Neuroimmunology Seminar Series 2008-2012


Michal Schwartz, Ph.D.

The Maurice and Ilse Katz Professorial Chair in Neuroimmunology
Laboratory of the Immunology of the Mind in Health and Disease
Weizmann Institute of Science
Rehovot, Israel”Protective anti-self immunity: A paradigm shift in the perception of brain inflammation in health, neurodegenerative diseases, and age-related dementia”
Friday, March 16, 2012
12:00 p.m.
Jordan Hall, Room 1-17

Neurodegenerative diseases are associated with neuronal loss occurring within the central nervous system (CNS), a compartment behind walls. Thus, it was assumed that these tissues are unable to benefit from the assistance provided by the immune system. Moreover, signs of inflammation accompanying brain pathology were believed to indicate immune cell infiltration from the circulation that should be mitigated. However, we have shown that both circulating blood macrophages and T lymphocytes are needed for recovery, and that these two cell types orchestrate neuroprotection and cell renewal. In contrast to the well-documented pro-inflammatory activity of the microglia (the CNS-resident macrophages) at the site of trauma, the infiltrating monocyte-derived macrophages express hallmarks of ‘alternatively’ activated (M2; resolving) phenotype. In healthy animals, we demonstrated that T cells recognizing CNS antigens reside in the CNS borders and are needed for the maintenance of brain plasticity, including cognitive ability, neurogenesis, and coping with stress. We found that such T cells, including effector CD4+ T cells and regulatory T cells (Treg), are part of a dynamic network that provides life-long brain maintenance. These and other studies have led us to propose that neurodegenerative diseases may remain dormant long before their onset as long as the circulating immune cells can contain the pathology-induced deviation; disease onset indicates that either the deviation overrides the ability of the immune cells to counterbalance the rise of the risk factors, or that the immune system becomes exhausted and deteriorates concomitantly with the disease process. Thus, an appreciation of the distinct temporal and spatial contributions of resident and systemic leukocytes to life-long brain plasticity is essential for CNS pathologies including neurodegenerative and mental diseases and aging.

Robert H. Glaser Professor of Neurology and Immunobiology
Chairman, Department of Neurology
Yale School of Medicine”Plasticity of Regulatory T Cells”Monday, February 27, 2012
4:00 p.m.
Jordan Hall, Room 1-17

Professor, Molecular & Human Genetics, Molecular Physiology & Biophysics
Baylor College of Medicine
Houston, TX

“Identifying suppressors of Mecp2 in the mouse:  a genetic approach to therapeutic intervention”

October 21, 2011
12:00 noon
MR-4, Room 5102

Mutations in the methyl CpG binding protein 2 (MeCP2) cause Rett Syndrome (RTT), a severe neurological disease with autistic features and developmental regression.  Mouse mutants that eliminate Mecp2 function provide an excellent animal model.  In fact, symptoms in male mice can be reversed by introduction of Mecp2 and partially rescued by other factors, providing substantial evidence that intervention is possible in human patients. Identifying genes that impact disease severity in an unbiased way will allow for novel approaches to therapeutic intervention.  We aim to identify advantageous modifiers using a forward genetic screen in mice.  In a preliminary screen, five lines that carry inherited suppressors, which increase lifespan and decrease other RTT-related symptoms in mice, were isolated.  Mutations in candidate genes were identified using NextGen sequencing approaches.  As expected, most of the suppressors act at the level of chromatin remodeling, and may be difficult to target therapeutically.  However, one reveals a “systems” component to disease pathology, and provides a therapeutic target.


David Stellwagen, Ph.D.
McGill Centre for Research in Neuroscience
Montreal, Quebec, CA
“TNFα-mediated Synaptic Plasticity in the Striatum”October 11th, 2011
4:00 p.m. Jordan Hall, Room 1-14

