Development of autoimmunity in mice lacking DNA topoisomerase 3beta.
Mice lacking DNA topoisomerase 3beta are predisposed to a shortened lifespan, infertility, and lesions in multiple organs resulting from inflammatory responses. Examination of the immune system of 6- and 52-week-old top3beta(-/-) mice revealed no significant aberrations in their central and peripheral tolerance or in T lymphocyte activation. However, the older but not the younger cohort shows a high incidence of serum autoantibodies relative to their TOP3beta(+/+) age-mates. The mutant mice also show an increase in numerical aberrations of chromosomes in splenocytes and bone marrow cells, as well as an increase in apoptotic cells in the thymus. Thus, it appears plausible that the inflammatory lesions in top3beta(-/-) mice are caused by the development of autoimmunity as they age: Chromosomal abnormalities in top3beta(-/-) mice might lead to a persistent increase in apoptotic cells, which might in turn lead to the progression of autoimmunity.
Kwan
Kelvin Y
KY
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
Greenwald
Rebecca J
RJ
Mohanty
Subhasis
S
Sharpe
Arlene H
AH
Shaw
Albert C
AC
Wang
James C
JC
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D049109:Cell Proliferation; D002872:Chromosome Deletion; D033481:Chromosomes, Mammalian / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007107:Immune System / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
D001323:Autoantibodies; D004264:DNA Topoisomerases, Type I