Rheumatic Diseases Research Core
Status of Women in Medicine Committee (SWIM)
Tissue Specific Stem Cells
We study cell trafficking and inflammation in autoimmunity and lymphoid organ development, particularly the roles of members of the lymphotoxin/tumor necrosis factor (LT/??TNF) family. We study acute inflammation and animal models of autoimmune diseases, including Type 1 diabetes mellitus and multiple sclerosis. LT is also crucial for lymphoid organ development; LT deficient mice lack lymph nodes and Peyer’s patches and exhibit profound alterations in spleen and nasal associated lymphoid tissue. Our studies demonstrate that cytokines’ functions in lymphoid organ development and inflammation are similar; they regulate chemokines and vascular adhesion molecules. Ectopic or “tertiary” lymphoid organs arising in chronic inflammation are lymphoid accumulations that permit the presentation of foreign and self-antigens at local sites of inflammation. Our studies on high endothelial venules and lymphatic vessels elucidate developmental mechanisms and point the way towards treatment and prevention of chronic inflammation.
Extensive Research Description
Professor Ruddle's research concentrates on cell trafficking and inflammation, particularly with regard to the lymphotoxin/tumor necrosis factor (LT/TNF) family. Her group studies these and other cytokines in autoimmune and infectious diseases. They study autoimmune diseases, the inflammatory stage of Type 1 diabetes mellitus, and experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. Cytokines, autoantigens, or infectious organisms can give rise to chronic cellular accumulations called "ectopic" or "tertiary lymphoid organs," through a process termed lymphoid organ neogenesis. Three “tertiary lymphoid organs” can contribute to diseases and even serve as a site of prion accumulations. Dr. Ruddle’s group identified a role for LT in normal lymphoid organ development. Their studies demonstrate that the roles of the cytokines in lymphoid organ development and inflammation are similar, in that in both contexts they induce chemokines and vascular adhesion molecules. The functions of lymph nodes and tertiary lymphoid organs may be comparable with regard to antigen presentation, serving both helpful and harmful roles in defense and autoimmunity.
- Liao, S., Bentley, K., Lebrun, M., Lesslauer, W., Ruddle, F.H, and Ruddle, N.H. (2007). Transgenic lacZ under control of hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules. Proc. Nat. Acad. Sci. (USA) 104:4577-4582.
- Drayton, D.L., Liao, S., Mounzer, R.H., and Ruddle, N.H. (2006). Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7:344-353.
- Marta, C.B., Oliver, A.R., Sweet, R.A., Pfeiffer, S.E., and Ruddle, N.H. Pathogenic Myelin Oligodendrocyte Glycoprotein Antibodies Recongize Glycosylated Epitopes and Perturb Oligodendrocyte Physiology. Proceedings of the National Academy of SciencesUSA 102(38) 2005
- Heikenwalder, M., Zeller, N., Seeger, H., Prinz, M., Klohn, P.C., Schwarz, P., Ruddle, N.H., Weissmann, C., and Aguzzi, A. Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions. Science 307(5712): 1107-1110, 2005.
- Drayton, D.L., Bonizzi, G., Ying, X., Liao, S., Karin, M., and Ruddle, N.H. ??? kinase complex a kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal associated lymphoid tissue. Journal of Immunology 173: 6161-6168, 2004.
- Soderberg, K.A., Linehan, M.M., Ruddle, N.H., and Iwasaki, A. MAdCAM-1 expressing sacral lymph node in the lymphotoxin-ß deficient mouse provides a site for immune generation following vaginal herpes simplex virus-2 infection. Journal of Immunology 173: 1908-1913, 2004.
- Drayton, D.L., Ying, Y., Lee, J., Lesslauer, W., and Ruddle, N.H. Ectopic LTaß Directs Lymphoid Lymphoid Organ Neogenesis with Concomitant Expression of Peripheral Node Addressin and a HEV-restricted Sulfotransferase. Journal of Experimental Medicine 197: 1153-63, 2003.
- Oliver A.R., Lyon G.M., and Ruddle N.H. Rat and human myelin oligodendrocyte glycoproteins induce experimental autoimmune encephalomyelitis by different mechanisms in C57BL/6 mice. Journal of Immunology 171: 462-468, 2003