Glia can regulate the development and function of the nervous system. We have previously demonstrated the the glial release of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) is an important modulator of synaptic function.  Through activation of neuronal TNF-R1 receptors, TNFα causes the exocytosis of GluR2-lacking AMPA receptors and results in an increase of excitatory synaptic strength.  Concurrently, TNFα application leads to an endocytosis of GABA-A receptors, and a decrease in inhibitory synaptic strength.  The release of TNFα is increased when neural activity is reduced and mediates homeostatic synaptic plasticity, where the nervous system compensates for a long-term reduction in neural activity levels by increasing the excitation and reducing the inhibition in the neural circuit.  These compensatory changes occur on excitatory projection neurons in the cortex or hippocampus, but evidence suggests that local interneurons respond quite differently to chronic activity manipulations. Here we present data that the GABAergic projection neurons in the striatum respond to the application of TNFα in a similar manner to hippocampal interneurons. This has important implications for the slow modification of striatal circuit function which can be observed in vivo, and underlies an adaptive response to the tardive dykinesia induced by chronic haloperidol treatment.

Gerald D. Fischbach, M.D.
Scientific Director
Simons Foundation Autism Research Initiative (SFARI)

New York, N.Y.

October 4th, 2011
4:00 p.m.  Jordan Hall, Room 1-14

“Autism and the Social Brain”

Joan Goverman, Ph.D.
Professor & Chair, Department of Immunology
University of Washington
Seattle, Washington”Mechanisms that determine inflammatory patterns in the central nervous system in an animal model of multiple sclerosis”Monday, September 26th, 2011
4:00 p.m., Jordan Hall, Room 1-14

Experimental autoimmune encephalomyelitis (EAE) is an animal model widely used to study multiple sclerosis that is induced by stimulating T cell-mediated immunity to myelin proteins.  TH1 (IFN-g secreting) and TH17 (IL-17 secreting) cells have been implicated in the pathogenesis of EAE. Our laboratory previously characterized an EAE model in which inflammation is regulated differently in the brain compared to the spinal cord.  Spinal cord inflammation was induced by central nervous system (CNS)-infiltrating T cells that exhibited a wide range in their TH17:TH1 ratio; however, inflammation in the brain was triggered only at higher TH17:TH1 ratios.  To define the roles of IL-17 and IFN-g in determining the sites targeted by inflammatory cells in the CNS, we utilized IFN-g receptor (R) and IL-17R-deficient mice.  Our results reveal complex roles for IL-17 and IFN-g-producing T cells that depend on the method of disease induction: surprisingly, IL-17signaling is not required to induce brain inflammation by immunization, however, transfer of wild-type T cells is less efficient in inducing EAE in IL-17 receptor-deficient hosts compared to wild-type hosts.  We have also developed new, myelin-specific T cell receptor transgenic mice that illustrate the importance of fine antigen-specificity in the pathogenesis of central nervous system autoimmunity.  Our goal is to use these new models to identify mechanisms that regulate autoimmune responses in the CNS and the role of inflammatory cytokines in regulating autoimmune disease.

Irina Grigorova, Ph.D.
Assistant Professor
Department of Microbiology & Immunology
University of Michigan Medical School”Immuno-dynamics of lymphocyte recirculation, antigen acquisition and humoral immune response initiation: Insights from 2-photon imaging, quantitative analysis and modeling”Monday, September 12th, 2011
4:00 p.m. Jordan Hall, Room 1-14

Lymphocyte recirculation between blood, lymphoid organs and lymph is crucial for efficient scanning of the lymphocytes for antigens and for their redistribution into the tissues where they exert effector functions. We are studying lymphocytes recirculation, antigen acquisition and initiation of adaptive immune response by integrating experimental data obtained by immunological approaches and intravital 2-photon imaging with quantitative modeling. Recently, based on the 2-photon and confocal imaging data and quantitative modeling, we demonstrated that residence time of naïve T lymphocytes within murine lymph nodes (LNs) is determined by their motility in the LN T zones, the distribution of lymphocyte entry (high endothelial venules, HEV) and exit (LYVE-1+ cotical and medullary sinuses) sites in the LNs, and the frequency of T cell transmigration into the exit sites upon contact. We have also identified that expression of S1P1 receptor on T cells, known to be required for T cell egress into lymph, affects their transmigration step into LYVE-1+ sinuses. We have also shown that high molecular weight antigens that can not readily access the LNs can penetrate into the LN LYVE-1+ sinuses by diffusion against the liquid flow. At these sites antigen-specific B cells pick up the antigens. We are currently using similar approaches to dissect multiple parameters underlying the immunodynamics of T-dependent humoral (antibody) immune response initiation. We are currently using similar approaches to dissect multiple parameters underlying the immunodynamics of T-dependent humoral (antibody) immune response initiation.

