A Tandem Repeat in Decay Accelerating Factor 1 Is Associated with Severity of Murine Mercury-Induced Autoimmunity

[摘要] Decay accelerating factor (DAF), a complement-regulatory protein, protects cells from bystander complement-mediated lysis and negatively regulates T cells. Reduced expression of DAF occurs in several systemic autoimmune diseases including systemic lupus erythematosus, and DAF deficiency exacerbates disease in several autoimmune models, including murine mercury-induced autoimmunity (mHgIA).Daf1, located withinHmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate. Here we show that reducedDaf1transcription in lupus-prone mice was not associated with a reduction in theDaf1transcription factor SP1. Studies of NZB mice congenic for the mHgIA-resistant DBA/2Hmr1locus suggested thatDaf1expression was controlled by the host genome and not theHmr1locus. A unique pentanucleotide repeat variant in the second intron ofDaf1in DBA/2 mice was identified and shown in F2 intercrosses to be associated with less severe disease; however, analysis ofHmr1congenics indicated that this most likely reflected the presence of autoimmunity-predisposing genetic variants within theHmr1locus or thatDaf1expression is mediated by the tandem repeat in epistasis with other genetic variants present in autoimmune-prone mice. These studies argue that the effect of DAF on autoimmunity is complex and may require multiple genetic elements.

[学科分类] 内科医学