Dissecting the Roles of the Non-canonical NF-kB signaling in the Pathogenesis of Lymphoma and Autoimmunity
Abstract (Summary)NF-?B2 (p52 and its precursor p100) is a member of the Rel/NF-?B family of transcription factors. The NF-?B2 gene is recurrently mutated in human lymphoid malignancies including both B cell and T cell lymphomas. The mechanism by which how these mutations lead to lymphomagenesis has not been unveiled. Using NF-?B2 deficient mice, we revealed that the loss of NF-?B2 p100 is not lymphomagenic, instead it predisposes mice to autoimmunity. Furthermore, we demonstrated that the NF-?B2 defecient mice have a defect in the development/maintenance of UEA-1+ mTECs, the main cell population expressing a wide variety of peripheral tissue-restricted antigens essential for induction of self-tolerance in thymus. The impaired development of UEA-1+ mTECs and the resulting breakdown in self-tolerance are probably the cause for the autoimmunity in these mice. We generated transgenic mice expressing an NF-?B2 mutant p80HT. We demonstrated that these mice develop malignant lymphomas mainly of B cell origin, we also found that p80HT promote lymphoma development primarily through a TRAF1-dependent antiapoptotic pathway. These findings provide direct evidence that the NF-?B2 mutation is oncogenic in vivo. It is well known that NF-?B2 mutants manifest constitutive processing to p52, and the constitutive production of p52 has been suggested as a major mechanism for lymphomagenesis induced by mutations of the NF-?B2 gene. To test this hypothesis, we generated transgenic mice expressing p52 using the same strategy as for p80HT mice. p52 transgenic mice do not develop lymphoma, instead they display autoimmunity characterized by multi-organ infiltration of activated lymphocytes, high levels of autoantibodies in the serum, and immune-complex glomerulonephritis. Mechanistically, p52 represses Bim expression, leading to defects in apoptotic processes critical for elimination of autoreactive lymphocytes and control of immune response. In summary, these studies provide in vivo evidence for a gain of oncogenic activity for NF-?B2 mutants and indicate that fine-tuning the alternative NF-?B signaling is required for control of autoimmunity.
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:nf kb apoptosis lymphoma autoimmunity
Date of Publication:01/01/2008