Human genetic approaches to diseases of lymphocyte activation

Abstract

Our laboratory focuses on the study of the molecular regulation of T lymphocyte homeostasis, particularly as it relates to immunological tolerance, apoptosis, and autoimmune diseases. Through intense molecular research on the regulation of lymphocyte fate, the Fas receptor and other tumor necrosis factor receptors as well as their ligands have emerged as key regulators of T lymphocyte apoptosis. We are studying genetic abnormalities of this death pathway, particularly in the context of autoimmune lymphoproliferative syndrome (ALPS) and other non-ALPS conditions affecting lymphocyte homeostasis. These studies have led to further investigations of the regulation of the NF-kappaB signaling pathway, the molecular basis for programed cell death and viral cytopathicity, mechanisms of autoimmunity, and the regulation of mature T-cell tolerance. Our investigations promise to provide insight into the molecular mechanisms behind the regulation of immune response and contribute to the development of novel diagnostic and treatment methods for autoimmune diseases.

Fig. 1

Nuclear translocation of NF-κB is defective in caspase-8 deficiency syndrome (CEDS). Confocal microscopy photomicrographs of peripheral blood lymphocytes from a normal control (N), the unaffected mother (M), and two affected siblings (P1 and P2) with either no stimulation (none) or following stimulation with 1 mcg per ml anti-CD3 and anti-28 for 4 h and then cell preparations were stained for the p65 subunit of NF-κB (green) and Hoeschst dye for nuclear DNA (red). There is coincidence of the stains (yellow) cells when NF-κB has translocated into the nucleus, but no coincidence of stains when nuclear translocation is defective