The association among autoimmunity, chronic inflammation and malignancy has been described and confirmed by epidemiological studies. In particular, patients suffering from autoimmune diseases are prone to develop B-cell Non-Hodgkin’s Lymphomas, but the mechanisms triggering the transition from benign B-cell proliferation to malignancy are still poorly understood. We investigated the role of IL-1R8 gene (also know as SIGIRR or TIR8), already known to be associated with autoimmunity, in the development of lymphoma. Indeed, the ability to dampen signalling from IL-1R and TLR family members confers IL-1R8 the ability to act as regulator of inflammation, cancer-related inflammation and autoimmunity. In this study we describe the occurrence of malignant lymphoma in B6lpr/lpr/il-1r8−/− and B6lpr/lpr mice. Both strains developed a B-cell lymphoma during their late age, but in B6lpr/lpr/il-1r8−/−mice, it occurred with higher frequency and earlier, and was more aggressive, causing higher mortality. Histopathologic analysis of spleen and lymph nodes of B6lpr/lpr/il-1r8−/− mice documented clear-cut Diffuse Large B-cell lymphoma (DLBCL) areas arising within a context of atypical lymphoproliferative disorder. These results were corroborated by both molecular analysis and transplantation experiments. Clonal rearrangement was present in both strains, however, only recipients of spleen or lymph node cells collected from B6lpr/lpr/il-1r8−/− mice developed DLBCL. In human, IL-1R8 expression was down-modulated in different lymphoma cell lines, compared to healthy B cells. These observations unveil the involvement of IL-1R8 in the occurrence and development of DLBCL, suggesting its potential role in targeted therapy. In addition, we propose B6lpr/lpr/il-1r8−/− mice as a novel model of autoimmunity-associated B cell lymphomas.
Il-1R8 deficiency increases the suscptibility of LPR mice to develop B-cell lymphoma / F. Riva, M. Ponzoni, N. Polentarutti, S. Bertilaccio, A. Anselmo, F. Feruglio, A. Innocenzi, T. Veliz-Rodriguez, G. Simonetti, M. Muzio, A. Mantovani, C. Garlanda - In: Immunotherapy: harnessing the power of the immune system[s.l] : Flipping book publisher, 2016 Aug. - pp. 284 (( Intervento presentato al 16. convegno International Congress of Immunology tenutosi a Melbourne nel 2016.
Il-1R8 deficiency increases the suscptibility of LPR mice to develop B-cell lymphoma
F. RivaPrimo
;A. Anselmo;T. Veliz-Rodriguez;M. Muzio;A. MantovaniPenultimo
;
2016
Abstract
The association among autoimmunity, chronic inflammation and malignancy has been described and confirmed by epidemiological studies. In particular, patients suffering from autoimmune diseases are prone to develop B-cell Non-Hodgkin’s Lymphomas, but the mechanisms triggering the transition from benign B-cell proliferation to malignancy are still poorly understood. We investigated the role of IL-1R8 gene (also know as SIGIRR or TIR8), already known to be associated with autoimmunity, in the development of lymphoma. Indeed, the ability to dampen signalling from IL-1R and TLR family members confers IL-1R8 the ability to act as regulator of inflammation, cancer-related inflammation and autoimmunity. In this study we describe the occurrence of malignant lymphoma in B6lpr/lpr/il-1r8−/− and B6lpr/lpr mice. Both strains developed a B-cell lymphoma during their late age, but in B6lpr/lpr/il-1r8−/−mice, it occurred with higher frequency and earlier, and was more aggressive, causing higher mortality. Histopathologic analysis of spleen and lymph nodes of B6lpr/lpr/il-1r8−/− mice documented clear-cut Diffuse Large B-cell lymphoma (DLBCL) areas arising within a context of atypical lymphoproliferative disorder. These results were corroborated by both molecular analysis and transplantation experiments. Clonal rearrangement was present in both strains, however, only recipients of spleen or lymph node cells collected from B6lpr/lpr/il-1r8−/− mice developed DLBCL. In human, IL-1R8 expression was down-modulated in different lymphoma cell lines, compared to healthy B cells. These observations unveil the involvement of IL-1R8 in the occurrence and development of DLBCL, suggesting its potential role in targeted therapy. In addition, we propose B6lpr/lpr/il-1r8−/− mice as a novel model of autoimmunity-associated B cell lymphomas.Pubblicazioni consigliate
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