There are two components to the Department’s Basic Science Research which include Neuroimmunology and Neurovirology laboratories. These labs are investigating basic disease mechanisms in experimental animal models for myasthenia gravis (MG) and multiple sclerosis (MS). In the first instance, the investigations are directed at developing improved ways of treating and managing MG, and in the latter, understanding how viruses persist and finding a viral trigger or cause of MS. It is worth pointing out that the notion that MS is an autoimmune disease while widely accepted by the current generation of students and physicians remains unproven. Immune-mediated tissue damage can also result from virus infections in which the host immune response is directed to viral rather than self proteins or as a consequence of a nonspecific or bystander immune response that changes the local cytokine environment.
Neuroimmunology
Dr. Matthew Meriggioli’s is director of the Neuroimmunology laboratory which is pursuing studies related to autoimmne MG. A focus of Dr. Meriggioli’s research is the experimental animal model of MG (EAMG). He is examining antigen-specific effects of modulation of dendritic cell subsets and regulatory T cells on the course of EAMG. Further information on Dr. Meriggioli’s research can be found on his faculty profile.
Neurovirology
Dr. Howard Lipton is director of the Neurovirology laboratory where the research is centered around the experimental animal model of Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice. TMEV is an enteric virus and member of the cardiovirus genus of the Picornaviridae family. Persistent central nervous system (CNS) infection in mice leads to inflammatory demyelination which is mediated by virus-specific CD4+ Th1 T lymphocytes. The merits of this experimental animal model lie in its chronicity with mice developing demyelination that lasts for months, the development of spastic paralysis as the result of demyelination, and the immune-mediated nature of the demyelinating process.
The Lipton laboratory is interested in understanding how TMEV persists in the CNS of mice, since persistent infection is required to drive demyelination. One potential mechanism is that of virus-induced apoptosis in macrophages which provide the main virus reservoir in the mouse CNS. TMEV-induced apoptosis in macrophages also is a means of attenuating the neurovirulence of this highly cytolytic virus enabling it to cause a persistent infection. The upstream signaling pathways involved in the induction of intrinsic apoptosis (through permeabilization of the outer mitochondrial membrane and activating caspases) is a major emphasis of the research. Another is elucidating the TMEV gene product(s) that trigger apoptosis and the mechanism(s) by which this occurs.
Recently, human Theiler’s viruses (human theiloviruses) have been discovered, and appear to be a common cause of upper respiratory and gastrointestional infections in young children worldwide. A natural extension of this discovery is determining whether human Theiloviruses are involved in the pathogenesis of MS. This is a recent area of research in the laboratory which is made more difficult because of the fact that human theiloviruses have been exceedingly difficult to grow in cell culture, the main way to work with viruses in a laboratory.
Personnel
Howard L. Lipton, M.D.
Zhiguo Liang, B.S., Ph.D. Research Scientist and molecular virologist.
Shannon Hertzer, B.S., M.S., Ph.D. Research Associate and molecular virologist.
Kyung-No Son, B.S., Ph.D. Post-doctoral fellow and viral immunologist
Patricia Kallio, B.S. Senior Research Technician
Sevim Yildiz, B.S., M.S . Ph.D graduate student.
Steve In-hyuk Ro, B.A., LLD. M.D. student
References
Please see Dr. Lipton’s faculty profile for a list of recent publications.
Research Support
NIH NS 21913-29 to 33. Molecular Pathogenesis of Theiler's Virus-Induced Demyelin-ating Disease in Mice. 4/1/06-3/31/11.
NIH POl NS 23349-12-17. Nervous System Damage from Viral Persistence: (Project IV. The role of apoptosis of macrophages in Theiler's virus persistence). 12/1/02-11/30/07. (No cost extension until 11/30/08)
National Multiple Sclerosis Society RG-4051-A-9. Establishing a Multiple Sclerosis Tissue Repository. 10/1/07-9/30/10.
Grant Healthcare Foundation. Strategies to Find a Persistent Virus Infection in Multiple Sclerosis. 1/1/08-12/31/08.
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