Jeffrey A. Rumbaugh, M.D., Ph.D.
Assistant Professor in Neurology, Division of Neuroimmunology & Neuro-infectious Disease
Emory University

“Novel Host Defense Mechanisms in the Neuropathogenesis of HIV Infection”

Friday, August 5th, 2011
12:00, Old Medical School Auditorium

Zoltan Fehervari, Ph.D.
Associate Editor, Nature Immunology

“Getting Published: tips and tricks of the trade”
Monday, June 20th, 2011
12:00 p.m. MR5, Room 1041

David Lo, M.D., Ph.D.
Professor, Biomedical Sciences
University of California-Riverside”M cells:  The ultimate mucosal immune surveillance machine”Monday, March 28th, 2011
4:00 p.m., Jordan Hall, Room 1-17

Ann Augustine, M.D.
Boston Medical Center”Sleep Disorders in Multiple Sclerosis”
Friday, March 25th, 2011
12:00, Jordan Hall, Room 1-5

MRC Centre for Stem Cell Biology &
Regenerative Medicine, Department of Veterinary Medicine
University of Cambridge
“Mechanisms of CNS myelin regeneration”
March 3rd, 2011

12:00 p.m., MR-5, Room 1005

Larry Benowitz, Ph.D.
Director, Laboratories for Neuroscience
Professor of Neurobiology and Neurosurgery
Children’s Hospital, Boston, MA
“Role of inflammatory mediators and other agents in promoting CNS rewiring after injury”
March 8th, 2011
4:00 p.m., Jordan Hall, Room 1-14

CNS damage commonly leads to life-long losses in sensory, motor, cognitive, and/or autonomic function, depending on the location and extent of injury. The optic nerve is a classic example of a CNS pathway that normally cannot regenerate when injured. However, the induction of a controlled inflammatory reaction in the eye causes retinal ganglion cells (RGCs), the projection neurons of the eye, to revert to an active growth state and begin regenerating lengthy axons beyond the site of optic nerve damage. This transformation is mediated primarily by oncomodulin (Ocm), a small calcium-binding protein that is secreted by neutrophils and macrophages. Ocm exhibits cAMP-dependent, high-affinity binding to a cell-surface receptor on RGCs. Gain-of-function and loss-of-function experiments show that Ocm is necessary and, in the presence of appropriate co-factors, sufficient to account for the effects of inflammation in stimulating optic nerve regeneration. When the gene encoding PTEN phosphatase is deleted from RGCs, inflammation combined with a cAMP analog enables RGCs to regenerate their axons all the way from the eye to the brain. Other work in our lab has shown that the protein kinase Mst3b is a key component of the signal-transduction pathway through which Ocm and other trophic factors lead to axon growth. Mst3b can be activated using inosine, a naturally occurring purine nucleoside. Inosine stimulates axon outgrowth from certain types of neurons in culture, and when tested in vivo, it promotes anatomical rewiring and improves functional recovery after stroke and spinal cord injury. Thus, agents that enhance neurons’ intrinsic growth potential can profoundly improve outcome after CNS injury.

Robert W. Motl, Ph.D.
Associate Professor
Department of Kinesiology and Community Health
University of Illinois at Urbana-Champaign”Exercise Psychology in Multiple Sclerosis”Friday, February 25, 2011
12:00 p.m., Jordan Hall, Room 1-5

Objective:  Understand physical activity, its measurement, antecedents, and consequences in multiple sclerosis

Bruce R. Ransom, M.D.
Warren and Jermaine Magnuson Professor & Chair
Department of Neurology
University of Washington School of Medicine”White Matter Ischemic Injury:  Yin Yang of Astrocyte Involvement”
February 1st, 2011

4:00 p.m., Jordan Hall, Room 1-14

Dan Levy, Ph.D.
Department of Anesthesia, Critical Care & Pain Medicine
Beth Israel Deaconess Medical Center for Life Science Boston, MA

“On the Origin of headache and the Search for a MASTer Trigger:  Meningeal Nociceptors and Mast Cells in Headache Triggering”

