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 signaling, 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. The broad, long term objective of this work is to understand the role of inducible Fas-resistance in normal immune responses and in the genesis of autoimmunity. Three anti-apoptotic gene products are implicated as proximate mediators for resistance to Fas killing:
F AIM, FLIP, and Bcl-xL. The specific goal of this work is to illuminate the capability of these molecules to enhance serological immune responses and to alter the behavior of autoreactive B cells, separate from any other collateral effects of sIg or IL-4R engagement. This will be accomplished through 4 specific aims. 1. Determine the FAIM-dependency of normal immune responses by constructing and evaluating FAIM-deficient (knock-out) mice. 2. Evaluate the level, timing, and cellular origin of upregulated FAIM, FLIP, and Bcl-XL expression in lymphoid tissue during in vivo immune responses. 3. Compare the relative potency of FAIM, FLIP, and Bcl-xL in producing Fas-resistance in primary B cells by retroviral transduction in vitro and in promoting normal immune responses in vivo by constructing mixed chimeras in which bone marrow donors overexpress anti-apoptotic molecules alone and together. 4. Test the individual influence of FAIM, FLIP, and Bcl-xL, on the behavior of autoreactive B cells in two well-defined models: a) Ig receptor transgenic mice expressing VH3H9 anti-dsDNA in which B cells normally fail to enter germinal centers but do so on a Fas-deficient background; and, b) doubly transgenic mice expressing anti-HEL B cell receptors and soluble HEL in which B cells are normally short-lived and tolerant but break tolerance in the presence of IL-4, B7.2 expression, or Fas-deficiency. The results of these studies will test the hypothesis that inducible Fas-resistance promotes normal immune responses, and the hypothesis that aberrant Fas-resistance contributes to a breakdown in autoreactive B cell tolerance, and will thereby enhance understanding of both immunization strategy and the origin of autoimmunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Johnson, David R
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Feinstein Institute for Medical Research
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