Ralph C. Budd, M.D.
Professor of Medicine
The Function of the Death Receptor Fas in the Immune System.
The laboratory is examining the signal pathways of Fas and its inhibitor, cFLIP, in murine models of autoimmunity and in human Lyme arthritis
Fas (CD95) and c-FLIP signaling in the immune system.
The Fas-deficient lymphoproliferative (lpr) mouse pictured above develops an autoimmune disease resembling human lupus, as well as profound enlargement of lymph nodes. We are studying the types of lymphocytes that accumulate in the absence of Fas-induced death. In parallel studies, we are examining the alterations in Fas signaling caused by its natural inhibitor, cFLIP. Ligation of Fas recruits the adaptor protein FADD, which then recruits the protease caspase-8. cFLIP is homologous to caspase-8 but lacks protease activity and hence is a competitive negative regulator of Fas-induced death. We have observed that cFLIP also connects to the MAP kinase ERK, and NF-kB pathways and can thus divert Fas death signals toward signal pathways associated with cell growth. We are examining this using overexpression of wild type and mutant forms of cFLIP in cell lines and transgenic mice.
The function of gamma/delta T cells in Lyme arthritis.Lyme Disease is the most common vector-borne disease in the U.S. It is caused by the spirochete, Borrelia burgdorferi, that is transmitted by the tick, Ixodes scapularis. We have observed that an unusual and small subpopulation of T lymphocytes known as gamma/delta T cells accumulate in the joint fluid in patients with Lyme arthritis. These gamma/delta T cells respond to lipopeptides from B. burgdorferi Our findings to date suggest a model whereby Borrelia lipopeptides bind to Toll-like receptor 2 on antigen presenting dendritic cells, which then upregulate surface molecules recognized by the gamma/delta T cells, such as the MHC-like molecules CD1b and MICA. This results in expression by the gamma/delta T cells of very high levels of surface FasL, and intense cytolysis of other neighboring T cells, especially Th2 CD4+ cells. However, due to high levels of cFLIP in dendritic cells, they are not only resistant to Fas-induced death, but are activated by Fas ligation.
Last modified May 31 2002 12:29 PM