January 27th
12:00 p.m., MR-5, Room 3005

Rachel R. Caspi, Ph.D.
Section Chief, Immunoregulation Section
Deputy Chief, Laboratory of Immunology National Eye Institute, NIH”Immune privilege, T-regulatory cells and automimmunity”January 10, 2011
4:00 p.m., Jordan Hall, Room 1-17

Immune privilege is a phenomenon used by the eye, brain, reproductive organs and gut to protect themselves from immune damage. The eye is arguably the most vulnerable, and therefore also the most “privileged” of tissues. Nevertheless, the eye is a target for autoimmune uveitis induced by retina-specific T cells activated in the periphery by a chance encounter with a retinal (trauma) or mimic antigen. Uveitis is a clinically heterogeneous disease. Both Th1 and Th17 responses have been implicated, and may underlie heterogeneity, but causal relationships are hard to prove. Experimental autoimmune uveitis (EAU) induced with the retinal antigen IRBP serves as a model for human uveitis. Using the EAU model, we demonstrate that EAU can be either Th17 or Th1 dependent, and that under some situations effector mechanisms can be more complex and can deviate from the Th1/Th17 paradigm. Tregs are responsible for prevention and remission of uveitis. As part of immune privilege, conventional T cells convert to FoxP3+ T-regulatory cells in the living eye through a process requiring local antigen recognition, TGF-b and retinoic acid (RA). Importantly, RA, which functions in the chemistry of vision and therefore is present at high levels in ocular fluids, plays a dual role: in vision and in ocular immune privilege. However, previously primed T cells are relatively resistant to the inhibitory and Treg-inducing effects of the ocular microenvironment. This may explain why autoimmune uveitis can be induced by T cells activated in the periphery despite ocular immune privilege. Our findings indicate that naïve T cells can be primed within the target tissue itself, not only in lymph nodes, and shed new light on the phenomenon of immune privilege and on its role in actively controlling immune responses in the tissue.

Department of Pathology & Microbiology
University of Nebraska Medical Center
“Interplay Between Innate and Adaptive Immunity During Central Nervous System Bacterial Infection”
Monday, December 13th, 2010
4:00 p.m., Jordan Hall, Room 1-17

Brain abscess is a serious neurological disease elicited by pyogenic bacteria and typified by inflammation and edema which often results in a multitude of long-term health problems. Staphylococcus aureus is a common etiologic agent of brain abscesses and possesses numerous virulence determinants that manipulate host immunity. One example is superantigens (SAG) that clonally expand T cell subsets bearing specific Vb receptors. Despite recent advances in defining innate immune pathways elicited during brain abscess development, little information is currently available regarding the functional importance of adaptive immunity during CNS parenchymal infection. Our studies have demonstrated that both CD4+ T cells and NKT cells are the major T cell infiltrates associated with brain abscesses. From a functional perspective, Th1 and Th17 cells are critical for bacterial clearance during later stages of brain abscess development and importantly, both subsets are required to maintain a productive innate anti-bacterial response. In contrast, NKT cells play a lesser role in bacterial containment compared to CD4+ T cell populations. In terms of antigen reactivity, both S. aureus-specific T cells and SAG-reactive Vb8.1,8.2 T cells are associated with brain abscesses and likely impact tissue damage during infection. Evidence to support this possibility was provided by studies in TCR a-deficient mice where tissue damage and fibrotic encapsulation were affected. Collectively, CD4+ T cells play an important role in regulating bacterial clearance, innate immune infiltrates, and tissue injury during brain abscess development, establishing a direct link between innate and adaptive immunity during CNS abscess formation. Understanding the cross-talk between these two arms of CNS immunity may identify targets to modulate disease outcome to minimize necrotic damage to the CNS parenchyma that typifies brain abscesses.

