Research in this laboratory focuses on central nervous system (CNS) (brain and spinal cord) inflammation and pathogenesis in a mouse model of multiple sclerosis. We have used genetically marked lymphocytes to study the mechanisms of their entry into the CNS to cause disease.
We have found that the initial compromise of the blood brain barrier requires that lymphocytes “see” a CNS antigen in the space between blood vessels and the parenchyma (body) of the CNS. This interaction initiates a “conversation” between cells originating in the blood and cells of the parenchyma itself that determines whether or not inflammatory invasion will occur.
The molecular language of this “conversation” is a group of small proteins (cytokines and chemokines) that regulate the expression of adhesion molecules (VCAM-1) on astrocytes in the parenchyma and recruit macrophages and other inflammatory cells. The VCAM-1 expression on astrocytes appears to be an important mechanism to allow both the recruitment and retention of the inflammatory infiltrate into the parenchyma, causing demyelination and axon loss associated with paralysis.
We have developed a novel technique to isolate the infiltrating lymphocytes at various stages of invasion. Current experiments are focused on understanding the molecular changes in the lymphocytes as they invade the CNS to identify possible targets for preventing their invasion of the CNS. We are also focusing on the role of the astrocyte in both promoting and protecting from or healing the inflammatory process. Our results suggest that there may be regionally specific “dialects” of the conversation making some CNS regions more susceptible to invasion than others and astrocytes are an important part of those regional differences.
1996-present, Professor of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO
1984-1996, Associate Professor of Pharmacology, Washington University School of Medicine, St. Louis, MO
1978-1984, Assistant Professor of Pharmacology, Washington University School of Medicine, St. Louis, MO
1974-1978, Postdoctoral Fellow, Laboratory of Herman Eisen, Massachusetts Institute of Technology, Cambridge, MA
Helen Hay Whitney Postdoctoral Fellowship, 1975-1978
Research Career Development Award, DHHS 1984-1989
Outstanding Mentor Award from Graduate Student Senate, 2000
Mentor Award from Academic Women’s Network, 2000
- Archambault AS, Sim J, McCandless EE, Klein RS, Russell JH. Region-specific regulation of inflammation and pathogenesis in experimental autoimmune encephalomyelitis. J Neuroimmunol 2006 181:122-132.
- Gimenez MA, Sim J, Archambault AS, Klein RS, Russell JH. A TNFR1-dependent conversation between CNS-specific T cells and the CNS is required for inflammatory infiltration of the spinal cord. Am J Pathol 2006 168:1200-1209.
- Lees JR, Archambault AS, Russell JH. T-cell trafficking competence is required for CNS invasion. J Neuroimmunol 2006 177:1-10.
- Archambault AS, Sim, J Gimenez MA, Russell JH. Defining Antigen Dependent Stages of T cell Migration from the Blood to the Central Nervous System Parenchyma. Eur J Immunol 2005 35:1076-1085.
- Gimenez MA., Sim J, Russell JH. TNFR1-Dependent Parenchymal VCAM-1 Expression Lays Down the Path for Destructive CNS Inflammation. J Neuroimmunol 2004 151:116-125.
- Yu, J.J., C.S.Tripp and J.H. Russell. (2003) Regulation and Phenotype of an innate Th1 Cell; Role of cytokines and the p38 kinase pathway. J. Immunol. 171:6112.
- Song, S. K., S. W. Sun, M. J. Ramsbottom, C. Chang, J. H. Russell and A. H. Cross. (2002) Dysmelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17:1429.
- Shenoy, S., T. Mohanakumar, T. Chatila, J. Tersak, B. Duffy, R. Wang, A. R. B. Thilenius and J. H. Russell. (2001) Defective apoptosis in Lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias. Clin. Immunol. 99: 266.
- Hurov, J. B., T. S. Steppenbeck, C. M. Zmasek, L. S. White, J. H. Russell, A. C. Chan, K. M. Murphy and H. Piwnica-Worms. (2001) Immune system dysfunction and autoimmune disease in mice lacking Emk (Par-1) protein kinase. Mol. Cell. Biol. 21:3206.
- Sabelko-Downes, K. A., M. T. Gimenez, G. C. Suvannavejh, S. D. Miller and J. H. Russell. (2000) Genetic control of pathogenic mechanisms in autoimmune demyelinating disease. J. Neuroimmunol.110:168.