Thursday, November 21, 2024
11/21/2024
DESCRIPTION: (Adapted from applicant's abstract) For more than a decade, our laboratory has been investigating the effects on the immune system of inherited mutations in Fas and Fasl that result in inactivation of the Fas apoptosis pathway. These mutations have profound and pleiotropic effects on the immune system in mice and man including the development of systemic autoimmunity and massive lymphoid hyperplasia resulting from the sequestering of anergic T cells, memory phenotype T and B cells and plasma cells. Recently, we observed that mice with Fas (lpr) or Fasl (gld)mutations have an increased risk of developing B cell malignancies. Parallel observations also have been made for ALPS patients with inherited Fas mutations and there is increasing evidence that somatic mutation of Fas is associated with a wide variety of human B lineage tumors. Thus, the Fas pathway appears to have an important anti-oncogenic function in B cells. In BALBgld/gld mice which have mutations in Fasl and a greatly increased risk of plasmacytoid tumors, we observed increased secretion of IL-10 by both activated T cells and the tumors. Abnormal production of IL-10 also has been observed in ALPS patients and is associated with increased disease severity. We hypothesize that germline Fas and Fasl mutations contribute to B cell transformation by creating an environment in which there is chronic B cell activation, increased opportunity for DNA damage, increased survival of mutated B cells and defects in T cell immune surveillance. In this proposal, we will use an in vivo mutagenesis assay employing BALB-gld/gld,lacZ plasmid Tg mice to test the hypothesis that inherent absence of the Fas pathway will result in the spontaneous accumulation of mutated B cells and that the frequency of mutated cells will increase further following chronic oxidative stress. To determine whether autoreactive B cells are selectively targeted for transformation and if antigen selection is occurring in the tumor population, we will examine the tumors for evidence of IgH variable region gene hypermutation and intraclonal variation, restricted use of VH families arid also for antibody specificity. Finally, we will use BALB-gld/gld IL-10 knockout mice to investigate the role of IL- 10 in chronic B cell activation and in the development of systemic autoimmunity and B lymphomas. We anticipate that these studies will provide important new insights into the mechanisms by which germline and somatic Fas mutations contribute to B lymphomagenesis.
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