Joseph El Khoury, M.D.Assistant Professor of Medicine, Harvard Medical School Neuroimmunology & Innate Immunity Lab
Center for Immunology & Inflammatory Diseases and Division of Infectious Diseases”Chemokines and Microglia in Alzheimer’s Disease:  Beyond Recruitment”Thursday, November 4th, 2010
2:00 p.m., Jordan Hall, Room 1-17

Alzheimer’s disease (AD) is associated with a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the principal cells involved, and they accumulate at perivascular sites of ß-amyloid (Aß) deposition and senile plaques. In this presentation I will review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the role of two chemokines and their receptors-MCP-1/CCR2 and Fractalkine/CX3CR1-in this process and propose a multi-step model for recruitment of mononuclear phagocytes into the brain. I will also present novel findings on how chemokines and their receptors can influence progression of AD by means beyond their role in chemotaxis and recruitment. Understanding the role of chemokines in AD is necessary to further understand the role of mononuclear phagocytes in the pathogenesis of AD and to identify any potential therapeutic use of these cells for the treatment of this disease.

Director, BioX
Stanford University
Stanford, CA
“Releasing the Brake on Ocular Dominance Plasticity”
Tuesday, October 26th, 2010
4:00 p.m., Jordan Hall 1-14

Connections in adult visual system are highly precise, but they do not start out that way. Precision emerges during critical periods of development as synaptic connections remodel, a process requiring neural activity and involving regression of some synapses and strengthening and stabilization of others. Activity also regulates neuronal genes; in an unbiased PCR-based differential screen, we discovered unexpectedly that MHC Class I genes are expressed in neurons and are regulated by spontaneous activity and visual experience (Corriveau et al, 1998; Goddard et al, 2007). These molecules may be crucial for controlling circuit excitability and stability in developing as well as adult brain, and changes in their function may contribute to developmental disorders such as Autism, Dyslexia and even Schizophrenia.

Benjamin M. Segal, M.D.

Holtom-Garrett Professor Neurology
Director, University of Michigan Multiple Sclerosis Center
Director, Holtom-Garrett Program in Neuroimmunology

“What Makes a T Cell Encephalitogenic?”

Monday, May 3rd, 2010
4:00 p.m., Jordan Hall, Room 1-17

Keith W. Kelley, Ph.D.
Professor of Immunophysiology
Departments of Animal Sciences & Medical Pathology
University of Illinois at Urbana-Champaign

“How Did the Immune System Ever Become Related to Behavior?”

Tuesday, April 27th, 2010
4:00 p.m., Jordan Hall, Room 1-14

Andrew A. Pieper, M.D., Ph.D.
Assistant Professor, Department of Psychiatry
University of Texas Southwestern Medical Center

“In vivo discovery of pharmacologic agents for treatment of neuropsychiatric disease”
Thursday, April 8th, 2010
Noon, Room 5102, MR-4

Monica J. Carson, Ph.D.Associate Professor
Division of Biomedical Sciences
University of California, Riverside

“Microglia:  a Moving Target During CNS Development and Neurodegenerative Disease”

Tuesday, March 30th, 2010
4:00 p.m., Jordan Hall, Room 1014

Ning Quan, Ph.D.

Associate Professor
College of Dentistry, Neuroscience Graduate Studies Program
The Ohio State University

“Integrating the Neuroimmune Super-System”

Monday, March 29th, 2010
2:30 p.m., MR-4, 5th floor Conference Room 5102

Dr Quan will discuss how neuroimmune communication provides a highway towards understanding mind-body interactions, including the role of blood-brain barrier in neuroimmune communication, and a description of a neuroimmune loop that integrates immune-brain communication with brain systems involved in immune regulation and host-defense responses. In this context, Dr. Quan will discuss the molecular basis for the diverse functions mediated by the cytokine IL-1, and the discovery of a neuronal specific IL-1 receptor.

Tammy L. Kielian, Ph.D.
Associate Professor
Department of Pathology and Microbiology
University of Nebraska Medical Center

“Interplay Between Innate and Adaptive Immunity During Central Nervous System Bacterial Infection”


Monday, February 8th, 2010
4:00 p.m., Jordan Hall, Room 1-17

Microglia and astrocytes are important effector cells of the central nervous system (CNS) innate immune response to parenchymal infections. Toll-like receptor 2 (TLR2) is pivotal for glial recognition of S. aureus, a prevalent CNS pathogen, and eliciting proinflammatory mediator release. In addition, signaling via the TLR/IL-1R adaptor MyD88 is essential for the induction of CNS immunity in a mouse model of experimental brain abscess. Studies using radiation bone marrow chimera mice have demonstrated a novel role for MyD88 in the CNS-intrinsic regulation of neuroinflammatory responses to S. aureus. With regard to adaptive immunity, recent evidence has demonstrated a pivotal role for T cells bearing the ab T cell receptor (TcR ab) in regulating innate immune infiltrates into the infected CNS as well as bacterial clearance. Collectively, these studies reveal important roles for both innate and adaptive immune responses during Gram-positive infections in the CNS parenchyma.

