Neuroimmunology Seminar Series
at the University of Virginia
Sponsored by
Gerd Kempermann, Ph.D.
Dresden International Graduate School for Biomedicine and Bioengineering
"Immune cells and activity in the control of neurogenesis in the adult
hippocampus"
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.
Linda Liau, M.D., Ph.D.
Professor of Neurosurgery
UCLA School of Medicine
August 20th-22nd, 2009
Lawrence Steinman, M.D.
Professor
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. mSOD1\RAG2-\- mice died earlier than mSOD1\RAG2+\- 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 mSOD1\RAG2-\- mice, to ages identical to mSOD1\RAG2+\- 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 mSOD1\RAG2-\- mice or in mSOD1\RAG2+\- 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
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. mSOD1\RAG2-\- mice died earlier than mSOD1\RAG2+\- 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 mSOD1\RAG2-\- mice, to ages identical to mSOD1\RAG2+\- 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 mSOD1\RAG2-\- mice or in mSOD1\RAG2+\- 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.
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
Friday, October 24th, 2008
12:00 p.m. Camp Heart Center
"Anti-NMDA receptor encephalitis and the new immune-mediated disorders of memory, behavior, and psychosis"
Etty (Tika) Benveniste, Ph.D.
Professor and Chair, Department of Biology
Basic Science Research, Comprehensive Cancer Center
University of Alabama at Birmingham
"Expression and funciton of SOCS proteins in glial cells"
Monday, September 22nd, 2008
4:00 p.m., Jordan 1-17
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.