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

David M Cauvi,Dwight H Kono,Per Hultman,Rodney Gabriel,K Michael Pollard

doi:10.1155/2014/260613

Abstract

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 within Hmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate. Here we show that reduced Daf1 transcription in lupus-prone mice was not associated with a reduction in the Daf1 transcription factor SP1. Studies of NZB mice congenic for the mHgIA-resistant DBA/2 Hmr1 locus suggested that Daf1 expression was controlled by the host genome and not the Hmr1 locus. A unique pentanucleotide repeat variant in the second intron of Daf1 in DBA/2 mice was identified and shown in F2 intercrosses to be associated with less severe disease; however, analysis of Hmr1 congenics indicated that this most likely reflected the presence of autoimmunity-predisposing genetic variants within the Hmr1 locus or that Daf1 expression 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.

Highlights

Decay accelerating factor (DAF [the gene and protein designations for decay accelerating factor in this paper are DAF for the human gene and DAF for the human protein; the mouse genes are Daf1 and Daf2 and corresponding proteins DAF1 and DAF2] or CD55) is a surface-expressed member of the complement-regulatory protein family that protects cells from attack by autologous complement proteins [1]
We show that Daf1 expression is reduced in multiple murine strains susceptible to spontaneous autoimmunity and identified a pentanucleotide tandem repeat in the second intron of Daf1, which in the mHgIA resistant DBA/2 consisted of eleven repeats while most other strains had 10, except for MRL-Faslpr and SJL/J, which lacked the repeat
We found that autoimmune prone NZB mice have reduced endogenous DAF1 expression [24]

Summary

Introduction

Decay accelerating factor (DAF [the gene and protein designations for decay accelerating factor in this paper are DAF for the human gene and DAF for the human protein; the mouse genes are Daf and Daf and corresponding proteins DAF1 and DAF2] or CD55) is a surface-expressed member of the complement-regulatory protein family that protects cells from attack by autologous complement proteins [1]. Recent studies suggest DAF regulates T cell activity [3,4,5,6]. DAF is a single gene on chromosome 1q32 encoding a glycosylphosphatidylinositol- (GPI-) anchored cell surface glycoprotein [7]. DAF expression is modulated by cytokines such as IL-1, IL-6, TNF-α, TGF-β1, and IFN-γ [13,14,15], prostaglandin PGE2 [16], and tissue specific factors [17]. There is evidence that DAF mRNA stability can be affected by tissue specific factors [17] and inflammation [18], most studies suggest that expression is primarily modulated at transcription [15,16,17, 19, 20]. Analysis of the key transcriptional regulatory elements controlling basal expression of mouse Daf showed that transcriptional activity requires the functional cooperation of two Sp1-binding sites and is enhanced by the presence of a CREB site [22]

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Discussion

Conclusion