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Pathogenetic Mechanisms in Systemic Lupus Erythematosus (SLE)
Females of the F1 cross between NZB and SWR mice develop a severe and accelerated glomerulonephritis, very similar to human SLE, and we are using this model to understand the pathogenetic mechanisms involved in the disease. Our hypothesis is that dysregulation of the production of immunoglobulins which are deposited in the kidneys and bear a unique marker, IdLNF1, is critical to disease development. T cell clones that react with a peptide which encodes this marker, accelerate disease, and, conversely, antibodies which react with this marker downregulate production of IdLNF1-expressing antibodies, leading to increased survival. Finally, vaccination of mice with this peptide early in life, before disease onset, leads to significantly longer survival. These studies suggest that it may be possible to develop therapeutic approaches that target specific pathogenic cells in SLE. They may also further our understanding of the role of female sex hormones in disease.
Characterization of the HTLV-I Receptor. With B. Poiesz, M. Lane
HTLV-I is believed to be the etiologic agent of adult T-cell leukemia (ATL) and Tropical Spastic Paraparesis (TSP) Binding of the virus to a specific cell surface molecule that is expressed on a wide variety of cell types appears to mediate infection. We have derived a monoclonal antibody which blocks binding of the virus to its receptor and infection of susceptible cells. We are currently using this antibody to isolate the gene encoding this molecule, and will characterize its product. These studies will contribute information critical to understanding the pathogenesis of HTLV-I diseases, and aid in the development of new approaches for their treatment.
Gavalchin, J., Fan, N., Waterbury, P.G., Corbett, E., Faldasz, B.D., Peshick, S.M., Poiesz, B.J., Papsidero, L., and Lane, M.J. (1995) Regional localization of the putative cell surface receptor for HTLV-q to human chromosome 17q23.2-17q25.3. Virology 212:196-203.
Knupp, C. J., Uner, A.H., Tatum, A.H., Kakanar, J.R. and Gavalchin, J. (1995) IdLNF1-specific T cell clones accelerate the production of IdLNF1+ IgG and nephritis in SNF1 mice. J. Autoimmunity 8: 367-380.
Uner, A., Tatum, A.H. Knupp, C. J. and Gavalchin, J. (1998) Characteristics of auto anti-idiotypic antibodies reactive with antibodies expressing the pathogenic idiotype, IdLNF1, in the (NZB x SWR)F1 model for lupus nephritis and its parental strains. In press, J. Autoimmunity.
Dudek, K., Knupp, C.J., Tatum, A.H., Stoll, M. and Gavalchin, J. (1998) Identification of pathogenic IdLNF1 autoantibody idiotypes derived from the (NZB x SWR)F1 model for systemic lupus erythematosus. In press, J. Autoimmunity.