Death receptor regulation of apoptosis in the immune system



Profile

Dr. Budd received his M.D. from Cornell University and then did a residency in Internal Medicine and Rheumatology Fellowship at Dartmouth Medical Center. Dr. Budd joined the faculty of the Department of Medicine at UVM in 1989 and became Professor of Medicine in 1997. He is a former recipient of a Pew Scholars Award in the Biomedical Sciences, a Fogarty Fellowship, has served on several NIH study sections, reviews for several journals, and is an editor for the Textbook of Rheumatology. Outside the lab, Dr. Budd is an avid swimmer, cross-country skier (all lab members are forced to XC ski), hiker, plays the organ, enjoys wine and espresso. Favorite novel: Captain Correli’s mandolin.

Research Description

The Fas-deficient lymphoproliferative (lpr) mouse develops an autoimmune disease resembling human lupus, as well as profound enlargement of lymph nodes. We are studying the origin and cause of the 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, c-FLIP. FLIP-transgenic mice manifest T cell hyperproliferation and a Th 2 cytokine bias. FLIP-Tg mice manifest worse allergic airway disease. We are studying how c-FLIP alters the signaling of T cells by associating with TRAF2 and RIP1 to augment activation of NF-?B, and with Raf-1 to increase ERK activation. We are also investigating the function of ?? 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 ?? T cells accumulate in the joint fluid in patients with Lyme arthritis. These ?? 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 ?? T cells, such as the MHC-like molecules CD1b and MICA. This results in expression by the ?? 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.

Highlighted Publications

Fortner, K.A., and Budd, R.C. The death receptor, CD95 (Fas/APO-1), mediates the deletion of T lymphocytes undergoing homeostatic proliferation. Submitted.

Chen, Y, Kelm, R.J., Budd, R.C., Sobel, B.E., and Schneider, D.J. Inhibition of Apoptosis and Caspase-3 in Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type-1. J. Cell. Biochem. 92:178-188, 2004

Wu, W., Fortner, K.A., Russell, J.Q.,Tschopp, J., and Budd, R.C. CD4+ T cells from c-FLIPL- transgenic mice express increased GATA-3, decreased NF-B and a Th2 cytokine bias J. Immunol. 172:4724-4732, 2004.

McLellan, B.S., Rincon, M., Bushway, P., Flavell, R.A., and Budd, R.C. Elevated NFAT transcriptional activity in lpr mature T cells. Submitted.

Roessner, K., Wolfe, J., Shi, C., Sigal, L.H., Huber, S.A., and Budd, R.C. High Expression of Fas-Ligand by Synovial Fluid-Derived γ δ T cells in Lyme Arthritis J. Immunol. 170:2702-2710, 2003.

View all Budd publications here.

* indicates equal contribution

Recent Publications

Buskiewicz IA, Koenig A, Roberts B, Russell J, Shi C, Lee SH, Jung JU, Huber SA, Budd RC (2014) c-FLIP-Short reduces type I interferon production and increases viremia with coxsackievirus B3. PLoS One 9(5): e96156.

Logan A, Shabalina IG, Prime TA, Rogatti S, Kalinovich AV, Hartley RC, Budd RC, Cannon B, Murphy MP (2014) In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice. Aging Cell 13(4): 765-8.

Saligrama PT, Fortner KA, Secinaro MA, Collins CC, Russell JQ, Budd RC (2014) IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3. Cell Death Differ 21(6): 904-14.

Koenig A, Sateriale A, Budd RC, Huber SA, Buskiewicz IA (2014) The role of sex differences in autophagy in the heart during coxsackievirus B3-induced myocarditis. J Cardiovasc Transl Res 7(2): 182-91.

Koenig A, Buskiewicz IA, Fortner KA, Russell JQ, Asaoka T, He YW, Hakem R, Eriksson JE, Budd RC (2014) The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival. J Biol Chem 289(2): 1183-91.

Ather JL, Fortner KA, Budd RC, Anathy V, Poynter ME (2013) Serum amyloid A inhibits dendritic cell apoptosis to induce glucocorticoid resistance in CD4(+) T cells. Cell Death Dis 4: e786.

Buskiewicz IA, Koenig A, Huber SA, Budd RC (2012) Caspase-8 and FLIP regulate RIG-I/MDA5-induced innate immune host responses to picornaviruses. Future Virol 7(12): 1221-1236.

View all Budd publications here.

Selected Awards

Pew Scholars Award in the Biomedical Sciences This award is given to 20 young investigators nationally each year in the area of biomedical research. The award is for 4 years and specifically encourages the recipients to take new risks in their research direction with the funds. (1990-1994)


Ralph Budd, M.D.

Ralph
Budd, M.D.

Professor
Department of Medicine

 

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