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B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas

Santiuste, Ines
Buelta, Luis
Iglesias, Marcos
Genre, Fernanda
Mazorra, Francisco
Merino, Jesus
Merino, Ramon
Published in Journal of Autoimmunity. 2010, vol. 35, no. 4, p. 316-324
Abstract Genetic abnormalities predisposing to autoimmunity generally act in a cooperative manner affecting one or several mechanisms regulating immunological tolerance. In addition, many of these genetic abnormalities are also involved in the development of lymphoproliferative diseases. In the present study, we have determined the possible cooperation between deficiencies in members of the Cip/Kip family of cell cycle regulators (p21(WAF1/Cip1) or p27(kip1)) and the overexpression of human Bcl-2 in B lymphocytes in the induction of autoimmune and lymphoproliferative diseases in non-autoimmune C57BL/6 (B6) mice. Unlike single mutant mice, B6.p21(-/-) mice transgenic for human Bcl-2 in B cells developed a lethal autoimmune syndrome characterized by the production of autoantibodies, the prominent expansion of memory B and CD4(+) T cells and the development of severe glomerular lesions resembling IgA nephropathy. Furthermore, these mice presented a high incidence of B-cell lymphoproliferative disorders. Such genetic cooperation in the induction of autoimmunity was not observed in B6.p27(-/-) mice transgenic for human Bcl-2 in B cells. Altogether, what we have demonstrated here is the existence of preferential interactions among particular regulators of the G(1)/S transition of the cell cycle and B-cell survival in the induction of systemic autoimmune and lymphoproliferative diseases.
Keywords AnimalsAutoantibodies/blood/immunologyAutoimmune Lymphoproliferative Syndrome/complications/genetics/*immunologyB-Lymphocytes/immunology/*metabolism/pathologyCD4-Positive T-Lymphocytes/immunology/*metabolism/pathologyCyclin-Dependent Kinase Inhibitor p21/deficiencyCyclin-Dependent Kinase Inhibitor p27/deficiencyDisease Models, AnimalEpistasis, Genetic/genetics/immunologyHumansImmunologic MemoryKidney/immunology/pathologyLupus Erythematosus, Systemic/complications/genetics/*immunologyMiceMice, Inbred C57BLMice, TransgenicProto-Oncogene Proteins c-bcl-2/genetics/immunology/*metabolismTransgenes/genetics
PMID: 20691570
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Research group Lupus érythémateux systémique, de l'anémie hémolytique et de la glomérulonéphrite (168)
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SANTIUSTE, Ines et al. B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas. In: Journal of Autoimmunity, 2010, vol. 35, n° 4, p. 316-324. doi: 10.1016/j.jaut.2010.07.002 https://archive-ouverte.unige.ch/unige:21285

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Deposited on : 2012-05-23

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