David N. Irani. M.D.
Associate Professor of Neurology
University of Michigan Medical School

“Mechanisms of Non-Cell Autonomous Motor Neuron Injury With Viral Infection of the Spinal Cord”

Tuesday, December 8th, 2009
4:00 p.m.
Jordan Hall 1-14

Alphaviruses and flaviviruses cause acute encephalomyelitis in humans worldwide. While natural transmission occurs via mosquito vectors, several of these pathogens can be spread as aerosols making them potential bioterrorism and biological warfare agents. Viral invasion the spinal cord causes acute flaccid paralysis due to destruction of ventral motor neurons. Using a mouse model of infection, we show that much of this motor neuron injury occurs among uninfected cells via glutamate excitotoxicity. Disrupted glutamate homeostasis in the spinal cord results from loss of astrocyte glutamate transporters, even as these glial cells are neither infected nor destroyed during disease. Proinflammatory host responses, perhaps in part arising from activated microglia, appear to drive this astrocyte dysfunction. Therapeutic interventions targeted at glutamate receptors or at these aberrantly functioning glial cells can mitigate motor neuron damage and paralysis without altering virus tropism, replication, or clearance from the spinal cord. These findings suggest novel treatment approaches that could eventually be applied in related human diseases.

Gerd Kempermann, Ph.D.
Dresden International Graduate School for Biomedicine and Bioengineering

“Immune cells and activity in the control of neurogenesis in the adult

Tuesday, October 13th, 2009
4:00 p.m., Jordan Hall 1-14

Adult neurogenesis listens to the body to an amazing degree: neuronal development is regulated by activity and seems to be adjusted to the level of experience an individual has. While there is good evidence that neuronal actiivity per se mediates much of this effect, the mechanism is far more complex. Especially the question how the thresholds are set and how a baseline control is maintained has yet not been answered. The immune system has been a prime candidate to provide such candidate, and indeed, it turned out that CD4-positive T cells play a major role in mediating this control. From this, first syntheses can be attempted, integrating cells, genes and environment into our understanding of how neurogenesis is regulated.

Lawrence Steinman, M.D.
Departments of Neurology and Neurological Sciences,
Pediatrics and Genetics
Stanford University
Stanford, CA

“A Molecular Trio for Relapse and Remission in Multiple Sclerosis”

Monday, May 4th, 2009
4:00 p.m., Jordan Hall 1-17

Two thirds of patients with multiple sclerosis have the relapsing-remitting form, which often progresses to more debilitating disease. Striking clinical recovery, termed remission, often follows these periodic neurological deficits, termed relapses. Recent work has revealed the role of three key molecules in relapse and remission. alpha4 beta1 integrin (VLA4) is an adhesion molecule that mediates T-cell migration from the blood into the brain. Osteopontin (OPN) binds to alpha4 beta1 integrin, stimulating the production of pro-inflammatory cytokines and inhibiting apoptosis. aB crystallin inhibits inflammation within the brain. This molecular trio interacts to initiate (OPN and alpha4 beta1 integrin) relapses and then to terminate (±B crystallin) them as remissions in multiple sclerosis.

Olaf Stuve, M.D., Ph.D.
Assistant Professor, Department of Neurology & Immunology
University of Texas, Southwestern Medical Center in Dallas

“Defining the Role of Natalizumab in MS Therapy”

Friday, April 17th, 2009
12:00 p.m. Camp Heart Auditorium

Stanley H. Appel, M.D.
Professor, Weill Medical College of Cornell University
Chair, Department of Neurology
Co-Director of the Methodist Neurological Institute, Houston, TX

“Immunomodulation in Amyotrophic Lateral Sclerosis: Friend or Foe?”

