E2F1-/- C57BL/6 mice overexpressing a human Bcl-2 transgene in B cells develop a mild autoimmune syndrome.
Bcl-2, besides having an anti-apoptotic function, delays cell cycle progression at G1 to S. Overexpression of Bcl-2 in B cells induces an autoimmune syndrome (AIS) in pro-autoimmune genetic backgrounds. E2F1, a member of the E2F transcription factors, controls cell cycle, but it also induces cell death. E2F1(-/-) mice show an altered negative thymic selection but a conserved peripheral tolerance. As a consequence, these mice do not develop autoimmunity. Our aim was to evaluate whether deregulation of both apoptosis and cell cycle alters the mechanisms of tolerance and induces an AIS. C57BL/6 E2F1(-/-) mice were crossed with C57BL/6 mice overexpressing a human Bcl-2 transgene in B cells to obtain E2F1(-/-) hbcl-2 Tg mice. These mice were followed for up to 15 months of age with bleedings every three months to obtain serum and whole blood. The production of an AIS was assessed by quantitation of serum anti-DNA antibodies, renal light microscopy, and direct immunofluorescence in search of immunoglobulin deposits. E2F1(-/-) hbcl-2 Tg mice developed an AIS characterized by anti-DNA autoantibody production with renal damage observed after the 9th month of age. The lesions consisted mainly on cellular proliferation and mesangial deposits, compatible with a mesangial glomerulonephritis. The composition of deposits was predominantly of IgA, followed by IgM and IgG. Despite the development of renal damage, the AIS observed did not induce an accelerated mortality. The coexistence of an altered B cell apoptosis, together with the lack of E2F1, induces a mild AIS in the non-autoimmune background of C57BL/6 mice.
Marín
María J
MJ
Servicio de Inmunología, Hospital Universitario Marqués de Valdecilla, Santander 39008, Spain.
García
Itxaso
I
Peña
Marta
M
Bolívar
Ainhoa
A
Zubiaga
Ana
A
Lóez-Hoyos
Marcos
M
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000209:etiology* / Q000473:pathology; D001402:B-Lymphocytes / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000172:deficiency*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D019076:Transgenes
D000974:Antibodies, Antinuclear; D050687:E2F1 Transcription Factor; D019253:Proto-Oncogene Proteins c-bcl-2