This project is based on our discovery that genetic mutations in molecules that control the programmed death, or apoptosis, of lymphocytes is responsible for the Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a disease affecting children that leads to loss of normal lymphocyte homeostasis leading to swollen lymph glands and organs. Because lymphocytes are the primary cell mediating immune reactions, this excess of lymphocytes leads to a pathological autoimmune attack on the patient's own tissues. We have identified mutations in a death-inducing cell surface receptor termed Fas (also known as APO-1 or CD95) and in other molecules that regulate apoptosis. We have also identified a new disease entity called, """"""""Caspase-eight deficiency state"""""""" (CEDS) that is due to a genetic deficiency of caspase-8. This disease involves a loss of apoptotic control and lymphocyte expansion combined with a failure of normal lymphocyte activation through the antigen receptors. The consequence of this is a profound immunodeficiency state and the new insight the capase-8, heretofore regarded solely as a cell death inducing protease, has a key role in antigen receptor signaling particularly for the induction of a gene regulatory factor called NF-kB. These studies promise to provide new insights into the molecular mechanisms that underlie autoimmune and immunodeficiency disease as well as revealing crucial steps in the pathway of programmed cell death in lymphocytes. We are presently studying a class of these patients called ALPS Type III which do not display mutations in the Fas receptor, its ligand (Fas ligand), or caspase-10. We are using a variety of molecular analyses to determine the gene mutation that underlies disease in ALPS Type III. Our guiding principle is that patient specimens from poorly understood diseases can yield valuable insights into disease mechanisms and normal physiology if investigated properly at the molecular level.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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Cerutti, Elisa; Campagnoli, Maria F; Ferretti, Massimo et al. (2007) Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome. BMC Immunol 8:28
Lemmers, Benedicte; Salmena, Leonardo; Bidere, Nicolas et al. (2007) Essential role for caspase-8 in Toll-like receptors and NFkappaB signaling. J Biol Chem 282:7416-23
Bi, Lilia L; Pan, George; Atkinson, T Prescott et al. (2007) Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib. BMC Med Genet 8:41
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Zhu, Shigui; Hsu, Amy P; Vacek, Marla M et al. (2006) Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum Genet 119:284-94
Su, Helen; Bidere, Nicolas; Zheng, Lixin et al. (2005) Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307:1465-8
Roesler, Joachim; Izquierdo, Jose-Maria; Ryser, Martin et al. (2005) Haploinsufficiency, rather than the effect of an excessive production of soluble CD95 (CD95{Delta}TM), is the basis for ALPS Ia in a family with duplicated 3' splice site AG in CD95 intron 5 on one allele. Blood 106:1652-9
Su, Helen; Bidere, Nicolas; Lenardo, Michael (2004) Another fork in the road: Foxo3a regulates NF-kappaB activation. Immunity 21:133-4
Kanno, Tomohiko; Kanno, Yuka; Siegel, Richard M et al. (2004) Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Mol Cell 13:33-43

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