Tuesday, January 20th, 2009
4:00 p.m., Jordan 1-14

Neuroinflammation, marked by gliosis and infiltrating T-cells, is a prominent pathological feature in human ALS as well as in models of neurodegenerative diseases. Transgenic mice ubiquitously over-expressing mutant Cu2+/Zn2+ superoxide dismutase (mSOD1), a chronic neurodegenerative model of inherited amyotrophic lateral sclerosis (ALS), exhibit such neuroinflammatory changes. We have documented that the innate immune system plays a pivotal role in determining the rate of disease progression in mSOD1 mice by demonstrating that microglia either lacking or with reduced mSOD1 expression enhance motoneuron protection and slow disease progression in such models. These studies were carried out in mice that are unable to develop myeloid cells, but in which both peripheral and central immune systems are modified.

To provide evidence for a potential role of the adaptive immune system in these models, we bred mSOD1 mice with RAG2-/- mice that are unable to develop mature and functional T- and B-cells. mSOD1RAG2– mice died earlier than mSOD1RAG2+- mice, and no T cells were present within the spinal cord. The onset of disease was unchanged. Following irradiation and transplantation with mSOD1 or WT-derived bone marrow, survival was extended in mSOD1RAG2– mice, to ages identical to mSOD1RAG2+- mice. Immunohistochemical analyses of spinal cord sections demonstrated that CD4+T cells had been restored by BMT, but there was no evidence for the presence of B cells either in mSOD1RAG2– mice or in mSOD1RAG2+- mice. When CD4-/- mice were crossed with mSOD1 mice, the CD4-/- mSOD1 mice died earlier than CD4+/-mSOD1 mice, confirming the importance of CD4+ T-cells in mediating neuroprotection. Mice lacking functional T-cells, or CD4+ T-cells also had increased mRNA levels for pro-inflammatory cytokines and NOX2, and decreased levels of trophic factors and glial glutamate transporters. Bone marrow transplants reconstituted mice with T-cells, prolonged survival, suppressed cytotoxicity, decreased mRNA levels for pro-inflammatory cytokines and NOX2, and increased mRNA expression of trophic factors and glial glutamate transporters. Thus CD4+ T-cells may provide neuroprotection by modulating the trophic/cytotoxic balance of glia; and glial/T-cell interactions may provide a novel target for therapeutic intervention in ALS and possibly other neurodegenerative diseases.

Supported by grants from the MDA and the NIH

Rodney Johnson, Ph.D.
Associate Professor of Integrative Immunology and Behavior
Department of Animal Sciences
University of Illinois, Urbana

“Aging, Microglial Cell Priming and Discordant Communication between the Immune System and Brain”

November 11, 2008
4:00, Jordan 1-14

Brain microglial cells are ordinarily quiescent but when stimulated can transition to a “primed” or activated state. Both primed and activated microglia are deramified and express markers that suggest activation, but only activated microglia produce appreciable levels of inflammatory cytokines. Primed microglia, however, are hyper-responsive to a secondary stimulus from the peripheral innate immune system and thus can produce an exaggerated cytokine response when provoked. The potential for primed microglia to mount an exaggerated response is important because inflammatory cytokines mediate the sickness behavior syndrome, induce deficits in cognition, and are involved in chronic neurodegenerative diseases. One physiological event that may prime microglial cells for an exaggerated response is aging. This presentation will provide a brief overview of how the peripheral innate immune system communicates with the brain, discuss evidence that suggests the emergence of a neuroinflammatory state during normal aging, and present new findings that suggest a peripheral infection induces an exaggerated neuroinflammatory response and severe behavioral deficits in the aged.

Josep Dalmau, M.D., Ph.D.
Division of Neuro-oncology
Institute of Neurological Sciences
University of Pennsylvania

“Anti-NMDA receptor encephalitis and the new immune-mediated disorders of memory, behavior, and psychosis”

Friday, October 24th, 2008
12:00 p.m. Camp Heart Center

Etty (Tika) Benveniste, Ph.D.
Professor and Chair, Department of Biology
Basic Science Research, Comprehensive Cancer Center
University of Alabama at Birmingham

“Expression and function of SOCS proteins in glial cells”

Monday, September 22nd, 2008
4:00 p.m., Jordan 1-17

Glial cells (astrocytes and microglia) participate in both inflammatory and anti-inflammatory responses within the Central Nervous System. Key regulators of inflammatory responses are the family of Suppressor of Cytokine Signaling (SOCS) proteins, which function predominantly to inhibit the JAK/STAT signaling pathway. This seminar will describe the ability of glial cells to express SOCS proteins in response to a variety of stimuli, the mechanisms underlying SOCS gene expression, and the functional consequences of expression, particularly as related to neuroinflammation. The importance of SOCS proteins in the context of CNS diseases such as Multiple Sclerosis and AIDS Dementia Complex will be discussed.

