage the brain by mediating neuroinflammation, autoimmune reactions, vascular breakdown, synapse loss, and neurodegeneration. It is thus crucial that we understand the mechanisms that give rise to these divergent outcomes. This course will bring together an interdisciplinary team of faculty and researchers to discuss these and other emerging topics in neuroimmunology, with an emphasis on the mechanisms underlying neural–immune system cross talk in health and disease. Faculty will highlight new discoveries, tools, and approaches to study and model neural–immune signaling in different contexts, including human disease. Lecture topics include the interactions between the brain and the periphery; mechanisms and implications of reactive gliosis; glymphatic–lymphatic system connections; microglia function and dysfunction; the microbiome and the gut–brain axis; and immune mechanisms of synapse loss during developmentally critical periods and in neurodegeneration. Multiple Sclerosis: From Bench to Bedside and Back Again Stephen L. Hauser, MD Weill Institute for Neurosciences University of California, San Francisco San Francisco, California © 2017 Hauser Multiple Sclerosis: From Bench to Bedside and Back Again 7 Introduction embryos at a time. Each fetus shares a common NOTES The goal of a career in biomedical research is blood supply, leading to the establishment of a to contribute meaningfully to medically useful permanent, stable, lifelong bone marrow chimerism discoveries: something that happens, if one is among fraternal twins or triplets. We found that this fortunate, perhaps a few times over the course of a chimeric state, as predicted, permitted the transfer of career. For those of us involved in the B-cell story in T-lymphocytes from one sibling to another without multiple sclerosis (MS), this occurred in September eliciting an alloresponse in the recipient. These data 2006 with the unblinding of the phase II anti-CD20 set the stage for adoptive transfer of encephalitogenic rituximab (RTX) study (Hauser et al., 2008). First, we T-cells in a species phylogenetically close to humans, saw evidence of a potentially powerful new approach analogous to earlier experiments in inbred mice for treating relapsing MS (RMS). Second, despite this that were critical for defining the immunology of success, it was also clear that the rationale behind the murine EAE. clinical testing of RTX for MS was almost certainly incorrect. In many respects, this was the best possible After several years of starts and stops, a model of result that one could wish for. A novel approach MS was successfully developed by Luca Massacesi, appeared to offer significant benefits for patients, and a postdoctoral fellow, in 1995 (Massacesi et al., yet the data also sent us back to the bench in new 1995). The key step, which had eluded us before and unexpected directions. The rubber meets the Luca’s arrival, was the creative use of different road when ideas born in the lab are formally tested immune adjutants (Genain and Hauser, 1996). at the bedside, and when data from real-life patients Following immunization with a myelin extract in create new, testable ideas for research. Translational incomplete Freund’s adjuvant, and later with myelin medicine is most effective when information flow is oligodendrocyte glycoprotein (MOG), animals bidirectional, linking the laboratory with the clinic. developed a mild relapsing–remitting disease and an acute pathology characterized by large concentric The Early Days areas of macrophage-mediated demyelination with relative axonal sparing and foci of remyelination; the In the late 1970s, during my neurology residency, I myelin membrane was destroyed and reconstituted was in a conference room at Massachusetts General into vesicular fragments (Fig. 1), a pattern termed Hospital in Boston with the chair of neurology, “vesicular demyelination” (Prineas and Connell, Raymond D. Adams. A postdoctoral fellow was 1978). This was our first eureka moment—we had presenting some work in experimental autoimmune replicated the MS-like pathology that we had sought encephalomyelitis (EAE) induced by myelin basic for a decade. protein. Adams noted, with a touch of sarcasm, that the paralysis observed in the rodents likely However, when we adoptively transferred MOG- resulted from peripheral nerve, and not CNS, reactive T-cell clones from an immunized C. jacchus disease. Indeed, he emphasized that the pathology animal into a chimeric sibling, we replicated the of EAE and MS was quite different. T-cell-mediated acute murine pathology of panencephalitis