Fas (CD95) is of principal importance to normal functioning of the immune system, as evidenced by the marked dysregulation of autoreactive B cells and accompanying autoantibody formation that characterize Fas-deficient animals. The sensitivity of B cells to Fas-mediated apoptosis is regulated by specific receptor signals, in which surface immunoglobulin engagement, and IL-4R engagement, produce a state of Fas-resistance. Modulation of susceptibility to Fas killing suggests a system that protects B cells during critical interactions with FasL-bearing, activated T cells, but that can contribute to the survival of autoreactive B cells when activated inappropriately.
F AIM i s a completely novel, evolutionarily conserved gene product that is induced by stimuli that produce Fas-resistance and that functions as a Fas Apoptosis Inhibitory Molecule. The broad, long term objective of this work is to understand the role of inducible Fas-resistance in B cell homeostasis, and immune activity. The specific goal is to determine the means by which FAIM produces Fas-resistance and the consequences of FAIM-induced Fas-resistance for serological autoreactivity and immune responsiveness. This will be accomplished through 3 specific aims. 1. Determine the point at which Fas-triggered signaling for B cell death is interrupted by FAIM, by assessing the activation and activity of specific caspases, monitoring pre-caspase events in the Fas pathway, and immunoprecipitating a FAIM-associated protein. 2. Identify the regions and residues of FAIM responsible for Fas-resistance, by truncating and mutating faim and correlating structural changes with anti-apoptotic function. 3. Evaluate the role of FAIM in directing autoreactive B cell dysfunction by producing FAIM-overexpressing transgenic mice combined with screening for autoantibody formation and evaluation of mixed bone marrow chimeras, and by examining mice that overexpress both FAIM and Bcl-XL, and that express FAIM on an MRL background. Because FAIM has no substantial regions of homology with any other defined sequence, the studies described herein are expected to identify a novel mammalian motif and strategy for regulating Fas-induced cell death, which may then become a target for therapeutic manipulation to enhance desired immune responses, such as anti- tumor immunity, and to diminish unwanted immune responses, such as autoimmune dyscrasias.
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