Uwe-Karsten Hanisch, Ph.D.
Institute of Neuropathology, University of Goettingen, Germany

Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Tuesday, September 22nd, 2008
4:00 p.m., Jordan 1-17

Hosted by Jonathan Kipnis, Department of Neuroscience

Microglia as the macrophage equivalent and the principal immunocompetent cells of the central nervous system are gathering enormous interest by basic and clinical neuroscientists. Their active or passive involvement in pathological processes ranging from trauma to neurodegeneration has been anticipated and studied since quite some time. However, we are currently witnessing major changes in the fundamental concepts of their populational organization, activities in the normal tissue and the variety of their reactive behavior upon different challenges. We address in our own work factors, mechanisms and consequences of microglial activation and activities. The talk will take examples to discuss the diversity and dynamics of microglial reactions. We will thereby especially concentrate on the potential role of plasma and coagulation factors as signals and modulators of these fascinating cells which – after all- are serving primarily in the protection of the structural and functional integrity of the central nervous system.

Doina Ganea, Ph.D.
Professor and Chair, Department of Microbiology and Immunology
Temple University School of Medicine

Neuropeptides as Endogenous Anti-Inflammatory Agents

Monday, June 9th, 2008
4:00 p.m., Jordan Hall, Room 1-17

Neuropeptides/neurohormones such as VIP, PACAP, cortistatin, a-MSH are potent immunosuppressors. The immunobiological activity of most of these endogenous immunosuppressive factors is mediated through the “deactivation” of innate immune cells such as macrophages, dendritic cells, microglia, through the shift towards Th2 immunity, and through the generation of Treg. VIP/PACAP induce antigen-specific Treg in vivo and in vitro, by recruiting new CD4+CD25+Foxp3+ Treg from the CD4+CD25- T cell population and through the generation of tolerogenic DCs. VIP and/or DCVIP have therapeutic effects in models of EAE (Fernandez-Martin et al, Eur. J. Immunol. 2006) , RA (Chorny et al, PNAS 2005, 102:13562), GVHR, and graft-versus-leukemia responses (Delgado et al, J. Leukoc. Biol. 2005, 78:1327; Chorny et al, Blood, 2006).

Michael K. Racke, M.D.
Professor and Chairman of Neurology
The Helen C. Kurtz Chair in Neurology
The Ohio State University Medical Center

Transcriptional Regulation of Encephalitogenic T Cells

Thursday, May 22nd, 2008
2:00 p.m., Jordan 1-17

Zsuzsanna Fabry, Ph.D.
Chair, Cellular and Molecular Pathology Graduate Program,
Department of Pathology and Laboratory Medicine
University of Wisconsin-Madison School of Medicine and Public Health

Neuroinflammation in the Central Nervous System

Tuesday, April 22nd, 2008
4:00, Jordan 1-5

Hosted by the Departments of Neuroscience and the Neuroscience Graduate Program

Richard Ransohoff, M.D.
Professor, Department of Molecular Medicine & Pathology
Director, Neuroinflammation Research Center, Department of Neuroscience

Chemokines in the CNS: Much More Than Leukocyte Trafficking

Thursday, March 27, 2008
2:00 pm, Jordan 1-14

Hosted by Jonathan Kipnis, Department of Neuroscience

Scott Zamvil, M.D., Ph.D.

Associate Professor, Department of Neurology
University of California, San Francisco

Type II Monocytes in Regulation of CNS Autoimmunity

Monday, January 21, 2008
4:00 pm, Jordan 1-17

Hosted by the Beirne B. Carter Center for Immunology Research and
the Departments of Neuroscience and Neurology