Induction and natural occurrence of serum nucleosomal DNA in autoimmune MRL/lpr/lpr mice: its relation to apoptosis in the thymus.
Long-term administration of low doses (5 micrograms) of recombinant nucleobindin (rNuc), which is an MRL/lpr/lpr (MRL/l) mouse-derived DNA-binding protein, induces autoimmunity in both young lupus-prone MRL/+/+ (MRL/n) and normal BALB/c mice. In relation to this autoimmunity, using agarose gel electrophoresis we found an approximately 160 bp mono-nucleosomal DNA (nsDNA) in the sera of 6-week-old normal mice 15 h after i.p. injection of 50 micrograms rNuc. Co-injection of rNuc (50 micrograms) and anti-CD3 monoclonal antibody (mAb, 50 micrograms) further accelerated the appearance of nsDNA in the serum together with DNA fragmentation (apoptosis) in the thymus, which had not been so clearly induced by either double amounts of rNuc or anti-CD3 mAb alone. Acceleration of the appearance of nsDNA in the serum by co-injection was also found in age-matched MRL/n and MRL/l mice, indicating the close association of apoptosis in the thymus with the appearance of nsDNA in the serum. Furthermore, we have detected naturally occurring tri-, di- and mono-nsDNAs from immune complexes (IC) of the sera of 20 approximately 22-week-old MRL/l mice, which indicates that apoptosis in the lymphoid tissues, including the thymus, is the source of serum nsDNA that may trigger or continue production of anti-nuclear antibodies. Evidence that clearance of nsDNA from the circulation is retarded in the presence of rNuc in BALB/c mice may give rationale to the induction of autoimmunity in normal mice by long-term administration of even low doses (5 micrograms) of rNuc after all.(ABSTRACT TRUNCATED AT 250 WORDS)
Kanai
Y
Y
Department of Molecular Oncology, University of Tokyo, Japan.
Kyuwa
S
S
Miura
K
K
Kurosawa
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics*; D002135:Calcium-Binding Proteins; D004247:DNA / Q000096:biosynthesis / Q000097:blood* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006133:Growth Substances / Q000494:pharmacology*; D007113:Immunity, Innate; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D009707:Nucleosomes / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology
D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D006133:Growth Substances; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D009707:Nucleosomes; D004247:DNA