NF-KappaB2 is an Autoimmunity Regulator and Its Mutation Leads to Lymphomagenesis in Mice
NF-KappaB2 (p52 and its precursor p100) is a member of the Rel/NF-KappaB family of transcription factors that also includes NF-KappaB1 (p50 and its precursor p105), RelA (p65), RelB, and c-Rel. The NF-KappaB2 gene is recurrently mutated in human lymphoid malignancies including both B cell and T cell lymphomas. A causal relationship between the genetic mutation and lymphomagenesis has not yet been established. Here, we report the generation of transgenic mice with high-level constitutive KappaB-binding activity in lymphoid cells by targeted expression of p80HT, a human lymphoma-derived NF-KappaB2 mutant. The transgenic mice demonstrate a marked expansion of B cell population and develop predominantly B cell lymphomas. Transgenic B cells show no sign of advantaged proliferation, however they display dramatic resistance to apoptosis induced by cytokine deprivation and mitogenic stimulation in vitro. Moreover, the transgenic B cells express high-level of TRAF1, an anti-apoptotic protein also implicated in lymphoid malignancies. Our studies demonstrate NF-KappaB2 mutations as an oncogenic lesion in vivo and suggest that NF-KappaB2 mutations promote lymphomagenesis by suppressing theapoptotic responses critical for the maintenance of B cell homeostasis. The physiological roles of NF-KappaB2 in the immune system have not yet been well characterized. Here we show that NF-KappaB2 deficient mice develop autoimmunity characterized by infiltration of activated T cells in multiple organs and high-level of autoantibodies in serum. A subpopulation of the mice also develop immune-complex 16 3 glomerulonephritis. Mechanistically, we found that NF-êB2 deficient mice display a marked reduction in the number of the medullary thymic epithelial cells that bind the lectin ulex europaeus agglutinin-1 (UEA-1). Given that UEA-1+ medullary thymic epithelial cells function as antigen-presenting cells in negative selection of thymocytes, a process essential for eliminating self-reactive T cell clones, our findings define a physiological function of NF-KappaB2 in the development of medullary thymic epithelial cells and thus in self-tolerance induction.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:transgenic mice lymphoma autoimmunity metc medullary thymic epithelial cell
Date of Publication:01/01/2006