Abstract

This project is based on our discovery that genetic mutations in molecules that control the programmed death, or apoptosis, of lymphocytes underlie the Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a disease affecting children in which a loss of normal lymphocyte homeostasis leads to swollen lymph glands and organs. Because lymphocytes are the primary cells 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 the past year, proteolytic enzymes that are crucial to lymphocyte programmed cell death. These studies promise to provide new insights into the molecular mechanisms that underly autoimmune disease as well as revealing crucial steps in the pathway of programmed cell death in lymphocytes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000769-02
Application #
6099085
Study Section
Special Emphasis Panel (LI)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

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
Oliveira, Joao B; Bidere, Nicolas; Niemela, Julie E et al. (2007) NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A 104:8953-8
Bidere, Nicolas; Su, Helen C; Lenardo, Michael J (2006) Genetic disorders of programmed cell death in the immune system. Annu Rev Immunol 24:321-52
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
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
Su, Helen; Bidere, Nicolas; Lenardo, Michael (2004) Another fork in the road: Foxo3a regulates NF-kappaB activation. Immunity 21:133-4

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