The combined effect of BCL-2 over-expression and E2F2 deficiency induces an autoimmune syndrome in non-susceptible mouse strain C57BL/6.
Multiple evidences support the notion that cell-cycle deregulation or apoptosis alterations can lead to autoimmune syndrome (AIS). Inactivation of the cell-cycle regulator E2F2 or over-expression of the anti-apoptotic Bcl-2 protein induces spontaneously an AIS in certain mouse strains. In the present study, we have examined the contribution of the genetic background on the development of autoimmunity after E2F2 gene inactivation, and the effect that a simultaneous inactivation of the E2F2 gene and over-expression of the Bcl-2 gene in B cells has on lymphoid homeostasis and autoimmunity. We show that E2F2(- / - ) mice carrying wild-type levels of Bcl-2 do not develop AIS when they are in a non-pro-autoimmune background (C57BL/6). However, mice harboring both genetic alterations concomitantly develop late AIS characterized by the presence of serum anti-nuclear antibodies, double and single strand anti-DNA antibodies, and the development of a mild glomerulonephritis with mesangial immunoglobulins, mainly IgA, deposits. These results suggest that alterations in cell-cycle and cell survival are critical contributing factors for the development of autoimmunity.
Marín-Vidalled
María José
MJ
Marqués de Valdecilla Hospital, Santander, Spain.
Bolívar
Ainhoa
A
Zubiaga
Ana
A
López-Hoyos
Marcos
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002452:Cell Count; D002453:Cell Cycle; D002469:Cell Separation; D050703:E2F2 Transcription Factor / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D013577:Syndrome; D015854:Up-Regulation
D050703:E2F2 Transcription Factor; C484940:E2f2 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2