PURPOSE: The association among autoimmunity, chronic inflammation and malignancy has been described and confirmed by epidemiological studies. Notwithstanding these achievements, the molecular mechanisms underlying this association are still unknown. Several evidences suggest that patients suffering from different autoimmune diseases are prone to develop B-cell Non-Hodgkin’s Lymphomas. We investigated the role of Tir8 gene, already known to be associated with autoimmunity, in the development of lymphoma. Indeed, the ability to dampen signaling from IL-1R and TLR family members confers TIR8/SIGIRR the ability to act as regulator of inflammation, cancer-related inflammation and autoimmunity. METHODS: B6lpr/lpr and B6lpr/lpr/Tir8−/− mice were followed up to 16 month of age and the mortality was reported. Histopathological and immunohistochemical analysis were performed on different tissues and organs of the mice. IgH gene rearrangement was investigate by Southern blot and PCR on gDNA from different organs of the mice. Transplantation in SCID mice of cells from B6lpr/lpr and B6lpr/lpr/Tir8−/− mice was performed. RESULTS: Both strains developed Diffuse Large B-Cell Lymphoma (DLBCL) during their late age, but in B6lpr/lpr/Tir8−/− mice DLBCL occurred earlier and were more aggressive, with significantly higher mortality. Histopathologic analysis of spleen and lymph nodes of B6lpr/lpr/Tir8−/− mice documented clear-cut DLBCL areas arising within a context of atypical lymphoproliferative disorder; these results were corroborated by both molecular analysis and transplantation experiments. DISCUSSION AND CONCLUSIONS: These observations unveil a role of TIR8 in the occurrence and development of DLBCL, suggesting its potential role in targeted therapy. Moreover, the B6lpr/lpr/Tir8−/− mouse could be a model to establish and evaluate studies of novel therapeutic protocols in DLBCL. BIBLIOGRAPHY: Garlanda et al. 2004, PNAS Lech et al. 2007, J Exp Med Bertilaccio et al. 2011, Blood
LPR mice with Toll-IL-1 Receptor 8 deficiency are prone to develop B-cell lymphomas / F. Riva, M. Ponzoni, S. Bertilaccio, N. Polentarutti, A. Anselmo, F. Feruglio, A. Innocenzi, F. Caligaris Cappio, A. Mantovani, M. Muzio, C. Garlanda, M. Massara. ((Intervento presentato al 9. convegno National Conference of the Italian Society of Immunology, Clinical Immunology and Allergology tenutosi a Firenze nel 2014.
LPR mice with Toll-IL-1 Receptor 8 deficiency are prone to develop B-cell lymphomas
F. RivaPrimo
;A. Anselmo;A. Mantovani;M. Massara
2014
Abstract
PURPOSE: The association among autoimmunity, chronic inflammation and malignancy has been described and confirmed by epidemiological studies. Notwithstanding these achievements, the molecular mechanisms underlying this association are still unknown. Several evidences suggest that patients suffering from different autoimmune diseases are prone to develop B-cell Non-Hodgkin’s Lymphomas. We investigated the role of Tir8 gene, already known to be associated with autoimmunity, in the development of lymphoma. Indeed, the ability to dampen signaling from IL-1R and TLR family members confers TIR8/SIGIRR the ability to act as regulator of inflammation, cancer-related inflammation and autoimmunity. METHODS: B6lpr/lpr and B6lpr/lpr/Tir8−/− mice were followed up to 16 month of age and the mortality was reported. Histopathological and immunohistochemical analysis were performed on different tissues and organs of the mice. IgH gene rearrangement was investigate by Southern blot and PCR on gDNA from different organs of the mice. Transplantation in SCID mice of cells from B6lpr/lpr and B6lpr/lpr/Tir8−/− mice was performed. RESULTS: Both strains developed Diffuse Large B-Cell Lymphoma (DLBCL) during their late age, but in B6lpr/lpr/Tir8−/− mice DLBCL occurred earlier and were more aggressive, with significantly higher mortality. Histopathologic analysis of spleen and lymph nodes of B6lpr/lpr/Tir8−/− mice documented clear-cut DLBCL areas arising within a context of atypical lymphoproliferative disorder; these results were corroborated by both molecular analysis and transplantation experiments. DISCUSSION AND CONCLUSIONS: These observations unveil a role of TIR8 in the occurrence and development of DLBCL, suggesting its potential role in targeted therapy. Moreover, the B6lpr/lpr/Tir8−/− mouse could be a model to establish and evaluate studies of novel therapeutic protocols in DLBCL. BIBLIOGRAPHY: Garlanda et al. 2004, PNAS Lech et al. 2007, J Exp Med Bertilaccio et al. 2011, Blood
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