Programmed cell death has been shown to be an essential feature of negative selection of autoreactive lymphocytes and regulation of both physiological and pathological immune responses. Fas, a member of the TNF-receptor superfamily also known as CD95, has been shown to be important in apoptosis of activated T and B lymphocytes initiated by signaling through their antigen receptors. Humans and mice with germ line dominant-negative mutations in Fas accumulate abnormal lymphocytes and develop systemic autoimmunity similar to patients with Systemic Lupus Erythematosus. While most patients with non-familial autoimmune disease do not carry Fas mutations, there is evidence that Fas-mediated apoptosis may be impaired in the milieu of chronic inflammation. We are investigating which signals regulate Fas-mediated apoptosis in T cells, with the eventual aim of harnessing these discoveries to modulate Fas-induced apoptosis for therapeutic goals in human disease. In activated CD4+ T cells, TCR restimulation triggers apoptosis that depends in large part on interactions between the death receptor Fas and its ligand FasL. This process, termed restimulation-induced cell death (RICD), is a mechanism of peripheral immune tolerance. TCR signaling sensitizes activated T cells to Fas-mediated apoptosis, but which pathways mediate this process are not known. Using a variety of approaches, we are investigating molecular and cellular mechanisms regulating the TCR- and Fas-induced apoptosis pathways. We have found considerable heterogeneity in the ability of various T cell subsets to undergo Fas-mediated apoptosis and are investigating the molecular mechanisms underlying this heterogeneity. The goal in understanding these mechanisms is to design specific therapies to sensitize autoreactive lymphocytes to Fas-mediated apoptosis, which could constitute a long-acting and potentially permanent treatment for various autoimmune diseases such as Systemic Lupus, Multiple Sclerosis, Rheumatoid Arthritis, Type-I diabetes, and others in which autoreactive lymphocytes play a role. Through collaborations with investigators at NIH studying patients with the Autoimmune LymphoProliferative Syndrome (ALPS), a rare disorder associated with dominant-interfering Fas mutations, and the more common polygenic autoimmune disease Systemic Lupus Erythematosus (SLE), we are investigating translational implications of these findings. We are also investigating the cell biological control of Fas Ligand (FasL), the TNF-family cytokine ligand for Fas. In addition to trafficking to the plasma membrane as a type II transmembrane protein, FasL is known to be sorted into secretory lysosomes, where it can be secreted in vesicles and cleaved by metalloproteases. We are investigating which forms of FasL particpate in restimulation-induced cell death, and which molecules and motifs within the FasL cytoplasmic N-terminal domain direct its trafficking to secretory lysosomes. In a collaboration with Raif Geha's laboratory at Childrens Hospital in Boston, we are investigating the mechanisms by which mutations in TACI, a TNF-family receptor important for regulating B cell survival and class-switching, cause familial cases of common variable immunodeficiency. In collaboration with the laboratory of Ken Smith at the University of Cambridge, we are using systems biology to study the impact of polymorphisms in genes encoding TNF-family cytokines and their receptors in aggregate on susceptibility to autoimmune and inflammatory disease

Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2013
Total Cost
$568,218
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Department
Type
DUNS #
City
State
Country
Zip Code
Ou-Yang, Chih-Wen; Siegel, Richard M (2014) Outflanking RANK with a Designer Antagonist Cytokine. Sci Signal 7:pe20
Pereira-Manfro, Wania F; Ribeiro-Gomes, Flavia L; Filardy, Alessandra Almeida et al. (2014) Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection. J Leukoc Biol 95:347-55
Lo, Bernice; Ramaswamy, Madhu; Davis, Joie et al. (2013) A rapid ex vivo clinical diagnostic assay for fas receptor-induced T lymphocyte apoptosis. J Clin Immunol 33:479-88
Murphy, Michael P; Siegel, Richard M (2013) Mitochondrial ROS fire up T cell activation. Immunity 38:201-2
Ramaswamy, Madhu; Cleland, Sophia Y; Cruz, Anthony C et al. (2009) Many checkpoints on the road to cell death: regulation of Fas-FasL interactions and Fas signaling in peripheral immune responses. Results Probl Cell Differ 49:17-47
Lee, John J; Rauter, Ingrid; Garibyan, Lilit et al. (2009) The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. Blood 114:2254-62
Goyal, Ramona; Bulua, Ariel C; Nikolov, Nikolay P et al. (2009) Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders. Curr Opin Rheumatol 21:78-84
Zhang, Yue; Murtha, James; Roberts, Margaret A et al. (2008) Type III secretion decreases bacterial and host survival following phagocytosis of Yersinia pseudotuberculosis by macrophages. Infect Immun 76:4299-310